Abstract - Edinburgh Research Explorer



The microbiota of the respiratory tract: gatekeeper to respiratory health Wing Ho Mana,b *, Wouter A.A. de Steenhuijsen Pitersa,c *, Debby Bogaerta,ca Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands; b Spaarne Gasthuis Academy, Hoofddorp and Haarlem, The Netherlands; c Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.*These authors contributed equally to this work.Correspondence to D.B. D.Bogaert@ed.ac.ukAbstractThe respiratory tract is a complex organ system that is responsible for the exchange of oxygen and carbon dioxide. The human airways extend from the nostrils to the lung alveoli and are inhabited by niche-specific bacterial communities. The microbiota of the respiratory tract likely acts as gatekeeper to provide colonization resistance to respiratory pathogens. The respiratory microbiota might also be involved in maturation and maintenance of homeostasis of respiratory physiology and immunity. The ecological and environmental factors that direct the development of respiratory microbial communities, and how these communities affect respiratory health are the focus of current research. At the same time, the functions of the upper and lower respiratory tract microbiome in the physiology of the human host are being studied in detail. In this review, we will discuss the epidemiological, biological and functional evidence that support the physiological role of the respiratory microbiome in the maintenance of human health.Microbial communities have co-evolved with humans and our ancestors for millions of years and they inhabit all surfaces of the human body, including the respiratory tract mucosa. Specific sites within the respiratory tract harbour specialized bacterial communities that are thought to play a major role in maintaining human health. In the previous decade, next generation sequencing has led to major advances in our understanding of possible functions of the resident microbiota. So far, research has largely focused on the gut microbiota, microbiota-derived metabolites and their influence on host metabolism and immunity. However, recent studies on microbial ecosystems of other body sites, including the respiratory tract, reveal an even broader role of the microbiota in human healthADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s13073-016-0307-y", "ISBN" : "1756-994x", "ISSN" : "1756-994X", "PMID" : "27122046", "abstract" : "Humans are virtually identical in their genetic makeup, yet the small differences in our DNA give rise to tremendous phenotypic diversity across the human population. By contrast, the metagenome of the human microbiome\u2014the total DNA content of microbes inhabiting our bodies\u2014is quite a bit more variable, with only a third of its constituent genes found in a majority of healthy individuals. Understanding this variability in the \u201chealthy microbiome\u201d has thus been a major challenge in microbiome research, dating back at least to the 1960s, continuing through the Human Microbiome Project and beyond. Cataloguing the necessary and sufficient sets of microbiome features that support health, and the normal ranges of these features in healthy populations, is an essential first step to identifying and correcting microbial configurations that are implicated in disease. Toward this goal, several population-scale studies have documented the ranges and diversity of both taxonomic compositions and functional potentials normally observed in the microbiomes of healthy populations, along with possible driving factors such as geography, diet, and lifestyle. Here, we review several definitions of a \u2018healthy microbiome\u2019 that have emerged, the current understanding of the ranges of healthy microbial diversity, and gaps such as the characterization of molecular function and the development of ecological therapies to be addressed in the future.", "author" : [ { "dropping-particle" : "", "family" : "Lloyd-Price", "given" : "Jason", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abu-Ali", "given" : "Galeb", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huttenhower", "given" : "Curtis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome Medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "12", "27" ] ] }, "page" : "51", "publisher" : "BioMed Central", "title" : "The healthy human microbiome", "type" : "article-journal", "volume" : "8" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹", "plainTextFormattedCitation" : "1", "previouslyFormattedCitation" : "¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }1. The respiratory tract is a complex organ system that is divided into the upper respiratory tract (URT) and lower respiratory tract (LRT). The URT includes the anterior nares, nasal passages, paranasal sinuses, the naso- and oropharynx, and the portion of the larynx above the vocal cords, whereas the LRT includes the portion of the larynx below the vocal cords, the trachea, smaller airways (i.e. bronchi and bronchioli) and alveoli. The primary role of the respiratory tract in human physiology is the exchange of oxygen and carbon dioxide. To this purpose, the human airways have a surface area of approximately 70 m2, 40 times the surface area of the skinADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/978-3-642-87553-3", "ISBN" : "978-3-642-87555-7", "author" : [ { "dropping-particle" : "", "family" : "Weibel", "given" : "Ewald R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1963" ] ] }, "publisher" : "Springer Berlin Heidelberg", "publisher-place" : "Berlin, Heidelberg", "title" : "Morphometry of the Human Lung", "type" : "book" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²", "plainTextFormattedCitation" : "2", "previouslyFormattedCitation" : "²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }2. This entire surface is inhabited by niche-specific bacterial communities, with the highest bacterial densities being observed in the URT (FIG. 1). Over the years, evidence for the role of URT bacterial communities in preventing respiratory pathogens from establishing an infection on the mucosal surface and spreading to the LRT has accumulated. For most respiratory bacterial pathogens, colonization of the URT is a necessary first step before causing an upper, lower or disseminated (respiratory) infectionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1473-3099(04)00938-7", "ISBN" : "1473-3099 (Print)\\r1473-3099 (Linking)", "ISSN" : "14733099", "PMID" : "14998500", "abstract" : "Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. The burden of disease is highest in the youngest and oldest sections of the population in both more and less developed countries. The treatment of pneumococcal infections is complicated by the worldwide emergence in pneumococci of resistance to penicillin and other antibiotics. Pneumococcal disease is preceded by asymptomatic colonisation, which is especially high in children. The current seven-valent conjugate vaccine is highly effective against invasive disease caused by the vaccine-type strains. However, vaccine coverage is limited, and replacement by non-vaccine serotypes resulting in disease is a serious threat for the near future. Therefore, the search for new vaccine candidates that elicit protection against a broader range of pneumococcal strains is important. Several surface-associated protein vaccines are currently under investigation. Another important issue is whether the aim should be to prevent pneumococcal disease by eradication of nasopharyngeal colonisation, or to prevent bacterial invasion leaving colonisation relatively unaffected and hence preventing the occurrence of replacement colonisation and disease. To illustrate the importance of pneumococcal colonisation in relation to pneumococcal disease and prevention of disease, we discuss the mechanism and epidemiology of colonisation, the complexity of relations within and between species, and the consequences of the different preventive strategies for pneumococcal colonisation.", "author" : [ { "dropping-particle" : "", "family" : "Bogaert", "given" : "D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "R.", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermans", "given" : "P. W M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lancet Infectious Diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "144-154", "title" : "Streptococcus pneumoniae colonisation: The key to pneumococcal disease", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³", "plainTextFormattedCitation" : "3", "previouslyFormattedCitation" : "³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3. Inhibition of this first step of pathogenesis of respiratory infections by the resident microbiota, a process which is also called ‘colonization resistance’, might be paramount to respiratory health. Furthermore, if a pathogen has colonized the mucosal surface, it might be beneficial to both the microbial community and the host that these pathogens are kept at bay, preventing their overgrowth, inflammation and subsequent local or systemic spreadADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature18849", "ISSN" : "0028-0836", "author" : [ { "dropping-particle" : "", "family" : "B\u00e4umler", "given" : "Andreas J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sperandio", "given" : "Vanessa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7610", "issued" : { "date-parts" : [ [ "2016", "7", "6" ] ] }, "page" : "85-93", "publisher" : "Nature Research", "title" : "Interactions between the microbiota and pathogenic bacteria in the gut", "type" : "article-journal", "volume" : "535" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴", "plainTextFormattedCitation" : "4", "previouslyFormattedCitation" : "⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }4. In addition to this symbiotic relationship, the respiratory microbiota likely has a role in the structural maturation of the airwaysADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0113466", "ISSN" : "19326203", "PMID" : "25470730", "abstract" : "Commensal bacteria control the micro-ecology of metazoan epithelial surfaces with pivotal effect on tissue homeostasis and host defense. In contrast to the upper respiratory tract, the lower respiratory tract of healthy individuals has largely been considered free of microorganisms. To understand airway micro-ecology we studied microbiota of sterilely excised lungs from mice of different origin including outbred wild mice caught in the natural environment or kept under non-specific-pathogen-free (SPF) conditions as well as inbred mice maintained in non-SPF, SPF or germ-free (GF) facilities. High-throughput pyrosequencing of reverse transcribed 16S rRNA revealed metabolically active murine lung microbiota in all but GF mice. The overall composition across samples was similar at the phylum and family level. However, species richness was significantly different between lung microbiota from SPF and non-SPF mice. Non-cultivatable Betaproteobacteria such as Ralstonia spp. made up the major constituents and were also confirmed by 16S rRNA gene cloning analysis. Additionally, Pasteurellaceae, Enterobacteria and Firmicutes were isolated from lungs of non-SPF mice. Bacterial communities were detectable by fluorescent in situ hybridization (FISH) at alveolar epithelia in the absence of inflammation. Notably, higher bacterial abundance in non-SPF mice correlated with more and smaller size alveolae, which was corroborated by transplanting Lactobacillus spp. lung isolates into GF mice. Our data indicate a common microbial composition of murine lungs, which is diversified through different environmental conditions and affects lung architecture. Identification of the microbiota of murine lungs will pave the path to study their influence on pulmonary immunity to infection and allergens using mouse models.", "author" : [ { "dropping-particle" : "", "family" : "Yun", "given" : "Yeojun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Srinivas", "given" : "Girish", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuenzel", "given" : "Sven", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Linnenbrink", "given" : "Miriam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alnahas", "given" : "Safa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruce", "given" : "Kenneth D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steinhoff", "given" : "Ulrich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baines", "given" : "John F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schaible", "given" : "Ulrich E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Di", "given" : "Yuanpu Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2014", "12", "3" ] ] }, "page" : "e113466", "publisher" : "Public Library of Science", "title" : "Environmentally determined differences in the murine lung microbiota and their relation to alveolar architecture", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵", "plainTextFormattedCitation" : "5", "previouslyFormattedCitation" : "⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }5 and in shaping local immunityADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.1219328", "ISSN" : "1095-9203", "PMID" : "22442383", "abstract" : "Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.", "author" : [ { "dropping-particle" : "", "family" : "Olszak", "given" : "Torsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "An", "given" : "Dingding", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeissig", "given" : "Sebastian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vera", "given" : "Miguel Pinilla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richter", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Franke", "given" : "Andre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glickman", "given" : "Jonathan N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Siebert", "given" : "Reiner", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baron", "given" : "Rebecca M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kasper", "given" : "Dennis L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blumberg", "given" : "Richard S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "6080", "issued" : { "date-parts" : [ [ "2012", "4", "27" ] ] }, "page" : "489-93", "publisher" : "NIH Public Access", "title" : "Microbial exposure during early life has persistent effects on natural killer T cell function.", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/nm.3568", "ISBN" : "1546-170X (Electronic)\\r1078-8956 (Linking)", "ISSN" : "1546-170X", "PMID" : "24813249", "abstract" : "Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.", "author" : [ { "dropping-particle" : "", "family" : "Gollwitzer", "given" : "Eva S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saglani", "given" : "Sejal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trompette", "given" : "Aur\u00e9lien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yadava", "given" : "Koshika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sherburn", "given" : "Rebekah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCoy", "given" : "Kathy D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nicod", "given" : "Laurent P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lloyd", "given" : "Clare M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marsland", "given" : "Benjamin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature medicine", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2014", "5", "11" ] ] }, "page" : "642-7", "publisher" : "Nature Publishing Group", "title" : "Lung microbiota promotes tolerance to allergens in neonates via PD-L1", "title-short" : "Nat Med", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^6,7", "plainTextFormattedCitation" : "6,7", "previouslyFormattedCitation" : "^6,7" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6,7. Current research questions address how the healthy respiratory microbiota is established and which ecological and environmental factors govern its development. At the same time, the broad palette of functions of the respiratory microbiome is starting to become clear. In this review, we focus on the role of the respiratory microbiota in the development and maintenance of human respiratory health.[H1] Anatomical development and the microbiota[H3] Anatomical development and physiologyThe development of the human respiratory tract structures is a complex, multistage process, which begins in the fourth week of gestation with the appearance of the nasal placodes, oropharyngeal membrane and the lung budsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3174/ajnr.A3415", "ISSN" : "0195-6108", "PMID" : "23493891", "abstract" : "The early embryological development of the face has been reviewed. One repeating theme to note is the serial closing and then the re-opening of a space. This is seen in the separation of the nasal and oral cavities, the nostrils, and in part 2 the developing eyelids fusing and then re-opening. Part 2 will discuss the further facial development as well as the changes in facial bone appearance after birth.", "author" : [ { "dropping-particle" : "", "family" : "Som", "given" : "P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naidich", "given" : "T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Neuroradiology", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2013", "12", "1" ] ] }, "page" : "2233-2240", "title" : "Illustrated Review of the Embryology and Development of the Facial Region, Part 1: Early Face and Lateral Nasal Cavities", "type" : "article-journal", "volume" : "34" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1242/dev.098186", "ISSN" : "1477-9129", "PMID" : "24449833", "abstract" : "The respiratory system, which consists of the lungs, trachea and associated vasculature, is essential for terrestrial life. In recent years, extensive progress has been made in defining the temporal progression of lung development, and this has led to exciting discoveries, including the derivation of lung epithelium from pluripotent stem cells and the discovery of developmental pathways that are targets for new therapeutics. These discoveries have also provided new insights into the regenerative capacity of the respiratory system. This Review highlights recent advances in our understanding of lung development and regeneration, which will hopefully lead to better insights into both congenital and acquired lung diseases.", "author" : [ { "dropping-particle" : "", "family" : "Herriges", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morrisey", "given" : "Edward E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Development (Cambridge, England)", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2014", "2" ] ] }, "page" : "502-13", "publisher" : "Company of Biologists", "title" : "Lung development: orchestrating the generation and regeneration of a complex organ.", "type" : "article-journal", "volume" : "141" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^8,9", "plainTextFormattedCitation" : "8,9", "previouslyFormattedCitation" : "^8,9" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8,9. The anatomy of the URT at birth is substantially different from the configuration in adults due to the higher position of the larynx, which results in a large nasopharynx relative to the oropharynxADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/gimo5", "author" : [ { "dropping-particle" : "", "family" : "German", "given" : "Rebecca Z.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Palmer", "given" : "Jeffrey B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "GI Motility online", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2006" ] ] }, "publisher" : "Nature Publishing Group", "title" : "Anatomy and development of oral cavity and pharynx", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰", "plainTextFormattedCitation" : "10", "previouslyFormattedCitation" : "¹⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }10. Additionally, the lack of alveoli in the newborn lungs underlines the immaturity of the LRT at birth. Indeed, the formation of alveoli begins in a late fetal stage and their development continues throughout the first three years of lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1146/annurev.ph.46.030184.003153", "ISSN" : "0066-4278", "PMID" : "6370120", "abstract" : "The life of a human lung can be subdivided into five distinct phases: embryonic, pseudoglandular, canalicular, saccular, and alveolar. The embryonic period, during which the lung primordium is laid down as a diverticulum of the foregut, lasts for about seven weeks. From the 5th to the 17th week the lung looks much like a tubulo-acinar gland, with epithelial tubes sprouting and branching into the surrounding mesenchyme. In the last week of this pseudoglandular stage the prospective conductive airways have been formed, and the acinar limits can be recognized. The events of the subsequent canalicular phase (17th-26th week) can be summarized as the widening of the peripheral tubules, the differentiation of the cuboidal epithelium into type I and type II cells, the formation of the first thin air-blood barriers, and the start of surfactant production. During the saccular stage, which follows and lasts until birth, the growth of the pulmonary parenchyma, the thinning of the connective tissue between the airspaces, and the further maturation of the surfactant system are the most important steps towards life. At birth, although already functional, the lung is structurally still in an immature condition, because alveoli, the gas exchange units of the adult lung, are practically missing. The airspaces present are smooth-walled transitory ducts and saccules with primitive type septa that are thick and contain a double capillary network. During the first 1-3 years of postnatal life, alveoli are formed through a septation process that greatly increases the gas exchange surface area. The primitive septa with their capillaries undergo a complete remodeling, gaining the mature slender morphology found in the adult lung.", "author" : [ { "dropping-particle" : "", "family" : "Burri", "given" : "P H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annual review of physiology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1984", "10" ] ] }, "page" : "617-28", "title" : "Fetal and postnatal development of the lung.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹", "plainTextFormattedCitation" : "11", "previouslyFormattedCitation" : "¹¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }11. By the time adulthood is reached, many distinct sub-compartments have developed within the respiratory tract, each of which has specific microbial, cellular and physiological features, such as oxygen and carbon dioxide tension, pH, humidity and temperature (FIG. 1). [H3] Microbiota and morphogenesis of the respiratory tract Parallel to the anatomical development of the respiratory tract, the initial acquisition of microorganisms marks the establishment of the respiratory microbiota in early life. The establishment of the respiratory microbiota is believed to play a role in the morphogenesis of the respiratory tract. Indeed, germfree rodents tend to have smaller lungsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1146/annurev.nu.01.070181.001353", "ISSN" : "0199-9885", "PMID" : "6764717", "author" : [ { "dropping-particle" : "", "family" : "Wostmann", "given" : "B S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annual review of nutrition", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1981" ] ] }, "page" : "257-79", "title" : "The germfree animal in nutritional studies.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²", "plainTextFormattedCitation" : "12", "previouslyFormattedCitation" : "¹²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }12 and a decreased number of mature alveoliADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0113466", "ISSN" : "19326203", "PMID" : "25470730", "abstract" : "Commensal bacteria control the micro-ecology of metazoan epithelial surfaces with pivotal effect on tissue homeostasis and host defense. In contrast to the upper respiratory tract, the lower respiratory tract of healthy individuals has largely been considered free of microorganisms. To understand airway micro-ecology we studied microbiota of sterilely excised lungs from mice of different origin including outbred wild mice caught in the natural environment or kept under non-specific-pathogen-free (SPF) conditions as well as inbred mice maintained in non-SPF, SPF or germ-free (GF) facilities. High-throughput pyrosequencing of reverse transcribed 16S rRNA revealed metabolically active murine lung microbiota in all but GF mice. The overall composition across samples was similar at the phylum and family level. However, species richness was significantly different between lung microbiota from SPF and non-SPF mice. Non-cultivatable Betaproteobacteria such as Ralstonia spp. made up the major constituents and were also confirmed by 16S rRNA gene cloning analysis. Additionally, Pasteurellaceae, Enterobacteria and Firmicutes were isolated from lungs of non-SPF mice. Bacterial communities were detectable by fluorescent in situ hybridization (FISH) at alveolar epithelia in the absence of inflammation. Notably, higher bacterial abundance in non-SPF mice correlated with more and smaller size alveolae, which was corroborated by transplanting Lactobacillus spp. lung isolates into GF mice. Our data indicate a common microbial composition of murine lungs, which is diversified through different environmental conditions and affects lung architecture. 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The latter finding was supported by experiments, in which the nasal cavity of germfree mouse pups was colonized with Lactobacillus spp., upon which the number of mature alveoli normalizedADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0113466", "ISSN" : "19326203", "PMID" : "25470730", "abstract" : "Commensal bacteria control the micro-ecology of metazoan epithelial surfaces with pivotal effect on tissue homeostasis and host defense. In contrast to the upper respiratory tract, the lower respiratory tract of healthy individuals has largely been considered free of microorganisms. To understand airway micro-ecology we studied microbiota of sterilely excised lungs from mice of different origin including outbred wild mice caught in the natural environment or kept under non-specific-pathogen-free (SPF) conditions as well as inbred mice maintained in non-SPF, SPF or germ-free (GF) facilities. 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Intriguingly, the nasopharyngeal-associated lymphoid tissue (NALT) also develops mainly after birth, which suggests that its development requires environmental cues, for example, from the local microbiotaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1074-7613(02)00339-4", "ISSN" : "1074-7613", "PMID" : "12150889", "abstract" : "Initiation of nasopharyngeal-associated lymphoid tissue (NALT) development is independent of the programmed cytokine cascade necessary for the formation of Peyer's patches (PP) and peripheral lymph nodes (PLN), a cytokine cascade which consists of IL-7R, LTalpha1beta2/LTbetaR, and NIK. However, the subsequent organization of NALT seems to be controlled by these cytokine signaling cascades since the maturation of NALT structure is generally incomplete in those cytokine cascade-deficient mice. NALT as well as PP and PLN are completely absent in Id2(-/-) mice. 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Aagaard, K. et al. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65 (2014).crobiomes have coevolved as a physiologic community composed of distinct body site niches with metabolic and antigenic diversity. The placental microbiome has not been robustly interrogated, despite recent demonstrations of intracellular bacteria with diverse metabolic and immune regulatory functions. A population-based cohort of placental specimens collected under sterile conditions from 320 subjects with extensive clinical data was established for comparative 16S ribosomal DNA-based and whole-genome shotgun (WGS) metagenomic studies. Identified taxa and their gene carriage patterns were compared to other human body site niches, including the oral, skin, airway (nasal), vaginal, and gut microbiomes from nonpregnant controls. We characterized a unique placental microbiome niche, composed of nonpathogenic commensal microbiota from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla. In aggregate, the placental microbiome profiles were most akin (Bray-Curtis dissimilarity <0.3) to the human oral microbiome. 16S-based operational taxonomic unit analyses revealed associations of the placental microbiome with a remote history of antenatal infection (permutational multivariate analysis of variance, P = 0.006), such as urinary tract infection in the first trimester, as well as with preterm birth <37 weeks (P = 0.001).", "author" : [ { "dropping-particle" : "", "family" : "Aagaard", "given" : "Kjersti", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Antony", "given" : "Kathleen M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ganu", "given" : "Radhika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petrosino", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Versalovic", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science translational medicine", "id" : "ITEM-1", "issue" : "237", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "237ra65", "title" : "The placenta harbors a unique microbiome.", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/srep23129", "ISSN" : "2045-2322", "abstract" : "Interaction with intestinal microbes in infancy has a profound impact on health and disease in later life through programming of immune and metabolic pathways. We collected maternal faeces, placenta, amniotic fluid, colostrum, meconium and infant faeces samples from 15 mother-infant pairs in an effort to rigorously investigate prenatal and neonatal microbial transfer and gut colonisation. To ensure sterile sampling, only deliveries at full term by elective caesarean section were studied. Microbiota composition and activity assessment by conventional bacterial culture, 16S rRNA gene pyrosequencing, quantitative PCR, and denaturing gradient gel electrophoresis revealed that the placenta and amniotic fluid harbour a distinct microbiota characterised by low richness, low diversity and the predominance of Proteobacteria. Shared features between the microbiota detected in the placenta and amniotic fluid and in infant meconium suggest microbial transfer at the foeto-maternal interface. At the age of 3\u20134 days, the infant gut microbiota composition begins to resemble that detected in colostrum. Based on these data, we propose that the stepwise microbial gut colonisation process may be initiated already prenatally by a distinct microbiota in the placenta and amniotic fluid. 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However, a challenge in working with specimens with low bacterial biomass, such as placental samples, is that some or all of the bacterial DNA may derive from contamination in dust or commercial reagents. To investigate this, we compared placental samples from healthy deliveries to a matched set of contamination controls, as well as to oral and vaginal samples from the same women. We quantified total 16S rRNA gene copies using quantitative PCR and found that placental samples and negative controls contained low and indistinguishable copy numbers. Oral and vaginal swab samples, in contrast, showed higher copy numbers. We carried out 16S rRNA gene sequencing and community analysis and found no separation between communities from placental samples and contamination controls, though oral and vaginal samples showed characteristic, distinctive composition. Two different DNA purification methods were compared with similar conclusions, though the composition of the contamination background differed. Authentically present microbiota should yield mostly similar results regardless of the purification method used\u2014this was seen for oral samples, but no placental bacterial lineages were (1) shared between extraction methods, (2) present at >1\u00a0% of the total, and (3) present at greater abundance in placental samples than contamination controls. 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Irrespectively, in utero transfer of maternal antibodies and microbial molecules strongly influences the postnatal immune developmentADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.aad2571", "ISSN" : "1095-9203", "PMID" : "26989247", "abstract" : "Postnatal colonization of the body with microbes is assumed to be the main stimulus to postnatal immune development. By transiently colonizing pregnant female mice, we show that the maternal microbiota shapes the immune system of the offspring. Gestational colonization increases intestinal group 3 innate lymphoid cells and F4/80(+)CD11c(+) mononuclear cells in the pups. Maternal colonization reprograms intestinal transcriptional profiles of the offspring, including increased expression of genes encoding epithelial antibacterial peptides and metabolism of microbial molecules. 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Mice acquire both IgG and IgA maternally; the former has primarily been implicated in passive immunity to pathogens while the latter mediates host-commensal mutualism. Here, we report the surprising observation that mice generate T cell-independent and largely Toll-like receptor (TLR)-dependent IgG2b and IgG3 antibody responses against their gut microbiota. We demonstrate that maternal acquisition of these antibodies dampens mucosal T follicular helper responses and subsequent germinal center B cell responses following birth. 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This in turn primes the newborn for the dramatically expanding microbial exposure after birth. Within the first hours of life, a wide range of microorganisms can be detected in the URT of healthy term neonatesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1002601107", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "0027-8424", "PMID" : "20566857", "abstract" : "Upon delivery, the neonate is exposed for the first time to a wide array of microbes from a variety of sources, including maternal bacteria. Although prior studies have suggested that delivery mode shapes the microbiota's establishment and, subsequently, its role in child health, most researchers have focused on specific bacterial taxa or on a single body habitat, the gut. Thus, the initiation stage of human microbiome development remains obscure. The goal of the present study was to obtain a community-wide perspective on the influence of delivery mode and body habitat on the neonate's first microbiota. We used multiplexed 16S rRNA gene pyrosequencing to characterize bacterial communities from mothers and their newborn babies, four born vaginally and six born via Cesarean section. Mothers' skin, oral mucosa, and vagina were sampled 1 h before delivery, and neonates' skin, oral mucosa, and nasopharyngeal aspirate were sampled <5 min, and meconium <24 h, after delivery. We found that in direct contrast to the highly differentiated communities of their mothers, neonates harbored bacterial communities that were undifferentiated across multiple body habitats, regardless of delivery mode. Our results also show that vaginally delivered infants acquired bacterial communities resembling their own mother's vaginal microbiota, dominated by Lactobacillus, Prevotella, or Sneathia spp., and C-section infants harbored bacterial communities similar to those found on the skin surface, dominated by Staphylococcus, Corynebacterium, and Propionibacterium spp. These findings establish an important baseline for studies tracking the human microbiome's successional development in different body habitats following different delivery modes, and their associated effects on infant health.", "author" : [ { "dropping-particle" : "", "family" : "Dominguez-Bello", "given" : "Maria G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Costello", "given" : "Elizabeth K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Contreras", "given" : "Monica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magris", "given" : "Magda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hidalgo", "given" : "Glida", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fierer", "given" : "Noah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "Rob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences of the United States of America", "id" : "ITEM-1", "issue" : "26", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "11971-11975", "title" : "Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.", "type" : "article-journal", "volume" : "107" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. Infants born by Caesarian section showed a delay in overall development of respiratory microbiota profiles with specifically reduced colonization with health-associated commensals like Corynebacterium and Dolosigranulum, thereby possibly influencing respiratory health later in life.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levin", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houten", "given" : "Marlies A.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalkman", "given" : "Gino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A.A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "Pieter-Kees C.M.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pernet", "given" : "Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EBioMedicine", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "336-345", "title" : "Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^19,20", "plainTextFormattedCitation" : "19,20", "previouslyFormattedCitation" : "^19,20" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }19,20. At first, these microorganisms are non-specific and of presumed maternal origin. Within the first week of life, niche differentiation in the URT leads to a high abundance of Staphylococcus spp., followed by enrichment of Corynebacterium spp. and Dolosigranulum spp., and subsequent predominance of Moraxella spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. Infants born by Caesarian section showed a delay in overall development of respiratory microbiota profiles with specifically reduced colonization with health-associated commensals like Corynebacterium and Dolosigranulum, thereby possibly influencing respiratory health later in life.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levin", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houten", "given" : "Marlies A.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalkman", "given" : "Gino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A.A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "Pieter-Kees C.M.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pernet", "given" : "Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EBioMedicine", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "336-345", "title" : "Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁰", "plainTextFormattedCitation" : "20", "previouslyFormattedCitation" : "²⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20. Microbiota profiles characterized by Corynebacterium spp. and Dolosigranulum spp. early in life, and Moraxella spp. at the age of 4-6 months, have been related to a stable bacterial community composition and respiratory healthADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201407-1240OC", "ISBN" : "2010081269", "ISSN" : "1535-4970", "PMID" : "25329446", "abstract" : "RATIONALE Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. OBJECTIVES To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. METHODS Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. MEASUREMENTS AND MAIN RESULTS Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. CONCLUSIONS These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with (NCT00189020).", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsivtsivadze", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1283-92", "title" : "Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.", "type" : "article-journal", "volume" : "190" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.chom.2015.03.008", "ISSN" : "1934-6069", "PMID" : "25865368", "abstract" : "The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.", "author" : [ { "dropping-particle" : "", "family" : "Teo", "given" : "Shu Mei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mok", "given" : "Danny", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pham", "given" : "Kym", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kusel", "given" : "Merci", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Serralha", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Troy", "given" : "Niamh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Barbara J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hales", "given" : "Belinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "Michael L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollams", "given" : "Elysia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bochkov", "given" : "Yury A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grindle", "given" : "Kristine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnston", "given" : "Sebastian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gern", "given" : "James E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sly", "given" : "Peter D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Patrick G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Kathryn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Inouye", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell host & microbe", "id" : "ITEM-2", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5", "13" ] ] }, "page" : "704-15", "publisher" : "Elsevier Inc.", "title" : "The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^21,22", "plainTextFormattedCitation" : "21,22", "previouslyFormattedCitation" : "^21,22" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21,22. Birth mode and feeding type are important drivers of early microbiota maturation, with children born vaginally and/or breastfed transitioning towards a presumed health-promoting microbiota profile more often and more swiftlyADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. 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Modulation of respiratory microbiota might be part of the natural mechanisms of protection against respiratory diseases induced by breastfeeding. OBJECTIVES To study the association between breastfeeding and nasopharyngeal microbial communities, including all cultivable and noncultivable bacteria. METHODS In this observational study, we analyzed the microbiota of infants that had received exclusive breastfeeding (n = 101) and exclusive formula feeding (n = 101) at age 6 weeks and 6 months by 16S-based GS-FLX-titanium-pyrosequencing. MEASUREMENTS AND MAIN RESULTS At 6 weeks of age the overall bacterial community composition was significantly different between breastfed and formula-fed children (nonmetric multidimensional scaling, P = 0.001). Breastfed children showed increased presence and abundance of the lactic acid bacterium Dolosigranulum (relative effect size [RES], 2.61; P = 0.005) and Corynebacterium (RES, 1.98; P = 0.039) and decreased abundance of Staphylococcus (RES, 0.48; P 0.03) and anaerobic bacteria, such as Prevotella (RES, 0.25; P < 0.001) and Veillonella (RES, 0.33; P < 0.001). Predominance (>50% of the microbial profile) of Corynebacterium and Dolosigranulum was observed in 45 (44.6%) breastfed infants compared with 19 (18.8%) formula-fed infants (relative risk, 2.37; P = 0.006). Dolosigranulum abundance was inversely associated with consecutive symptoms of wheezing and number of mild respiratory tract infections experienced. At 6 months of age associations between breastfeeding and nasopharyngeal microbiota composition had disappeared. CONCLUSIONS Our data suggest a strong association between breastfeeding and microbial community composition in the upper respiratory tract of 6-week-old infants. Observed differences in microbial community profile may contribute to the protective effect of breastfeeding on respiratory infections and wheezing in early infancy. Clinical trial registered with (NCT 00189020).", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Xinhui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2014", "6", "12" ] ] }, "page" : "140612135546007", "title" : "The Impact of Breastfeeding on Nasopharyngeal Microbial Communities in Infants", "type" : "article-journal", "volume" : "190" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^20,23", "plainTextFormattedCitation" : "20,23", "previouslyFormattedCitation" : "^20,23" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20,23. These findings were corroborated by epidemiological findings that show breastfeeding-mediated protection against infectionsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1542/peds.2008-3256", "ISSN" : "1098-4275", "PMID" : "20566605", "abstract" : "OBJECTIVE To examine the associations of duration of exclusive breastfeeding with infections in the upper respiratory (URTI), lower respiratory (LRTI), and gastrointestinal tracts (GI) in infancy. METHODS This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onward in the Netherlands. Rates of breastfeeding during the first 6 months (never; partial for <4 months, not thereafter; partial for 4-6 months; exclusive for 4 months, not thereafter; exclusive for 4 months, partial thereafter; and exclusive for 6 months) and doctor-attended infections in the URTI, LRTI, and GI until the age of 12 months were assessed by questionnaires and available for 4164 subjects. RESULTS Compared with never-breastfed infants, those who were breastfed exclusively until the age of 4 months and partially thereafter had lower risks of infections in the URTI, LRTI, and GI until the age of 6 months (adjusted odds ratio [aOR]: 0.65 [95% confidence interval (CI): 0.51-0.83]; aOR: 0.50 [CI: 0.32-0.79]; and aOR: 0.41 [CI: 0.26-0.64], respectively) and of LRTI infections between the ages of 7 and 12 months (aOR: 0.46 [CI: 0.31-0.69]). Similar tendencies were observed for infants who were exclusively breastfed for 6 months or longer. Partial breastfeeding, even for 6 months, did not result in significantly lower risks of these infections. CONCLUSIONS Exclusive breastfeeding until the age of 4 months and partially thereafter was associated with a significant reduction of respiratory and gastrointestinal morbidity in infants. Our findings support health-policy strategies to promote exclusive breastfeeding for at least 4 months, but preferably 6 months, in industrialized countries.", "author" : [ { "dropping-particle" : "", "family" : "Duijts", "given" : "Liesbeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Jaddoe", "given" : "Vincent W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hofman", "given" : "Albert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moll", "given" : "Henri\u00ebtte A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatrics", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2010", "7" ] ] }, "page" : "e18-25", "title" : "Prolonged and exclusive breastfeeding reduces the risk of infectious diseases in infancy.", "type" : "article-journal", "volume" : "126" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁴", "plainTextFormattedCitation" : "24", "previouslyFormattedCitation" : "²⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }24, presumably as a consequence of the transfer of maternal antibodiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2016.04.055", "ISSN" : "00928674", "PMID" : "27153495", "abstract" : "To maintain a symbiotic relationship between the host and its resident intestinal microbiota, appropriate mucosal T cell responses to commensal antigens must be established. Mice acquire both IgG and IgA maternally; the former has primarily been implicated in passive immunity to pathogens while the latter mediates host-commensal mutualism. Here, we report the surprising observation that mice generate T cell-independent and largely Toll-like receptor (TLR)-dependent IgG2b and IgG3 antibody responses against their gut microbiota. We demonstrate that maternal acquisition of these antibodies dampens mucosal T follicular helper responses and subsequent germinal center B cell responses following birth. This work reveals a feedback loop whereby T cell-independent, TLR-dependent antibodies limit mucosal adaptive immune responses to newly acquired commensal antigens and uncovers a broader function for maternal IgG.", "author" : [ { "dropping-particle" : "", "family" : "Koch", "given" : "Meghan A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reiner", "given" : "Gabrielle L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lugo", "given" : "Kyler A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kreuk", "given" : "Lieselotte S.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stanbery", "given" : "Alison G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ansaldo", "given" : "Eduard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seher", "given" : "Thaddeus D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ludington", "given" : "William B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barton", "given" : "Gregory M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2016", "5", "5" ] ] }, "page" : "827-841", "title" : "Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life", "type" : "article-journal", "volume" : "165" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸", "plainTextFormattedCitation" : "18", "previouslyFormattedCitation" : "¹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }18 as well as beneficial breast milk microbiota members, including Bifidobacterium spp. and Lactobacillus spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s00284-015-0843-5", "ISSN" : "0343-8651", "author" : [ { "dropping-particle" : "", "family" : "Schanche", "given" : "Melissa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Avershina", "given" : "Ekaterina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dotterud", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "\u00d8ien", "given" : "Torbj\u00f8rn", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Storr\u00f8", "given" : "Ola", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : 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"Beneficial Microbes", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "17-30", "title" : "Human milk: a source of more life than we imagine", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^25,26", "plainTextFormattedCitation" : "25,26", "previouslyFormattedCitation" : "^25,26" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }25,26. On the other hand, the development of the respiratory microbiota can be disturbed, for example through antibiotics, which are commonly used in young children to treat infectionsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMc1212055", "ISSN" : "0028-4793", "abstract" : "Treating infections is one of the greatest successes in medicine, but it may be too easy to prescribe antibiotics. This report reviews U.S. outpatient antibiotic use in 2010.", "author" : [ { "dropping-particle" : "", "family" : "Hicks", "given" : "Lauri A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taylor", "given" : "Thomas H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hunkler", "given" : "Robert J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "New England Journal of Medicine", "id" : "ITEM-1", "issue" : "15", "issued" : { "date-parts" : [ [ "2013", "4", "11" ] ] }, "page" : "1461-1462", "publisher" : "Massachusetts Medical Society", "title" : "U.S. Outpatient Antibiotic Prescribing, 2010", "type" : "article-journal", "volume" : "368" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁷", "plainTextFormattedCitation" : "27", "previouslyFormattedCitation" : "²⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }27. Antibiotic perturbations were characterized by a reduced abundance of presumed beneficial commensals like Dolosigranulum spp. and Corynebacterium spp. in the URT of healthy childrenADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.chom.2015.03.008", "ISSN" : "1934-6069", "PMID" : "25865368", "abstract" : "The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.", "author" : [ { "dropping-particle" : "", "family" : "Teo", "given" : "Shu Mei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mok", "given" : "Danny", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pham", "given" : "Kym", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kusel", "given" : "Merci", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Serralha", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Troy", "given" : "Niamh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Barbara J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hales", "given" : "Belinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "Michael L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollams", "given" : "Elysia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bochkov", "given" : "Yury A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grindle", "given" : "Kristine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnston", "given" : "Sebastian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gern", "given" : "James E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sly", "given" : "Peter D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Patrick G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Kathryn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Inouye", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell host & microbe", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5", "13" ] ] }, "page" : "704-15", "publisher" : "Elsevier Inc.", "title" : "The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1164/rccm.201509-1759OC", "ISSN" : "1535-4970", "PMID" : "26492486", "abstract" : "RATIONALE Cystic fibrosis (CF) is characterized by early structural lung disease caused by pulmonary infections. The nasopharynx of infants is a major ecological reservoir of potential respiratory pathogens. OBJECTIVES To investigate the development of nasopharyngeal microbiota profiles in infants with CF compared with those of healthy control subjects during the first 6 months of life. METHODS We conducted a prospective cohort study, from the time of diagnosis onward, in which we collected questionnaires and 324 nasopharynx samples from 20 infants with CF and 45 age-matched healthy control subjects. Microbiota profiles were characterized by 16S ribosomal RNA-based sequencing. MEASUREMENTS AND MAIN RESULTS We observed significant differences in microbial community composition (P < 0.0002 by permutational multivariate analysis of variance) and development between groups. In infants with CF, early Staphylococcus aureus and, to a lesser extent, Corynebacterium spp. and Moraxella spp. dominance were followed by a switch to Streptococcus mitis predominance after 3 months of age. In control subjects, Moraxella spp. enrichment occurred throughout the first 6 months of life. In a multivariate analysis, S. aureus, S. mitis, Corynebacterium accolens, and bacilli were significantly more abundant in infants with CF, whereas Moraxella spp., Corynebacterium pseudodiphtericum and Corynebacterium propinquum and Haemophilus influenzae were significantly more abundant in control subjects, after correction for age, antibiotic use, and respiratory symptoms. Antibiotic use was independently associated with increased colonization of gram-negative bacteria such as Burkholderia spp. and members of the Enterobacteriaceae bacteria family and reduced colonization of potential beneficial commensals. CONCLUSIONS From diagnosis onward, we observed distinct patterns of nasopharyngeal microbiota development in infants with CF under 6 months of age compared with control subjects and a marked effect of antibiotic therapy leading toward a gram-negative microbial composition.", "author" : [ { "dropping-particle" : "", "family" : "Prevaes", "given" : "Sabine M P J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Winter-de Groot", "given" : "Karin M", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Janssens", "given" : "Hettie M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A A", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tramper-Stranders", "given" : "Gerdien A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wyllie", "given" : "Anne L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tiddens", "given" : "Harm A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Westreenen", "given" : "Mireille", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ent", "given" : "Cornelis K", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-2", "issue" : "5", "issued" : { "date-parts" : [ [ "2016", "3", "1" ] ] }, "page" : "504-15", "title" : "Development of the Nasopharyngeal Microbiota in Infants with Cystic Fibrosis.", "type" : "article-journal", "volume" : "193" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1128/AEM.01051-12", "ISBN" : "1098-5336 (Electronic)\\n0099-2240 (Linking)", "ISSN" : "00992240", "PMID" : "22752171", "abstract" : "The composition of the upper respiratory tract microbial community may influence the risk for colonization by the acute otitis media (AOM) pathogens Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. We used culture-independent methods to describe upper respiratory tract microbial communities in healthy children and children with upper respiratory tract infection with and without concurrent AOM. Nasal swabs and data were collected in a cross-sectional study of 240 children between 6 months and 3 years of age. Swabs were cultured for S. pneumoniae, and real-time PCR was used to identify S. pneumoniae, H. influenzae, and M. catarrhalis. The V1-V2 16S rRNA gene regions were sequenced using 454 pyrosequencing. Microbial communities were described using a taxon-based approach. Colonization by S. pneumoniae, H. influenzae, and M. catarrhalis was associated with lower levels of diversity in upper respiratory tract flora. We identified commensal taxa that were negatively associated with colonization by each AOM bacterial pathogen and with AOM. The balance of these relationships differed according to the colonizing AOM pathogen and history of antibiotic use. Children with antibiotic use in the past 6 months and a greater abundance of taxa, including Lactococcus and Propionibacterium, were less likely to have AOM than healthy children (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25 to 0.85). Children with no antibiotic use in the past 6 months, a low abundance of Streptococcus and Haemophilus, and a high abundance of Corynebacterium and Dolosigranulum were less likely to have AOM (OR, 0.51; 95% CI, 0.31 to 0.83). An increased understanding of polymicrobial interactions will facilitate the development of effective AOM prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Pettigrew", "given" : "Melinda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laufer", "given" : "Alison S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gent", "given" : "Janneane F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fennie", "given" : "Kristopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metlay", "given" : "Joshua P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Applied and Environmental Microbiology", "id" : "ITEM-3", "issue" : "17", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "6262-6270", "title" : "Upper respiratory tract microbial communities, acute otitis media pathogens, and antibiotic use in healthy and sick children", "type" : "article-journal", "volume" : "78" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^22,28,29", "plainTextFormattedCitation" : "22,28,29", "previouslyFormattedCitation" : "^22,28,29" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }22,28,29. This, in turn, might increase the risk of respiratory tract infections following antibiotic treatmentADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/01.inf.0000066798.69778.07", "ISSN" : "0891-3668", "PMID" : "12634580", "abstract" : "OBJECTIVES (1) To determine the relationship between acute otitis media (AOM) pathogens isolated in cases of early clinical recurrence of AOM (occurring within 1 month from completion of therapy) to the original pathogens causing the initial AOM episode; and (2) To determine whether shorter time intervals between completion of antibiotic therapy and clinical recurrences of AOM are associated with higher rates of true bacteriologic relapse. PATIENTS AND METHODS From 1995 through 2000, 1077 infants and young children ages 3 to 36 months with AOM were enrolled in double tympanocentesis (performed on Day 1 in all patients and Days 4 to 6 in those initially culture-positive) studies. Of these, 834 (77%) completed successfully the antibiotic treatment [pathogen eradication on Days 4 to 6 of therapy or no pathogen on middle ear fluid (MEF) culture on Day 1 and clinical improvement at end of therapy]. Patients were followed for 3 to 4 weeks after completion of therapy, and additional MEF cultures were obtained if clinical recurrence occurred. True bacteriologic relapse was defined as the presence of a pathogen identical with that isolated before therapy by serotype and pulsed field gel electrophoresis for and by pulsed field gel electrophoresis for Streptococcus pneumoniae and beta-lactamase production for Haemophilus influenzae. RESULTS MEF cultures were performed in 108 consecutive patients with early recurrent AOM. One hundred pathogens were isolated at recurrence in 88 of 108 (81%) patients: 54 H. influenzae; 45 S. pneumoniae; and 1 Moraxella catarrhalis. Most recurrent AOM episodes developed during the first 2 weeks of follow-up; 39 (36%), 38 (35%), 21 (19%) and 10 (9%) recurrent AOM episodes occurred on Days 1 to 7, 8 to 14, 15 to 21 and 22 to 28 after completion of therapy, respectively. In most patients these episodes were caused by a new pathogen. True bacteriologic relapses were found in 30 (28%) of 108 patients whose MEF cultures were positive for 35 pathogens: 13 of 108 (12%) S. pneumoniae; 12 of 108 (11%) H. influenzae; and 5 of 108 (5%) both. When timing of recurrent AOM after completion of therapy was analyzed, true bacteriologic relapses were found in 16 of 39 (41%), 10 of 38 (26%), 3 of 21 (14%) and 1 of 10 (10%) of all episodes on Days 1 to 7, 8 to 14, 15 to 21 and 22 to 28 after completion of therapy, respectively (P = 0.01). The respective rates for were 11 of 17 (65%), 3 of 10 (30%), 3 of 13 (23%) and 1 of 5 (20%) (P = 0.02). For H. influen\u2026", "author" : [ { "dropping-particle" : "", "family" : "Leibovitz", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greenberg", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Piglansky", "given" : "Lolita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Raiz", "given" : "Simon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Porat", "given" : "Nurith", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Press", "given" : "Joseph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leiberman", "given" : "Alberto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dagan", "given" : "Ron", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Pediatric infectious disease journal", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2003", "3" ] ] }, "page" : "209-16", "title" : "Recurrent acute otitis media occurring within one month from completion of antibiotic therapy: relationship to the original pathogen.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁰", "plainTextFormattedCitation" : "30", "previouslyFormattedCitation" : "³⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }30. Additionally, season, vaccination, presence of siblings, day care attendance, smoke exposure and prior infections can also impact the infant microbiotaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.chom.2015.03.008", "ISSN" : "1934-6069", "PMID" : "25865368", "abstract" : "The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.", "author" : [ { "dropping-particle" : "", "family" : "Teo", "given" : "Shu Mei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mok", "given" : "Danny", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pham", "given" : "Kym", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kusel", "given" : "Merci", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Serralha", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Troy", "given" : "Niamh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Barbara J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hales", "given" : "Belinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "Michael L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollams", "given" : "Elysia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bochkov", "given" : "Yury A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grindle", "given" : "Kristine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnston", "given" : "Sebastian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gern", "given" : "James E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sly", "given" : "Peter D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Patrick G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Kathryn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Inouye", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell host & microbe", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5", "13" ] ] }, "page" : "704-15", "publisher" : "Elsevier Inc.", "title" : "The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1371/journal.pone.0017035", "ISBN" : "1932-6203 (Electronic)\\n1932-6203 (Linking)", "ISSN" : "1932-6203", "PMID" : "21386965", "abstract" : "The nasopharynx is the ecological niche for many commensal bacteria and for potential respiratory or invasive pathogens like Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Disturbance of a balanced nasopharyngeal (NP) microbiome might be involved in the onset of symptomatic infections with these pathogens, which occurs primarily in fall and winter. It is unknown whether seasonal infection patterns are associated with concomitant changes in NP microbiota. As young children are generally prone to respiratory and invasive infections, we characterized the NP microbiota of 96 healthy children by barcoded pyrosequencing of the V5-V6 hypervariable region of the 16S-rRNA gene, and compared microbiota composition between children sampled in winter/fall with children sampled in spring. The approximately 1,000,000 sequences generated represented 13 taxonomic phyla and approximately 250 species-level phyla types (OTUs). The 5 most predominant phyla were Proteobacteria (64%), Firmicutes (21%), Bacteroidetes (11%), Actinobacteria (3%) and Fusobacteria (1,4%) with Moraxella, Haemophilus, Streptococcus, Flavobacteria, Dolosigranulum, Corynebacterium and Neisseria as predominant genera. The inter-individual variability was that high that on OTU level a core microbiome could not be defined. Microbiota profiles varied strongly with season, with in fall/winter a predominance of Proteobacteria (relative abundance (% of all sequences): 75% versus 51% in spring) and Fusobacteria (absolute abundance (% of children): 14% versus 2% in spring), and in spring a predominance of Bacteroidetes (relative abundance: 19% versus 3% in fall/winter, absolute abundance: 91% versus 54% in fall/winter), and Firmicutes. The latter increase is mainly due to (Brevi)bacillus and Lactobacillus species (absolute abundance: 96% versus 10% in fall/winter) which are like Bacteroidetes species generally related to healthy ecosystems. The observed seasonal effects could not be attributed to recent antibiotics or viral co-infection.The NP microbiota of young children is highly diverse and appears different between seasons. These differences seem independent of antibiotic use or viral co-infection.", "author" : [ { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huse", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossen", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gils", "given" : "Elske", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruin", "given" : "Jacob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonten", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Semple", "given" : "Malcolm", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "2", "28" ] ] }, "page" : "e17035", "title" : "Variability and Diversity of Nasopharyngeal Microbiota in Children: A Metagenomic Analysis", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/S0140-6736(04)16357-5", "ISBN" : "1474-547X (Electronic)\\r0140-6736 (Linking)", "ISSN" : "01406736", "PMID" : "15183627", "abstract" : "A trial with a 7-valent pneumococcal-conjugate vaccine in children with recurrent acute otitis media showed a shift in pneumococcal colonisation towards non-vaccine serotypes and an increase in Staphylococcus aureus-related acute otitis media after vaccination. We investigated prevalence and determinants of nasopharyngeal carriage of Streptococcus pneumoniae and S aureus in 3198 healthy children aged 1-19 years. Nasopharyngeal carriage of S pneumoniae was detected in 598 (19%) children, and was affected by age (peak incidence at 3 years) and day-care attendance (odds ratio [OR] 2.14, 95% CI 1.44-3.18). S aureus carriage was affected by age (peak incidence at 10 years) and male sex (OR 1.46, 1.25-1.70). Serotyping showed 42% vaccine type pneumococci. We noted a negative correlation for co-colonisation of S aureus and vaccine-type pneumococci (OR 0.68, 0.48-0.94), but not for S aureus and non-vaccine serotypes. These findings suggest a natural competition between colonisation with vaccine-type pneumococci and S aureus, which might explain the increase in S aureus-related otitis media after vaccination.", "author" : [ { "dropping-particle" : "", "family" : "Bogaert", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belkum", "given" : "A", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sluijter", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luijendijk", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "R", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "R\u00fcmke", "given" : "HC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbrugh", "given" : "HA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermans", "given" : "PWM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet", "id" : "ITEM-3", "issue" : "9424", "issued" : { "date-parts" : [ [ "2004", "6" ] ] }, "page" : "1871-1872", "title" : "Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children", "type" : "article-journal", "volume" : "363" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/j.jaci.2014.12.1909", "ISBN" : "0091-6749", "ISSN" : "10976825", "PMID" : "25636948", "abstract" : "Background Understanding the composition and dynamics of the upper respiratory tract microbiota in healthy infants is a prerequisite to investigate the role of the microbiota in patients with respiratory diseases. This is especially true in early life, when the immune system is in development. Objective We sought to describe the dynamics of the upper respiratory tract microbiota in healthy infants within the first year of life. Methods After exclusion of low-quality samples, microbiota characterization was performed by using 16S rDNA pyrosequencing of 872 nasal swabs collected biweekly from 47 unselected infants. Results Bacterial density increased and diversity decreased within the first year of life (R² = 0.95 and 0.73, respectively). A distinct profile for the first 3 months of life was found with increased relative abundances of Staphlyococcaceae and Corynebacteriaceae (exponential decay: R² = 0.94 and 0.96, respectively). In addition, relative bacterial abundance and composition differed significantly from summer to winter months. The individual composition of the microbiota changed with increasing time intervals between samples and was best modeled by an exponential function (R² = 0.97). Within-subject dissimilarity in a 2-week time interval was consistently lower than that between subjects, indicating a personalized microbiota. Conclusion This study reveals age and seasonality as major factors driving the composition of the nasal microbiota within the first year of life. A subject's microbiota is personalized but dynamic throughout the first year. These data are indispensable to interpretation of cross-sectional studies and investigation of the role of the microbiota in both healthy subjects and patients with respiratory diseases. They might also serve as a baseline for future intervention studies.", "author" : [ { "dropping-particle" : "", "family" : "Mika", "given" : "Moana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mack", "given" : "Ines", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Korten", "given" : "Insa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qi", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aebi", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frey", "given" : "Urs", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Latzin", "given" : "Philipp", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hilty", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Allergy and Clinical Immunology", "id" : "ITEM-4", "issue" : "4", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "905-912.e11", "publisher" : "Elsevier Inc.", "title" : "Dynamics of the nasal microbiota in infancy: A prospective cohort study", "type" : "article-journal", "volume" : "135" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1371/journal.pone.0039730", "ISBN" : "1932-6203 (Electronic)\\r1932-6203 (Linking)", "ISSN" : "19326203", "PMID" : "22761879", "abstract" : "BACKGROUND: Shifts in pneumococcal serotypes following introduction of 7-valent pneumococcal conjugate vaccine (PCV-7) may alter the presence of other bacterial pathogens co-inhabiting the same nasopharyngeal niche.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: Nasopharyngeal prevalence rates of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis were investigated before, 3 and 4.5 years after introduction of PCV-7 in the national immunisation program in children at 11 and 24 months of age, and parents of 24-month-old children (n\u2248330/group) using conventional culture methods. Despite a virtual disappearance of PCV-7 serotypes over time, similar overall pneumococcal rates were observed in all age groups, except for a significant reduction in the 11-month-old group (adjusted Odds Ratio after 4.5 years 0.48, 95% Confidence Interval 0.34-0.67). Before, 3 and 4.5 years after PCV-7 implementation, prevalence rates of S. aureus were 5%, 9% and 14% at 11 months of age (3.59, 1.90-6.79) and 20%, 32% and 34% in parents (1.96, 1.36-2.83), but remained similar at 24 months of age, respectively. Prevalence rates of H. influenzae were 46%, 65% and 65% at 11 months (2.22, 1.58-3.13), 52%, 73% and 76% at 24 months of age (2.68, 1.88-3.82) and 23%, 30% and 40% in parents (2.26, 1.58-3.33), respectively. No consistent changes in M. catarrhalis carriage rates were observed over time.\\n\\nCONCLUSIONS/SIGNIFICANCE: In addition to large shifts in pneumococcal serotypes, persistently higher nasopharyngeal prevalence rates of S. aureus and H. influenzae were observed among young children and their parents after PCV-7 implementation. These findings may have implications for disease incidence and antibiotic treatment in the post-PCV era.", "author" : [ { "dropping-particle" : "", "family" : "Spijkerman", "given" : "Judith", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prevaes", "given" : "Sabine M P J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gils", "given" : "Elske J M", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruin", "given" : "Jacob P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wijmenga-Monsuur", "given" : "Alienke J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dobbelsteen", "given" : "Germie P J M", "non-dropping-particle" : "van den", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "id" : "ITEM-5", "issue" : "6", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "e39730", "title" : "Long-term effects of pneumococcal conjugate vaccine on nasopharyngeal carriage of S. pneumoniae, S. aureus, H. influenzae and M. catarrhalis", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1086/500935", "ISSN" : "1537-6591", "PMID" : "16511750", "abstract" : "BACKGROUND Exposure to tobacco smoke is associated with higher risk of Streptococcus pneumoniae and Haemophilus influenzae infection. The aim of this study was to determine the influence of smoking and exposure to tobacco smoke on S. pneumoniae and H. influenzae carriage rates in children and their mothers. PATIENTS AND METHODS We performed a cross-sectional surveillance study of nasopharyngeal and oropharyngeal carriage of S. pneumoniae and H. influenzae in 208 children aged <60 months and their mothers. Smoking exposure and medical history were recorded. Carriage rates for children and their mothers in nasopharyngeal and oropharyngeal specimens were analyzed on the basis of smoking exposure. RESULTS The S. pneumoniae carriage rate was higher among children exposed to smoking than among nonexposed children (76% vs. 60%; P=.016). Exposed children more frequently carried S. pneumoniae serotypes included in the conjugate 7-valent vaccine, compared with nonexposed children (49% vs. 30% of all S. pneumoniae-positive nasopharyngeal cultures; P=.02). Carriage rates of S. pneumoniae were higher among mothers who smoked than among mothers exposed to smoking and among nonexposed mothers (32%, 15%, and 12%, respectively; P=.03). There were no differences in H. influenzae carriage rates between children and mothers from smoking and nonsmoking families. CONCLUSIONS Exposure to tobacco smoke increased S. pneumoniae carriage rates in general and for carriage of serotypes included in the conjugate 7-valent vaccine in particular in children. Smoking mothers had a higher S. pneumoniae carriage rate than did nonsmoking mothers. Smoking or exposure to smoking did not increase H. influenzae carriage rates in children and mothers.", "author" : [ { "dropping-particle" : "", "family" : "Greenberg", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Givon-Lavi", "given" : "Noga", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Broides", "given" : "Arnon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blancovich", "given" : "Irena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peled", "given" : "Nechama", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dagan", "given" : "Ron", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "id" : "ITEM-6", "issue" : "7", "issued" : { "date-parts" : [ [ "2006", "4", "1" ] ] }, "page" : "897-903", "title" : "The contribution of smoking and exposure to tobacco smoke to Streptococcus pneumoniae and Haemophilus influenzae carriage in children and their mothers.", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^{22,31\u201335}", "plainTextFormattedCitation" : "22,31\u201335", "previouslyFormattedCitation" : "^{22,31\u201335}" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }22,31–35, which indicates that the early life microbiota is dynamic and affected by numerous host and environmental factors (FIG. 2). Host genetics seem to have a minor effect on the URT microbiota in healthy individuals, only influencing the nasal bacterial density, but not microbiota compositionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/sciadv.1400216", "ISSN" : "2375-2548", "PMID" : "26601194", "abstract" : "The human microbiome can play a key role in host susceptibility to pathogens, including in the nasal cavity, a site favored by Staphylococcus aureus. However, what determines our resident nasal microbiota-the host or the environment-and can interactions among nasal bacteria determine S. aureus colonization? Our study of 46 monozygotic and 43 dizygotic twin pairs revealed that nasal microbiota is an environmentally derived trait, but the host's sex and genetics significantly influence nasal bacterial density. Although specific taxa, including lactic acid bacteria, can determine S. aureus colonization, their negative interactions depend on thresholds of absolute abundance. These findings demonstrate that nasal microbiota is not fixed by host genetics and opens the possibility that nasal microbiota may be manipulated to prevent or eliminate S. aureus colonization.", "author" : [ { "dropping-particle" : "", "family" : "Liu", "given" : "Cindy M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "Lance B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hungate", "given" : "Bruce A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abraham", "given" : "Alison G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Larsen", "given" : "Lisbeth A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Christensen", "given" : "Kaare", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stegger", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Skov", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Andersen", "given" : "Paal Skytt", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science advances", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "6" ] ] }, "page" : "e1400216", "publisher" : "American Association for the Advancement of Science", "title" : "Staphylococcus aureus and the ecology of the nasal microbiome.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁶", "plainTextFormattedCitation" : "36", "previouslyFormattedCitation" : "³⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }36. By contrast, the composition of the sputum microbiota seemed equally influenced by host genetics and environmental factorsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/srep23745", "ISSN" : "2045-2322", "PMID" : "27030383", "abstract" : "Recent studies showing clear differences in the airway microbiota between healthy and diseased individuals shed light on the importance of the airway microbiota in health. Here, we report the associations of host genetics and lifestyles such as smoking, alcohol consumption, and physical activity with the composition of the sputum microbiota using 16S rRNA gene sequence data generated from 257 sputum samples of Korean twin-family cohort. By estimating the heritability of each microbial taxon, we found that several taxa, including Providencia and Bacteroides, were significantly influenced by host genetic factors. Smoking had the strongest effect on the overall microbial community structure among the tested lifestyle factors. The abundances of Veillonella and Megasphaera were higher in current-smokers, and increased with the pack-year value and the Fagerstrom Test of Nicotine Dependence (FTND) score. In contrast, Haemophilus decreased with the pack-year of smoking and the FTND score. Co-occurrence network analysis showed that the taxa were clustered according to the direction of associations with smoking, and that the taxa influenced by host genetics were found together. These results demonstrate that the relationships among sputum microbial taxa are closely associated with not only smoking but also host genetics.", "author" : [ { "dropping-particle" : "", "family" : "Lim", "given" : "Mi Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yoon", "given" : "Hyo Shin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rho", "given" : "Mina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sung", "given" : "Joohon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Song", "given" : "Yun-Mi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Kayoung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ko", "given" : "GwangPyo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scientific Reports", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "3", "31" ] ] }, "language" : "en", "page" : "23745", "publisher" : "Nature Publishing Group", "title" : "Analysis of the association between host genetics, smoking, and sputum microbiota in healthy humans", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁷", "plainTextFormattedCitation" : "37", "previouslyFormattedCitation" : "³⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }37.While the gut microbiota matures into an adult-like community within the first 3 years of lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature11053", "ISBN" : "1476-4687 (Electronic)\\r0028-0836 (Linking)", "ISSN" : "1476-4687", "PMID" : "22699611", "abstract" : "Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.", "author" : [ { "dropping-particle" : "", "family" : "Yatsunenko", "given" : "Tanya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rey", "given" : "Federico E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Manary", "given" : "Mark J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trehan", "given" : "Indi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dominguez-Bello", "given" : "Maria Gloria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Contreras", "given" : "Monica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magris", "given" : "Magda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hidalgo", "given" : "Glida", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baldassano", "given" : "Robert N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Anokhin", "given" : "Andrey P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heath", "given" : "Andrew C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Warner", "given" : "Barbara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reeder", "given" : "Jens", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kuczynski", "given" : "Justin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caporaso", "given" : "J Gregory", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lozupone", "given" : "Catherine A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lauber", "given" : "Christian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose Carlos", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knights", "given" : "Dan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "Rob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gordon", "given" : "Jeffrey I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7402", "issued" : { "date-parts" : [ [ "2012", "6", "14" ] ] }, "page" : "222-227", "title" : "Human gut microbiome viewed across age and geography", "type" : "article-journal", "volume" : "486" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁸", "plainTextFormattedCitation" : "38", "previouslyFormattedCitation" : "³⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }38, the time to establish a stable respiratory microbiota remains to be determined. Although niche-differentiation occurs as early as 1 week of lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. Infants born by Caesarian section showed a delay in overall development of respiratory microbiota profiles with specifically reduced colonization with health-associated commensals like Corynebacterium and Dolosigranulum, thereby possibly influencing respiratory health later in life.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levin", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houten", "given" : "Marlies A.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalkman", "given" : "Gino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A.A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "Pieter-Kees C.M.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pernet", "given" : "Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EBioMedicine", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "336-345", "title" : "Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁰", "plainTextFormattedCitation" : "20", "previouslyFormattedCitation" : "²⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20, the respiratory microbiota evolves throughout the first few years of lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201407-1240OC", "ISBN" : "2010081269", "ISSN" : "1535-4970", "PMID" : "25329446", "abstract" : "RATIONALE Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. OBJECTIVES To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. METHODS Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. MEASUREMENTS AND MAIN RESULTS Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. CONCLUSIONS These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with (NCT00189020).", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsivtsivadze", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1283-92", "title" : "Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.", "type" : "article-journal", "volume" : "190" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/ismej.2014.250", "ISSN" : "1751-7370", "PMID" : "25575312", "abstract" : "The upper respiratory tract (URT) is a crucial site for host defense, as it is home to bacterial communities that both modulate host immune defense and serve as a reservoir of potential pathogens. Young children are at high risk of respiratory illness, yet the composition of their URT microbiota is not well understood. Microbial profiling of the respiratory tract has traditionally focused on culturing common respiratory pathogens, whereas recent culture-independent microbiome profiling can only report the relative abundance of bacterial populations. In the current study, we used both molecular profiling of the bacterial 16S rRNA gene and laboratory culture to examine the bacterial diversity from the oropharynx and nasopharynx of 51 healthy children with a median age of 1.1 years (range 1-4.5 years) along with 19 accompanying parents. The resulting profiles suggest that in young children the nasopharyngeal microbiota, much like the gastrointestinal tract microbiome, changes from an immature state, where it is colonized by a few dominant taxa, to a more diverse state as it matures to resemble the adult microbiota. Importantly, this difference in bacterial diversity between adults and children accompanies a change in bacterial load of three orders of magnitude. This indicates that the bacterial communities in the nasopharynx of young children have a fundamentally different structure from those in adults and suggests that maturation of this community occurs sometime during the first few years of life, a period that includes ages at which children are at the highest risk for respiratory disease.", "author" : [ { "dropping-particle" : "", "family" : "Stearns", "given" : "Jennifer C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "Carla J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKeon", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Fiona J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fontes", "given" : "Michelle E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schryvers", "given" : "Anthony B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowdish", "given" : "Dawn M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kellner", "given" : "James D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Surette", "given" : "Michael G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME journal", "id" : "ITEM-2", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5" ] ] }, "page" : "1246-59", "publisher" : "Nature Publishing Group", "title" : "Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.jaci.2014.12.1909", "ISBN" : "0091-6749", "ISSN" : "10976825", "PMID" : "25636948", "abstract" : "Background Understanding the composition and dynamics of the upper respiratory tract microbiota in healthy infants is a prerequisite to investigate the role of the microbiota in patients with respiratory diseases. This is especially true in early life, when the immune system is in development. Objective We sought to describe the dynamics of the upper respiratory tract microbiota in healthy infants within the first year of life. Methods After exclusion of low-quality samples, microbiota characterization was performed by using 16S rDNA pyrosequencing of 872 nasal swabs collected biweekly from 47 unselected infants. Results Bacterial density increased and diversity decreased within the first year of life (R² = 0.95 and 0.73, respectively). A distinct profile for the first 3 months of life was found with increased relative abundances of Staphlyococcaceae and Corynebacteriaceae (exponential decay: R² = 0.94 and 0.96, respectively). In addition, relative bacterial abundance and composition differed significantly from summer to winter months. The individual composition of the microbiota changed with increasing time intervals between samples and was best modeled by an exponential function (R² = 0.97). Within-subject dissimilarity in a 2-week time interval was consistently lower than that between subjects, indicating a personalized microbiota. Conclusion This study reveals age and seasonality as major factors driving the composition of the nasal microbiota within the first year of life. A subject's microbiota is personalized but dynamic throughout the first year. These data are indispensable to interpretation of cross-sectional studies and investigation of the role of the microbiota in both healthy subjects and patients with respiratory diseases. They might also serve as a baseline for future intervention studies.", "author" : [ { "dropping-particle" : "", "family" : "Mika", "given" : "Moana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mack", "given" : "Ines", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Korten", "given" : "Insa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qi", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aebi", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frey", "given" : "Urs", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Latzin", "given" : "Philipp", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hilty", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Allergy and Clinical Immunology", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "905-912.e11", "publisher" : "Elsevier Inc.", "title" : "Dynamics of the nasal microbiota in infancy: A prospective cohort study", "type" : "article-journal", "volume" : "135" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^21,33,39", "plainTextFormattedCitation" : "21,33,39", "previouslyFormattedCitation" : "^21,33,39" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21,33,39. After establishment of the respiratory microbiota, antibiotic treatment remains an important perturbing factor of the microbial equilibrium throughout lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0009836", "ISSN" : "1932-6203", "author" : [ { "dropping-particle" : "", "family" : "Jakobsson", "given" : "Hedvig E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jernberg", "given" : "Cecilia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Andersson", "given" : "Anders F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sj\u00f6lund-Karlsson", "given" : "Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jansson", "given" : "Janet K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Engstrand", "given" : "Lars", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Ratner", "given" : "Adam J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010", "3", "24" ] ] }, "page" : "e9836", "publisher" : "Public Library of Science", "title" : "Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴⁰", "plainTextFormattedCitation" : "40", "previouslyFormattedCitation" : "⁴⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }40. Active smoking also impacts the URT microbial communitiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0015216", "ISSN" : "1932-6203", "author" : [ { "dropping-particle" : "", "family" : "Charlson", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Custers-Allen", "given" : "Rebecca", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Hongzhe", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sinha", "given" : "Rohini", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hwang", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "Frederic D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Heimesaat", "given" : "Markus M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2010", "12", "20" ] ] }, "page" : "e15216", "publisher" : "Public Library of Science", "title" : "Disordered Microbial Communities in the Upper Respiratory Tract of Cigarette Smokers", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/srep23745", "ISSN" : "2045-2322", "PMID" : "27030383", "abstract" : "Recent studies showing clear differences in the airway microbiota between healthy and diseased individuals shed light on the importance of the airway microbiota in health. Here, we report the associations of host genetics and lifestyles such as smoking, alcohol consumption, and physical activity with the composition of the sputum microbiota using 16S rRNA gene sequence data generated from 257 sputum samples of Korean twin-family cohort. By estimating the heritability of each microbial taxon, we found that several taxa, including Providencia and Bacteroides, were significantly influenced by host genetic factors. Smoking had the strongest effect on the overall microbial community structure among the tested lifestyle factors. The abundances of Veillonella and Megasphaera were higher in current-smokers, and increased with the pack-year value and the Fagerstrom Test of Nicotine Dependence (FTND) score. In contrast, Haemophilus decreased with the pack-year of smoking and the FTND score. Co-occurrence network analysis showed that the taxa were clustered according to the direction of associations with smoking, and that the taxa influenced by host genetics were found together. These results demonstrate that the relationships among sputum microbial taxa are closely associated with not only smoking but also host genetics.", "author" : [ { "dropping-particle" : "", "family" : "Lim", "given" : "Mi Young", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yoon", "given" : "Hyo Shin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rho", "given" : "Mina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sung", "given" : "Joohon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Song", "given" : "Yun-Mi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Kayoung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ko", "given" : "GwangPyo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Scientific Reports", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016", "3", "31" ] ] }, "language" : "en", "page" : "23745", "publisher" : "Nature Publishing Group", "title" : "Analysis of the association between host genetics, smoking, and sputum microbiota in healthy humans", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^37,41", "plainTextFormattedCitation" : "37,41", "previouslyFormattedCitation" : "^37,41" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }37,41, however, no clear influence of smoking on the composition of the LRT microbiota was observedADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201210-1913OC", "ISBN" : "4126922210", "ISSN" : "1073449X", "PMID" : "23491408", "abstract" : "RATIONALE: Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome.\\n\\nOBJECTIVES: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort.\\n\\nMETHODS: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome.\\n\\nMEASUREMENTS AND MAIN RESULTS: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not.\\n\\nCONCLUSIONS: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.", "author" : [ { "dropping-particle" : "", "family" : "Morris", "given" : "Alison", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schloss", "given" : "Patrick D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campbell", "given" : "Thomas B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crothers", "given" : "Kristina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Sonia C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fontenot", "given" : "Andrew P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghedin", "given" : "Elodie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jablonski", "given" : "Kathleen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kleerup", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Lynch", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Twigg", "given" : "Homer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Venkataraman", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1067-1075", "title" : "Comparison of the respiratory microbiome in healthy nonsmokers and smokers", "type" : "article-journal", "volume" : "187" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴²", "plainTextFormattedCitation" : "42", "previouslyFormattedCitation" : "⁴²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }42. Interestingly, it has been suggested that the niche-specific differences disappear again with elderly ageADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1513/AnnalsATS.201310-351OC", "ISBN" : "9055226750", "ISSN" : "23256621", "PMID" : "24601676", "abstract" : "Rationale: The microbial communities inhabiting the upper respiratory tract protect from respiratory infection. The maturity of the immune system is a major influence on the composition of the microbiome and, in youth, the microbiota and immune system are believed to mature in tandem. With age, immune function declines and susceptibility to respiratory infection increases. Whether these changes contribute to the microbial composition of the respiratory tract is unknown. Objectives: Our goal was to determine whether the microbes of the upper respiratory tract differ between mid-aged adults (18-40 yr) and the elderly (>65 yr). Methods: Microbiomes of the anterior nares and oropharynx of elderly individuals were evaluated by 16S rRNA gene sequencing. These communities were compared with data on mid-aged adults obtained from the Human Microbiome Project. Measurements and Main Results: The microbiota of the elderly showed no associations with sex, comorbidities, residence, or vaccinations. Comparisons of mid-aged adults and the elderly demonstrated significant differences in the composition of the anterior nares and oropharynx, including a population in the anterior nares of the elderly that more closely resembled the oropharynx than the anterior nares of adults. The elderly oropharyngeal microbiota were characterized by increased abundance of streptococci, specifically, Streptococcus salivarius group species, but not Streptococcus pneumoniae, carriage of which was low (<3% of participants), as demonstrated by PCR (n = 4/123). Conclusions: Microbial populations of the upper respiratory tract in mid-aged adults and the elderly differ; it is possible that these differences contribute to the increased risk of respiratory infections experienced by the elderly.", "author" : [ { "dropping-particle" : "", "family" : "Whelan", "given" : "Fiona J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verschoor", "given" : "Chris P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stearns", "given" : "Jennifer C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossi", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luinstra", "given" : "Kathy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loeb", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smieja", "given" : "Marek", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnstone", "given" : "Jennie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Surette", "given" : "Michael G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowdish", "given" : "Dawn M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "5" ] ] }, "page" : "513-521", "title" : "The loss of topography in the microbial communities of the upper respiratory tract in the elderly", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴³", "plainTextFormattedCitation" : "43", "previouslyFormattedCitation" : "⁴³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }43.Strikingly, not only exposure to beneficial bacteria seems to be important, but also the timing of these exposures seems to play a critical role in maintaining respiratory health, as especially aberrant respiratory colonization patterns in infancy appear to be a major determinant of respiratory disease later in lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201407-1240OC", "ISBN" : "2010081269", "ISSN" : "1535-4970", "PMID" : "25329446", "abstract" : "RATIONALE Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. OBJECTIVES To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. METHODS Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. MEASUREMENTS AND MAIN RESULTS Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. CONCLUSIONS These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with (NCT00189020).", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsivtsivadze", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1283-92", "title" : "Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.", "type" : "article-journal", "volume" : "190" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1164/rccm.201302-0215OC", "ISBN" : "1073-449X", "ISSN" : "1073449X", "PMID" : "24090102", "abstract" : "RATIONALE: The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children.\\n\\nOBJECTIVES: To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first 3 years of life.\\n\\nMETHODS: Participants comprised children of the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort, a prospective birth cohort study of 411 children born to mothers with asthma. Aspirates from the hypopharynx at age 4 weeks were cultured for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus. Clinical information on pneumonia and bronchiolitis within the first 3 years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated with pneumonia and bronchiolitis and bacterial airway colonization.\\n\\nMEASUREMENTS AND MAIN RESULTS: Hypopharyngeal aspirates and full clinical follow-up until 3 years of age were available for 265 children. Of these, 56 (21%) neonates were colonized with S. pneumoniae, H. influenzae, and/or M. catarrhalis at 4 weeks of age. Colonization with at least one of these microorganisms (but not S. aureus) was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted incidence rate ratio, 1.79 [1.29-2.48]; P < 0.005) independently of concurrent or later asthma.\\n\\nCONCLUSIONS: Neonatal airway colonization with S. pneumoniae, H. influenzae, or M. catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.", "author" : [ { "dropping-particle" : "", "family" : "Vissing", "given" : "Nadja H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chawes", "given" : "Bo L K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bisgaard", "given" : "Hans", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-2", "issue" : "10", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1246-1252", "title" : "Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates", "type" : "article-journal", "volume" : "188" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.chom.2015.03.008", "ISSN" : "1934-6069", "PMID" : "25865368", "abstract" : "The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.", "author" : [ { "dropping-particle" : "", "family" : "Teo", "given" : "Shu Mei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mok", "given" : "Danny", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pham", "given" : "Kym", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kusel", "given" : "Merci", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Serralha", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Troy", "given" : "Niamh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Barbara J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hales", "given" : "Belinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "Michael L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollams", "given" : "Elysia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bochkov", "given" : "Yury A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grindle", "given" : "Kristine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnston", "given" : "Sebastian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gern", "given" : "James E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sly", "given" : "Peter D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Patrick G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Kathryn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Inouye", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell host & microbe", "id" : "ITEM-3", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5", "13" ] ] }, "page" : "704-15", "publisher" : "Elsevier Inc.", "title" : "The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^21,22,44", "plainTextFormattedCitation" : "21,22,44", "previouslyFormattedCitation" : "^21,22,44" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21,22,44. This could be due to the role of early life host-microbial interactions in immune educationADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.1219328", "ISSN" : "1095-9203", "PMID" : "22442383", "abstract" : "Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.", "author" : [ { "dropping-particle" : "", "family" : "Olszak", "given" : "Torsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "An", "given" : "Dingding", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeissig", "given" : "Sebastian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vera", "given" : "Miguel Pinilla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richter", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Franke", "given" : "Andre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glickman", "given" : "Jonathan N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Siebert", "given" : "Reiner", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baron", "given" : "Rebecca M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kasper", "given" : "Dennis L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blumberg", "given" : "Richard S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "6080", "issued" : { "date-parts" : [ [ "2012", "4", "27" ] ] }, "page" : "489-93", "publisher" : "NIH Public Access", "title" : "Microbial exposure during early life has persistent effects on natural killer T cell function.", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6. It has been proposed that the dynamic nature of the developing microbiota early in life might provide a window of opportunity for the modulation of microbiota towards a beneficial compositionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm.4039", "ISSN" : "1546-170X", "PMID" : "26828196", "abstract" : "Exposure of newborns to the maternal vaginal microbiota is interrupted with cesarean birthing. Babies delivered by cesarean section (C-section) acquire a microbiota that differs from that of vaginally delivered infants, and C-section delivery has been associated with increased risk for immune and metabolic disorders. Here we conducted a pilot study in which infants delivered by C-section were exposed to maternal vaginal fluids at birth. Similarly to vaginally delivered babies, the gut, oral and skin bacterial communities of these newborns during the first 30 d of life was enriched in vaginal bacteria--which were underrepresented in unexposed C-section-delivered infants--and the microbiome similarity to those of vaginally delivered infants was greater in oral and skin samples than in anal samples. Although the long-term health consequences of restoring the microbiota of C-section-delivered infants remain unclear, our results demonstrate that vaginal microbes can be partially restored at birth in C-section-delivered babies.", "author" : [ { "dropping-particle" : "", "family" : "Dominguez-Bello", "given" : "Maria G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jesus-Laboy", "given" : "Kassandra M", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shen", "given" : "Nan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Laura M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amir", "given" : "Amnon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gonzalez", "given" : "Antonio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bokulich", "given" : "Nicholas A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Song", "given" : "Se Jin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoashi", "given" : "Marina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivera-Vinas", "given" : "Juana I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mendez", "given" : "Keimari", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "Rob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2016", "3", "1" ] ] }, "language" : "en", "page" : "250-3", "publisher" : "Nature Publishing Group", "title" : "Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴⁵", "plainTextFormattedCitation" : "45", "previouslyFormattedCitation" : "⁴⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }45, however, the extent of this period is currently unknown. [H1] The microbiota of the upper respiratory tract[H3] Gatekeeper of respiratory healthThe URT consists of different anatomical structures with different epithelial cell types, and is exposed to various environmental factors. These diverse micro-niches are colonized by specialized bacterial communities, viruses and fungi.The anterior nares are closest to the outside environment and are paved with skin-like keratinized squamous epithelium, including serous and sebaceous glands, which lead to the enrichment of lipophilic skin colonizers, including Staphylococcus spp., Propionibacterium spp. and Corynebacterium spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0010598", "ISSN" : "1932-6203", "PMID" : "20498722", "abstract" : "BACKGROUND Colonization of humans with Staphylococcus aureus is a critical prerequisite of subsequent clinical infection of the skin, blood, lung, heart and other deep tissues. S. aureus persistently or intermittently colonizes the nares of approximately 50% of healthy adults, whereas approximately 50% of the general population is rarely or never colonized by this pathogen. Because microbial consortia within the nasal cavity may be an important determinant of S. aureus colonization we determined the composition and dynamics of the nasal microbiota and correlated specific microorganisms with S. aureus colonization. METHODOLOGY/PRINCIPAL FINDINGS Nasal specimens were collected longitudinally from five healthy adults and a cross-section of hospitalized patients (26 S. aureus carriers and 16 non-carriers). Culture-independent analysis of 16S rRNA sequences revealed that the nasal microbiota of healthy subjects consists primarily of members of the phylum Actinobacteria (e.g., Propionibacterium spp. and Corynebacterium spp.), with proportionally less representation of other phyla, including Firmicutes (e.g., Staphylococcus spp.) and Proteobacteria (e.g. Enterobacter spp). In contrast, inpatient nasal microbiotas were enriched in S. aureus or Staphylococcus epidermidis and diminished in several actinobacterial groups, most notably Propionibacterium acnes. Moreover, within the inpatient population S. aureus colonization was negatively correlated with the abundances of several microbial groups, including S. epidermidis (p = 0.004). CONCLUSIONS/SIGNIFICANCE The nares environment is colonized by a temporally stable microbiota that is distinct from other regions of the integument. Negative association between S. aureus, S. epidermidis, and other groups suggests microbial competition during colonization of the nares, a finding that could be exploited to limit S. aureus colonization.", "author" : [ { "dropping-particle" : "", "family" : "Frank", "given" : "Daniel N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feazel", "given" : "Leah M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bessesen", "given" : "Mary T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "Connie S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Janoff", "given" : "Edward N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pace", "given" : "Norman R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2010", "5", "17" ] ] }, "page" : "e10598", "title" : "The human nasal microbiota and Staphylococcus aureus carriage.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/nature13786", "ISSN" : "1476-4687", "PMID" : "25279917", "abstract" : "The varied topography of human skin offers a unique opportunity to study how the body's microenvironments influence the functional and taxonomic composition of microbial communities. Phylogenetic marker gene-based studies have identified many bacteria and fungi that colonize distinct skin niches. Here metagenomic analyses of diverse body sites in healthy humans demonstrate that local biogeography and strong individuality define the skin microbiome. We developed a relational analysis of bacterial, fungal and viral communities, which showed not only site specificity but also individual signatures. We further identified strain-level variation of dominant species as heterogeneous and multiphyletic. Reference-free analyses captured the uncharacterized metagenome through the development of a multi-kingdom gene catalogue, which was used to uncover genetic signatures of species lacking reference genomes. This work is foundational for human disease studies investigating inter-kingdom interactions, metabolic changes and strain tracking, and defines the dual influence of biogeography and individuality on microbial composition and function.", "author" : [ { "dropping-particle" : "", "family" : "Oh", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Byrd", "given" : "Allyson L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deming", "given" : "Clay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conlan", "given" : "Sean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "NISC Comparative Sequencing Program", "given" : "NISC Comparative Sequencing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Heidi H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Segre", "given" : "Julia A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-2", "issue" : "7520", "issued" : { "date-parts" : [ [ "2014", "10", "2" ] ] }, "page" : "59-64", "publisher" : "NIH Public Access", "title" : "Biogeography and individuality shape function in the human skin metagenome.", "type" : "article-journal", "volume" : "514" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1186/gb-2014-15-5-r66", "ISBN" : "1465-6914 (Electronic)\\n1465-6906 (Linking)", "ISSN" : "1465-6914", "PMID" : "24887286", "abstract" : "BACKGROUND: Determining bacterial abundance variation is the first step in understanding bacterial similarity between individuals. Categorization of bacterial communities into groups or community classes is the subsequent step in describing microbial distribution based on abundance patterns. Here, we present an analysis of the groupings of bacterial communities in stool, nasal, skin, vaginal and oral habitats in a healthy cohort of 236 subjects from the Human Microbiome Project. RESULTS: We identify distinct community group patterns in the anterior nares, four skin sites, and vagina at the genus level. We also confirm three enterotypes previously identified in stools. We identify two clusters with low silhouette values in most oral sites, in which bacterial communities are more homogeneous. Subjects sharing a community class in one habitat do not necessarily share a community class in another, except in the three vaginal sites and the symmetric habitats of the left and right retroauricular creases. Demographic factors, including gender, age, and ethnicity, significantly influence community composition in several habitats. Community classes in the vagina, retroauricular crease and stool are stable over approximately 200 days. CONCLUSION: The community composition, association of demographic factors with community classes, and demonstration of community stability deepen our understanding of the variability and dynamics of human microbiomes. This also has significant implications for experimental designs that seek microbial correlations with clinical phenotypes.", "author" : [ { "dropping-particle" : "", "family" : "Zhou", "given" : "Yanjiao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mihindukulasuriya", "given" : "Kathie a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Hongyu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosa", "given" : "Patricio S", "non-dropping-particle" : "La", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wylie", "given" : "Kristine M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "John C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kota", "given" : "Karthik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shannon", "given" : "William D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitreva", "given" : "Makedonka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome biology", "id" : "ITEM-3", "issue" : "5", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "R66", "publisher" : "BioMed Central", "title" : "Exploration of bacterial community classes in major human habitats.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^46\u201348", "plainTextFormattedCitation" : "46\u201348", "previouslyFormattedCitation" : "^46\u201348" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }46–48. Bacteria that are frequently found in other respiratory niches, including Moraxella spp., Dolosigranulum spp. and Streptococcus spp. have also been reported present in the anterior naresADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/AEM.01051-12", "ISBN" : "1098-5336 (Electronic)\\n0099-2240 (Linking)", "ISSN" : "00992240", "PMID" : "22752171", "abstract" : "The composition of the upper respiratory tract microbial community may influence the risk for colonization by the acute otitis media (AOM) pathogens Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. We used culture-independent methods to describe upper respiratory tract microbial communities in healthy children and children with upper respiratory tract infection with and without concurrent AOM. Nasal swabs and data were collected in a cross-sectional study of 240 children between 6 months and 3 years of age. Swabs were cultured for S. pneumoniae, and real-time PCR was used to identify S. pneumoniae, H. influenzae, and M. catarrhalis. The V1-V2 16S rRNA gene regions were sequenced using 454 pyrosequencing. Microbial communities were described using a taxon-based approach. Colonization by S. pneumoniae, H. influenzae, and M. catarrhalis was associated with lower levels of diversity in upper respiratory tract flora. We identified commensal taxa that were negatively associated with colonization by each AOM bacterial pathogen and with AOM. The balance of these relationships differed according to the colonizing AOM pathogen and history of antibiotic use. Children with antibiotic use in the past 6 months and a greater abundance of taxa, including Lactococcus and Propionibacterium, were less likely to have AOM than healthy children (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25 to 0.85). Children with no antibiotic use in the past 6 months, a low abundance of Streptococcus and Haemophilus, and a high abundance of Corynebacterium and Dolosigranulum were less likely to have AOM (OR, 0.51; 95% CI, 0.31 to 0.83). An increased understanding of polymicrobial interactions will facilitate the development of effective AOM prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Pettigrew", "given" : "Melinda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laufer", "given" : "Alison S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gent", "given" : "Janneane F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fennie", "given" : "Kristopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metlay", "given" : "Joshua P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Applied and Environmental Microbiology", "id" : "ITEM-1", "issue" : "17", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "6262-6270", "title" : "Upper respiratory tract microbial communities, acute otitis media pathogens, and antibiotic use in healthy and sick children", "type" : "article-journal", "volume" : "78" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1513/AnnalsATS.201310-351OC", "ISBN" : "9055226750", "ISSN" : "23256621", "PMID" : "24601676", "abstract" : "Rationale: The microbial communities inhabiting the upper respiratory tract protect from respiratory infection. The maturity of the immune system is a major influence on the composition of the microbiome and, in youth, the microbiota and immune system are believed to mature in tandem. With age, immune function declines and susceptibility to respiratory infection increases. Whether these changes contribute to the microbial composition of the respiratory tract is unknown. Objectives: Our goal was to determine whether the microbes of the upper respiratory tract differ between mid-aged adults (18-40 yr) and the elderly (>65 yr). Methods: Microbiomes of the anterior nares and oropharynx of elderly individuals were evaluated by 16S rRNA gene sequencing. These communities were compared with data on mid-aged adults obtained from the Human Microbiome Project. Measurements and Main Results: The microbiota of the elderly showed no associations with sex, comorbidities, residence, or vaccinations. Comparisons of mid-aged adults and the elderly demonstrated significant differences in the composition of the anterior nares and oropharynx, including a population in the anterior nares of the elderly that more closely resembled the oropharynx than the anterior nares of adults. The elderly oropharyngeal microbiota were characterized by increased abundance of streptococci, specifically, Streptococcus salivarius group species, but not Streptococcus pneumoniae, carriage of which was low (<3% of participants), as demonstrated by PCR (n = 4/123). Conclusions: Microbial populations of the upper respiratory tract in mid-aged adults and the elderly differ; it is possible that these differences contribute to the increased risk of respiratory infections experienced by the elderly.", "author" : [ { "dropping-particle" : "", "family" : "Whelan", "given" : "Fiona J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verschoor", "given" : "Chris P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stearns", "given" : "Jennifer C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossi", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luinstra", "given" : "Kathy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loeb", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smieja", "given" : "Marek", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnstone", "given" : "Jennie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Surette", "given" : "Michael G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowdish", "given" : "Dawn M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "5" ] ] }, "page" : "513-521", "title" : "The loss of topography in the microbial communities of the upper respiratory tract in the elderly", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1111/1462-2920.13378", "ISSN" : "14622920", "PMID" : "27207744", "abstract" : "The human nasal passage, from the anterior nares through the nasal vestibule to the nasal cavities, is an important habitat for opportunistic pathogens and commensals alike. This work sampled four different anatomical regions within the human nasal passage across a large cohort of individuals (n = 79) comprising individuals suffering from chronic nasal inflammation clinically known as chronic rhinosinusitis (CRS) and individuals not suffering from inflammation (CRS-free). While individuals had their own unique bacterial fingerprint that was consistent across the anatomical regions, these bacterial fingerprints formed into distinct delineated groups comprising core bacterial members, which were consistent across all four swabbed anatomical regions irrespective of health status. The most significant observed pattern was the difference between the global bacterial profiles of swabbed and tissue biopsy samples from the same individuals, being also consistent across different anatomical regions. Importantly, no statistically significant differences could be observed concerning the global bacterial communities, any of the bacterial species or the range of diversity indices used to compare between CRS and CRS-free individuals, and between two CRS phenotypes (without nasal polyps and with nasal polyps). Thus, the role of bacteria in the pathogenesis of sinusitis remains uncertain.", "author" : [ { "dropping-particle" : "", "family" : "Wos-Oxley", "given" : "Melissa L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaves-Moreno", "given" : "Diego", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "J\u00e1uregui", "given" : "Ruy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oxley", "given" : "Andrew P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kaspar", "given" : "Ursula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plumeier", "given" : "Iris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kahl", "given" : "Silke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rudack", "given" : "Claudia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Becker", "given" : "Karsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pieper", "given" : "Dietmar H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Environmental Microbiology", "id" : "ITEM-3", "issue" : "7", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "2259-2271", "title" : "Exploring the bacterial assemblages along the human nasal passage", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1186/gb-2014-15-5-r66", "ISBN" : "1465-6914 (Electronic)\\n1465-6906 (Linking)", "ISSN" : "1465-6914", "PMID" : "24887286", "abstract" : "BACKGROUND: Determining bacterial abundance variation is the first step in understanding bacterial similarity between individuals. Categorization of bacterial communities into groups or community classes is the subsequent step in describing microbial distribution based on abundance patterns. Here, we present an analysis of the groupings of bacterial communities in stool, nasal, skin, vaginal and oral habitats in a healthy cohort of 236 subjects from the Human Microbiome Project. RESULTS: We identify distinct community group patterns in the anterior nares, four skin sites, and vagina at the genus level. We also confirm three enterotypes previously identified in stools. We identify two clusters with low silhouette values in most oral sites, in which bacterial communities are more homogeneous. Subjects sharing a community class in one habitat do not necessarily share a community class in another, except in the three vaginal sites and the symmetric habitats of the left and right retroauricular creases. Demographic factors, including gender, age, and ethnicity, significantly influence community composition in several habitats. Community classes in the vagina, retroauricular crease and stool are stable over approximately 200 days. CONCLUSION: The community composition, association of demographic factors with community classes, and demonstration of community stability deepen our understanding of the variability and dynamics of human microbiomes. This also has significant implications for experimental designs that seek microbial correlations with clinical phenotypes.", "author" : [ { "dropping-particle" : "", "family" : "Zhou", "given" : "Yanjiao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mihindukulasuriya", "given" : "Kathie a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Hongyu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosa", "given" : "Patricio S", "non-dropping-particle" : "La", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wylie", "given" : "Kristine M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "John C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kota", "given" : "Karthik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shannon", "given" : "William D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitreva", "given" : "Makedonka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome biology", "id" : "ITEM-4", "issue" : "5", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "R66", "publisher" : "BioMed Central", "title" : "Exploration of bacterial community classes in major human habitats.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^29,43,48,49", "plainTextFormattedCitation" : "29,43,48,49", "previouslyFormattedCitation" : "^29,43,48,49" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }29,43,48,49. The nasopharynx is located deeper in the nasal cavity and is covered with stratified squamous epithelium with patches of respiratory epithelial cells. The bacterial community composition in the nasopharynx is more diverse than in the anterior partsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.chom.2013.11.005", "ISBN" : "2122633255", "ISSN" : "19313128", "PMID" : "24331461", "abstract" : "The indigenous microbiota of the nasal cavity plays important roles in human health and disease. Patterns of spatial variation in microbiota composition may help explain Staphylococcus aureus colonization and reveal interspecies and species-host interactions. To assess the biogeography of the nasal microbiota, we sampled healthy subjects, representing both S. aureus carriers and noncarriers at three nasal sites (anterior naris, middle meatus, and sphenoethmoidal recess). Phylogenetic compositional and sparse linear discriminant analyses revealed communities that differed according to site epithelium type and S. aureus culture-based carriage status. Corynebacterium accolens and C. pseudodiphtheriticum were identified as the most important microbial community determinants of S. aureus carriage, and competitive interactions were only evident at sites with ciliated pseudostratified columnar epithelium. In vitro cocultivation experiments provided supporting evidence of interactions among these species. These results highlight spatial variation in nasal microbial communities and differences in community composition between S. aureus carriers and noncarriers. ?? 2013 Elsevier Inc.", "author" : [ { "dropping-particle" : "", "family" : "Yan", "given" : "Miling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pamp", "given" : "S\u00fcnje J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukuyama", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hwang", "given" : "Peter H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Do Yeon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holmes", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Relman", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell Host and Microbe", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "12", "11" ] ] }, "page" : "631-640", "title" : "Nasal microenvironments and interspecific interactions influence nasal microbiota complexity and S. aureus carriage", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵⁰", "plainTextFormattedCitation" : "50", "previouslyFormattedCitation" : "⁵⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }50 and demonstrates considerable overlap with the anterior nares; it also contains Moraxella spp., Staphylococcus spp. and Corynebacterium spp. However, other bacteria more typically inhabit the nasopharyngeal niche, notably Dolosigranulum spp., Haemophilus spp. and Streptococcus spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201407-1240OC", "ISBN" : "2010081269", "ISSN" : "1535-4970", "PMID" : "25329446", "abstract" : "RATIONALE Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. OBJECTIVES To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. METHODS Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. MEASUREMENTS AND MAIN RESULTS Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. CONCLUSIONS These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with (NCT00189020).", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsivtsivadze", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1283-92", "title" : "Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.", "type" : "article-journal", "volume" : "190" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. Infants born by Caesarian section showed a delay in overall development of respiratory microbiota profiles with specifically reduced colonization with health-associated commensals like Corynebacterium and Dolosigranulum, thereby possibly influencing respiratory health later in life.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levin", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houten", "given" : "Marlies A.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalkman", "given" : "Gino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A.A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "Pieter-Kees C.M.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pernet", "given" : "Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EBioMedicine", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "336-345", "title" : "Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.jaci.2014.12.1909", "ISBN" : "0091-6749", "ISSN" : "10976825", "PMID" : "25636948", "abstract" : "Background Understanding the composition and dynamics of the upper respiratory tract microbiota in healthy infants is a prerequisite to investigate the role of the microbiota in patients with respiratory diseases. This is especially true in early life, when the immune system is in development. Objective We sought to describe the dynamics of the upper respiratory tract microbiota in healthy infants within the first year of life. Methods After exclusion of low-quality samples, microbiota characterization was performed by using 16S rDNA pyrosequencing of 872 nasal swabs collected biweekly from 47 unselected infants. Results Bacterial density increased and diversity decreased within the first year of life (R² = 0.95 and 0.73, respectively). A distinct profile for the first 3 months of life was found with increased relative abundances of Staphlyococcaceae and Corynebacteriaceae (exponential decay: R² = 0.94 and 0.96, respectively). In addition, relative bacterial abundance and composition differed significantly from summer to winter months. The individual composition of the microbiota changed with increasing time intervals between samples and was best modeled by an exponential function (R² = 0.97). Within-subject dissimilarity in a 2-week time interval was consistently lower than that between subjects, indicating a personalized microbiota. Conclusion This study reveals age and seasonality as major factors driving the composition of the nasal microbiota within the first year of life. A subject's microbiota is personalized but dynamic throughout the first year. These data are indispensable to interpretation of cross-sectional studies and investigation of the role of the microbiota in both healthy subjects and patients with respiratory diseases. They might also serve as a baseline for future intervention studies.", "author" : [ { "dropping-particle" : "", "family" : "Mika", "given" : "Moana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mack", "given" : "Ines", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Korten", "given" : "Insa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qi", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aebi", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frey", "given" : "Urs", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Latzin", "given" : "Philipp", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hilty", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Allergy and Clinical Immunology", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "905-912.e11", "publisher" : "Elsevier Inc.", "title" : "Dynamics of the nasal microbiota in infancy: A prospective cohort study", "type" : "article-journal", "volume" : "135" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1016/j.chom.2015.03.008", "ISSN" : "1934-6069", "PMID" : "25865368", "abstract" : "The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. 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Young children are at high risk of respiratory illness, yet the composition of their URT microbiota is not well understood. Microbial profiling of the respiratory tract has traditionally focused on culturing common respiratory pathogens, whereas recent culture-independent microbiome profiling can only report the relative abundance of bacterial populations. In the current study, we used both molecular profiling of the bacterial 16S rRNA gene and laboratory culture to examine the bacterial diversity from the oropharynx and nasopharynx of 51 healthy children with a median age of 1.1 years (range 1-4.5 years) along with 19 accompanying parents. The resulting profiles suggest that in young children the nasopharyngeal microbiota, much like the gastrointestinal tract microbiome, changes from an immature state, where it is colonized by a few dominant taxa, to a more diverse state as it matures to resemble the adult microbiota. Importantly, this difference in bacterial diversity between adults and children accompanies a change in bacterial load of three orders of magnitude. This indicates that the bacterial communities in the nasopharynx of young children have a fundamentally different structure from those in adults and suggests that maturation of this community occurs sometime during the first few years of life, a period that includes ages at which children are at the highest risk for respiratory disease.", "author" : [ { "dropping-particle" : "", "family" : "Stearns", "given" : "Jennifer C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davidson", "given" : "Carla J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McKeon", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whelan", "given" : "Fiona J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fontes", "given" : "Michelle E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schryvers", "given" : "Anthony B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowdish", "given" : "Dawn M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kellner", "given" : "James D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Surette", "given" : "Michael G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME journal", "id" : "ITEM-3", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5" ] ] }, "page" : "1246-59", "publisher" : "Nature Publishing Group", "title" : "Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1038/ismej.2015.99", "ISSN" : "1751-7362", "PMID" : "26151645", "abstract" : "Bacterial pneumonia is a major cause of morbidity and mortality in elderly. We hypothesize that dysbiosis between regular residents of the upper respiratory tract (URT) microbiome, that is balance between commensals and potential pathogens, is involved in pathogen overgrowth and consequently disease. We compared oropharyngeal microbiota of elderly pneumonia patients (n=100) with healthy elderly (n=91) by 16S-rRNA-based sequencing and verified our findings in young adult pneumonia patients (n=27) and young healthy adults (n=187). Microbiota profiles differed significantly between elderly pneumonia patients and healthy elderly (PERMANOVA, P<0.0005). Highly similar differences were observed between microbiota profiles of young adult pneumonia patients and their healthy controls. Clustering resulted in 11 (sub)clusters including 95% (386/405) of samples. We observed three microbiota profiles strongly associated with pneumonia (P<0.05) and either dominated by lactobacilli (n=11), Rothia (n=51) or Streptococcus (pseudo)pneumoniae (n=42). In contrast, three other microbiota clusters (in total n=183) were correlated with health (P<0.05) and were all characterized by more diverse profiles containing higher abundances of especially Prevotella melaninogenica, Veillonella and Leptotrichia. For the remaining clusters (n=99), the association with health or disease was less clear. A decision tree model based on the relative abundance of five bacterial community members in URT microbiota showed high specificity of 95% and sensitivity of 84% (89% and 73%, respectively, after cross-validation) for differentiating pneumonia patients from healthy individuals. These results suggest that pneumonia in elderly and young adults is associated with dysbiosis of the URT microbiome with bacterial overgrowth of single species and absence of distinct anaerobic bacteria. Whether the observed microbiome changes are a cause or a consequence of the development of pneumonia or merely coincide with disease status remains a question for future research.The ISME Journal advance online publication, 7 July 2015; doi:10.1038/ismej.2015.99.", "author" : [ { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter a a", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huijskens", "given" : "Elisabeth G W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wyllie", "given" : "Anne L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergh", "given" : "Menno R", "non-dropping-particle" : "van den", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Xinhui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzci\u0144ski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonten", "given" : "Marc J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossen", "given" : "John W a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth a M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME Journal", "id" : "ITEM-4", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1", "7" ] ] }, "page" : "97-108", "title" : "Dysbiosis of upper respiratory tract microbiota in elderly pneumonia patients", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^39,41,51,52", "plainTextFormattedCitation" : "39,41,51,52", "previouslyFormattedCitation" : "^39,41,51,52" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }39,41,51,52. In addition to bacterial inhabitants, PCR-based studies suggest extensive presence of viral ‘pathogens’ in the URT. These studies have reported an overall respiratory virus detection rate of 67% in healthy asymptomatic children, including human rhinovirus, human bocavirus, polyomaviruses, human adenovirus and human coronavirusADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0017035", "ISBN" : "1932-6203 (Electronic)\\n1932-6203 (Linking)", "ISSN" : "1932-6203", "PMID" : "21386965", "abstract" : "The nasopharynx is the ecological niche for many commensal bacteria and for potential respiratory or invasive pathogens like Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. Disturbance of a balanced nasopharyngeal (NP) microbiome might be involved in the onset of symptomatic infections with these pathogens, which occurs primarily in fall and winter. It is unknown whether seasonal infection patterns are associated with concomitant changes in NP microbiota. As young children are generally prone to respiratory and invasive infections, we characterized the NP microbiota of 96 healthy children by barcoded pyrosequencing of the V5-V6 hypervariable region of the 16S-rRNA gene, and compared microbiota composition between children sampled in winter/fall with children sampled in spring. The approximately 1,000,000 sequences generated represented 13 taxonomic phyla and approximately 250 species-level phyla types (OTUs). The 5 most predominant phyla were Proteobacteria (64%), Firmicutes (21%), Bacteroidetes (11%), Actinobacteria (3%) and Fusobacteria (1,4%) with Moraxella, Haemophilus, Streptococcus, Flavobacteria, Dolosigranulum, Corynebacterium and Neisseria as predominant genera. The inter-individual variability was that high that on OTU level a core microbiome could not be defined. Microbiota profiles varied strongly with season, with in fall/winter a predominance of Proteobacteria (relative abundance (% of all sequences): 75% versus 51% in spring) and Fusobacteria (absolute abundance (% of children): 14% versus 2% in spring), and in spring a predominance of Bacteroidetes (relative abundance: 19% versus 3% in fall/winter, absolute abundance: 91% versus 54% in fall/winter), and Firmicutes. The latter increase is mainly due to (Brevi)bacillus and Lactobacillus species (absolute abundance: 96% versus 10% in fall/winter) which are like Bacteroidetes species generally related to healthy ecosystems. The observed seasonal effects could not be attributed to recent antibiotics or viral co-infection.The NP microbiota of young children is highly diverse and appears different between seasons. These differences seem independent of antibiotic use or viral co-infection.", "author" : [ { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huse", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossen", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gils", "given" : "Elske", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruin", "given" : "Jacob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonten", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Semple", "given" : "Malcolm", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2011", "2", "28" ] ] }, "page" : "e17035", "title" : "Variability and Diversity of Nasopharyngeal Microbiota in Children: A Metagenomic Analysis", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1371/journal.pone.0047711", "ISBN" : "1932-6203", "ISSN" : "1932-6203", "PMID" : "23082199", "abstract" : "BACKGROUND: High rates of potentially pathogenic bacteria and respiratory viruses can be detected in the upper respiratory tract of healthy children. Investigating presence of and associations between these pathogens in healthy individuals is still a rather unexplored field of research, but may have implications for interpreting findings during disease.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We selected 986 nasopharyngeal samples from 433 6- to 24-month-old healthy children that had participated in a randomized controlled trial. We determined the presence of 20 common respiratory viruses using real-time PCR. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus were identified by conventional culture methods. Information on risk factors was obtained by questionnaires. We performed multivariate logistic regression analyses followed by partial correlation analysis to identify the overall pattern of associations. S. pneumoniae colonization was positively associated with the presence of H. influenzae (adjusted odds ratio 1.60, 95% confidence interval 1.18-2.16), M. catarrhalis (1.78, 1.29-2.47), human rhinoviruses (1.63, 1.19-2.22) and enteroviruses (1.97, 1.26-3.10), and negatively associated with S. aureus presence (0.59, 0.35-0.98). H. influenzae was positively associated with human rhinoviruses (1.63, 1.22-2.18) and respiratory syncytial viruses (2.78, 1.06-7.28). M. catarrhalis colonization was positively associated with coronaviruses (1.99, 1.01-3.93) and adenoviruses (3.69, 1.29-10.56), and negatively with S. aureus carriage (0.42, 0.25-0.69). We observed a strong positive association between S. aureus and influenza viruses (4.87, 1.59-14.89). In addition, human rhinoviruses and enteroviruses were positively correlated (2.40, 1.66-3.47), as were enteroviruses and human bocavirus, WU polyomavirus, parainfluenza viruses, and human parechovirus. A negative association was observed between human rhinoviruses and coronaviruses.\\n\\nCONCLUSIONS/SIGNIFICANCE: Our data revealed high viral and bacterial prevalence rates and distinct bacterial-bacterial, viral-bacterial and viral-viral associations in healthy children, hinting towards the complexity and potential dynamics of microbial communities in the upper respiratory tract. 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Recent advances in metagenomics, however, have revealed that the entire respiratory virome contains many other viruses as well. For example, the recently discovered Anelloviridae have been identified as the most prevalent virus family in the URT viromeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cmi.2016.01.006", "ISSN" : "1469-0691", "PMID" : "26802214", "abstract" : "Severe acute respiratory infection (SARI) in children is thought to be mainly caused by infection with various viruses, some of which have been well characterized; however, analyses of respiratory tract viromes among children with SARI versus those without are limited. In this study, nasopharyngeal swabs from children with and without SARI (135 versus 15) were collected in China between 2008 and 2010 and subjected to multiplex metagenomic analyses using a next-generation sequencing platform. The results show that members of the Paramyxoviridae, Coronaviridae, Parvoviridae, Orthomyxoviridae, Picornaviridae, Anelloviridae and Adenoviridae families represented the most abundant species identified (>50% genome coverage) in the respiratory tracts of children with SARI. The viral population found in the respiratory tracts of children without SARI was less diverse and mainly dominated by the Anelloviridae family with only a small proportion of common epidemic respiratory viruses. Several almost complete viral genomes were assembled, and the genetic diversity was determined among several samples based on next-generation sequencing. This research provides comprehensive mapping of the viromes of children with SARI and indicates high heterogeneity of known viruses present in the childhood respiratory tract, which may benefit the detection and prevention of respiratory disease.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhu", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lu", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zou", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xie", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2016", "5" ] ] }, "note" : "NP, including 35 healthy \nThe viral composition in children without SARI was much less diverse with the majority of reads corresponding to 89.3% Anelloviridae family (mainly TTV and TTMV) . \nSick children Paramyxoviridae (RSV 48%, human parainfluenza viruses (HPIV) (2.0%)), Coronaviridae (coronavirus 24%) Anelloviridae (TTV 17%), \u00a0Parvoviridae, \n\u00a0Higher diversity in diseased cohort, potentially because of intra-individual differences observed in the larger group", "page" : "458.e1-9", "title" : "Metagenomic analysis of viral genetic diversity in respiratory samples from children with severe acute respiratory infection in China.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1371/journal.pone.0027735", "ISSN" : "1932-6203", "author" : [ { "dropping-particle" : "", "family" : "Wylie", "given" : "Kristine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mihindukulasuriya", "given" : "Kathie A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Storch", "given" : "Gregory A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Zhang", "given" : "Chiyu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2012", "6", "13" ] ] }, "page" : "e27735", "publisher" : "Public Library of Science", "title" : "Sequence Analysis of the Human Virome in Febrile and Afebrile Children", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^54,55", "plainTextFormattedCitation" : "54,55", "previouslyFormattedCitation" : "^54,55" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }54,55. Moreover, the healthy URT also harbours a mycobiota, including Aspergillus spp., Penicillium spp., Candida spp. and Alternaria spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.17795/jhealthscope-30033", "ISSN" : "2251-8959", "author" : [ { "dropping-particle" : "", "family" : "Eidi", "given" : "Samaneh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kamali", "given" : "Seyed Amir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hajari", "given" : "Zahra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fata", "given" : "Abdolmajid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farid Hosseini", "given" : "Reza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naseri", "given" : "Ali", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bakhshaee", "given" : "Mehdi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Health Scope", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "2", "15" ] ] }, "publisher" : "Zahedan University of Medical Sciences", "title" : "Nasal and Indoors Fungal Contamination in Healthy Subjects", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1164/rccm.201204-0693OC", "ISSN" : "1073-449X", "abstract" : "Rationale: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers.Objectives: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing.Methods: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover.Measurements and Main Results: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tra...", "author" : [ { "dropping-particle" : "", "family" : "Charlson", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "Joshua M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Ayannah S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yadav", "given" : "Anjana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "Andrew R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "Frederic D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2012", "9", "15" ] ] }, "page" : "536-545", "publisher" : "American Thoracic Society", "title" : "Lung-enriched Organisms and Aberrant Bacterial and Fungal Respiratory Microbiota after Lung Transplant", "type" : "article-journal", "volume" : "186" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^56,57", "plainTextFormattedCitation" : "56,57", "previouslyFormattedCitation" : "^56,57" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }56,57. Although the size of the respiratory mycobiome is unknown, the gut and skin mycobiome are approximated 0.1% and 3.9%, respectively, of the total microbiome in their corresponding nicheADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature08821", "ISBN" : "0028-0836", "ISSN" : "0028-0836", "PMID" : "20203603", "abstract" : "To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. 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}, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/nature13786", "ISSN" : "1476-4687", "PMID" : "25279917", "abstract" : "The varied topography of human skin offers a unique opportunity to study how the body's microenvironments influence the functional and taxonomic composition of microbial communities. Phylogenetic marker gene-based studies have identified many bacteria and fungi that colonize distinct skin niches. Here metagenomic analyses of diverse body sites in healthy humans demonstrate that local biogeography and strong individuality define the skin microbiome. We developed a relational analysis of bacterial, fungal and viral communities, which showed not only site specificity but also individual signatures. We further identified strain-level variation of dominant species as heterogeneous and multiphyletic. Reference-free analyses captured the uncharacterized metagenome through the development of a multi-kingdom gene catalogue, which was used to uncover genetic signatures of species lacking reference genomes. This work is foundational for human disease studies investigating inter-kingdom interactions, metabolic changes and strain tracking, and defines the dual influence of biogeography and individuality on microbial composition and function.", "author" : [ { "dropping-particle" : "", "family" : "Oh", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Byrd", "given" : "Allyson L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deming", "given" : "Clay", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conlan", "given" : "Sean", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "NISC Comparative Sequencing Program", "given" : "NISC Comparative Sequencing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Heidi H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Segre", "given" : "Julia A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-2", "issue" : "7520", "issued" : { "date-parts" : [ [ "2014", "10", "2" ] ] }, "page" : "59-64", "publisher" : "NIH Public Access", "title" : "Biogeography and individuality shape function in the human skin metagenome.", "type" : "article-journal", "volume" : "514" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^47,58", "plainTextFormattedCitation" : "47,58", "previouslyFormattedCitation" : "^47,58" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }47,58.Both environmental pressures as well as microbe-microbe and host-microbe interactions, influence the bacterial ecosystem composition in the human host, and as a consequence, its function. For a variety of macroscale ecosystems, such as forests and coral reefs, it is well established that greater biodiversity increases the efficiency by which ecological communities are capable of utilizing essential resourcesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature11148", "ISSN" : "1476-4687", "PMID" : "22678280", "abstract" : "The most unique feature of Earth is the existence of life, and the most extraordinary feature of life is its diversity. Approximately 9 million types of plants, animals, protists and fungi inhabit the Earth. So, too, do 7 billion people. Two decades ago, at the first Earth Summit, the vast majority of the world's nations declared that human actions were dismantling the Earth's ecosystems, eliminating genes, species and biological traits at an alarming rate. This observation led to the question of how such loss of biological diversity will alter the functioning of ecosystems and their ability to provide society with the goods and services needed to prosper.", "author" : [ { "dropping-particle" : "", "family" : "Cardinale", "given" : "Bradley J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duffy", "given" : "J Emmett", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gonzalez", "given" : "Andrew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hooper", "given" : "David U", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perrings", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Venail", "given" : "Patrick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Narwani", "given" : "Anita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mace", "given" : "Georgina M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tilman", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wardle", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kinzig", "given" : "Ann P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Daily", "given" : "Gretchen C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loreau", "given" : "Michel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grace", "given" : "James B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Larigauderie", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Srivastava", "given" : "Diane S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Naeem", "given" : "Shahid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7401", "issued" : { "date-parts" : [ [ "2012", "6", "6" ] ] }, "page" : "59-67", "title" : "Biodiversity loss and its impact on humanity.", "type" : "article-journal", "volume" : "486" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵⁹", "plainTextFormattedCitation" : "59", "previouslyFormattedCitation" : "⁵⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }59. In parallel, diversity of specific microscale ecosystems within the human host, such as the gut microbiota, has been associated with health outcomes. For example, increased intestinal bacterial diversity has been linked to the absence of inflammatory bowel disease, obesityADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.immuni.2014.05.013", "ISSN" : "1097-4180", "PMID" : "24950204", "abstract" : "The inflammatory bowel diseases (IBDs) are among the most closely studied chronic inflammatory disorders that involve environmental, host genetic, and commensal microbial factors. This combination of features has made IBD both an appropriate and a high-priority platform for translatable research in host-microbiome interactions. Decades of epidemiology have identified environmental risk factors, although most mechanisms of action remain unexplained. The genetic architecture of IBD has been carefully dissected in multiple large populations, identifying several responsible host epithelial and immune pathways but without yet a complete systems-level explanation. Most recently, the commensal gut microbiota have been found to be both ecologically and functionally perturbed during the disease, but with as-yet-unexplained heterogeneity among IBD subtypes and individual patients. IBD thus represents perhaps the most comprehensive current model for understanding the human microbiome's role in complex inflammatory disease. Here, we review the influences of the microbiota on IBD and its potential for translational medicine.", "author" : [ { "dropping-particle" : "", "family" : "Huttenhower", "given" : "Curtis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kostic", "given" : "Aleksandar D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xavier", "given" : "Ramnik J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Immunity", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2014", "6", "19" ] ] }, "page" : "843-54", "title" : "Inflammatory bowel disease as a model for translating the microbiome.", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶⁰", "plainTextFormattedCitation" : "60", "previouslyFormattedCitation" : "⁶⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }60, and resilience against acute infections by enteropathogensADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cmi.2015.09.004", "ISSN" : "1198743X", "PMID" : "26369602", "abstract" : "In mice, specific species composition of gut microbiota enhances susceptibility to Campylobacter jejuni but little is known about the specific composition of the human gut microbiota in providing protection from infections caused by enteropathogens. Healthy adult individuals, who travelled in groups from Sweden to destinations with an estimated high risk for acquisition of Campylobacter infection, were enrolled. Faecal samples, collected before travelling and after returning home, were cultured for bacterial enteropathogens, and analysed for Campylobacter by PCR and for the species composition of the microbiota by 16S amplicon massive parallel sequencing. The microbiota compositions were compared between persons who became infected during their travel and those who did not. A total of 63 participants completed the study; 14 became infected with Campylobacter, two with Salmonella and 47 remained negative for the enteropathogens tested. After exclusion of samples taken after antimicrobial treatment, 49 individuals were included in the final analyses. Intra-individual stability of the microbiota was demonstrated for samples taken before travelling. The original diversity of the faecal microbiota was significantly lower among individuals who later became infected compared with those who remained uninfected. The relative abundances of bacteria belonging to the family Lachnospiraceae, and more specifically its two genera Dorea and Coprococcus, were significantly higher among those who remained uninfected. The travel-related infection did not significantly modify the faecal microbiota composition. Species composition of human gut microbiota is important for colonization resistance to Campylobacter infection. Especially individuals with a lower diversity are more susceptible to Campylobacter infection.", "author" : [ { "dropping-particle" : "", "family" : "Kampmann", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dicksved", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Engstrand", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rautelin", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical Microbiology and Infection", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1" ] ] }, "page" : "61.e1-61.e8", "title" : "Composition of human faecal microbiota in resistance to Campylobacter infection", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶¹", "plainTextFormattedCitation" : "61", "previouslyFormattedCitation" : "⁶¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }61. Conversely, in other body sites, such as the vagina, low diversity is considered ‘healthy’ as it is associated with decreased incidences of bacterial vaginosisADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1056/NEJMoa043802", "ISSN" : "0028-4793", "abstract" : "Background Bacterial vaginosis affects millions of women and is associated with several serious health conditions. The cause of bacterial vaginosis remains poorly understood despite numerous studies based on cultures. Bacteria in microbial communities can be identified without cultivation by characterizing their ribosomal DNA (rDNA) sequences. Methods We identified bacteria in samples of vaginal fluid with a combination of broad-range polymerase-chain-reaction (PCR) amplification of 16S rDNA with clone analysis, bacterium-specific PCR assay of 16S rDNA, and fluorescence in situ hybridization (FISH) performed directly on vaginal fluid from 27 subjects with bacterial vaginosis and 46 without the condition. Twenty-one subjects were studied with the use of broad-range PCR of 16S rDNA, and 73 subjects were studied with the use of bacterium-specific PCR. Results Women without bacterial vaginosis had 1 to 6 vaginal bacterial species (phylotypes) in each sample (mean, 3.3), as detected by broad-range PCR of 16S r...", "author" : [ { "dropping-particle" : "", "family" : "Fredricks", "given" : "David N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fiedler", "given" : "Tina L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marrazzo", "given" : "Jeanne M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "New England Journal of Medicine", "id" : "ITEM-1", "issue" : "18", "issued" : { "date-parts" : [ [ "2005", "11", "3" ] ] }, "page" : "1899-1911", "publisher" : "Massachusetts Medical Society", "title" : "Molecular Identification of Bacteria Associated with Bacterial Vaginosis", "type" : "article-journal", "volume" : "353" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1073/pnas.1002611107", "ISSN" : "0027-8424", "PMID" : "20534435", "abstract" : "The means by which vaginal microbiomes help prevent urogenital diseases in women and maintain health are poorly understood. To gain insight into this, the vaginal bacterial communities of 396 asymptomatic North American women who represented four ethnic groups (white, black, Hispanic, and Asian) were sampled and the species composition characterized by pyrosequencing of barcoded 16S rRNA genes. The communities clustered into five groups: four were dominated by Lactobacillus iners, L. crispatus, L. gasseri, or L. jensenii, whereas the fifth had lower proportions of lactic acid bacteria and higher proportions of strictly anaerobic organisms, indicating that a potential key ecological function, the production of lactic acid, seems to be conserved in all communities. The proportions of each community group varied among the four ethnic groups, and these differences were statistically significant [\u03c7(2)(10) = 36.8, P < 0.0001]. Moreover, the vaginal pH of women in different ethnic groups also differed and was higher in Hispanic (pH 5.0 \u00b1 0.59) and black (pH 4.7 \u00b1 1.04) women as compared with Asian (pH 4.4 \u00b1 0.59) and white (pH 4.2 \u00b1 0.3) women. Phylotypes with correlated relative abundances were found in all communities, and these patterns were associated with either high or low Nugent scores, which are used as a factor for the diagnosis of bacterial vaginosis. The inherent differences within and between women in different ethnic groups strongly argues for a more refined definition of the kinds of bacterial communities normally found in healthy women and the need to appreciate differences between individuals so they can be taken into account in risk assessment and disease diagnosis.", "author" : [ { "dropping-particle" : "", "family" : "Ravel", "given" : "Jacques", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gajer", "given" : "Pawel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abdo", "given" : "Zaid", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schneider", "given" : "G Maria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koenig", "given" : "Sara S K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCulle", "given" : "Stacey L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Karlebach", "given" : "Shara", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gorle", "given" : "Reshma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russell", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tacket", "given" : "Carol O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brotman", "given" : "Rebecca M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "Catherine C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ault", "given" : "Kevin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peralta", "given" : "Ligia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forney", "given" : "Larry J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences", "id" : "ITEM-2", "issue" : "Supplement_1", "issued" : { "date-parts" : [ [ "2011", "3", "15" ] ] }, "page" : "4680-4687", "publisher" : "National Academy of Sciences", "title" : "Vaginal microbiome of reproductive-age women", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^62,63", "plainTextFormattedCitation" : "62,63", "previouslyFormattedCitation" : "^62,63" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }62,63 and premature birthADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1073/pnas.1517939112", "ISSN" : "0027-8424", "PMID" : "26515091", "author" : [ { "dropping-particle" : "", "family" : "DiGiulio", "given" : "Daniel B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stevenson", "given" : "David K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shaw", "given" : "Gary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lyell", "given" : "Deirdre J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Relman", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences", "id" : "ITEM-1", "issue" : "47", "issued" : { "date-parts" : [ [ "2015", "11", "24" ] ] }, "page" : "E6415-E6415", "publisher" : "National Academy of Sciences", "title" : "Reply to Keelan and Payne: Microbiota-related pathways for preterm birth", "type" : "article-journal", "volume" : "112" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶⁴", "plainTextFormattedCitation" : "64", "previouslyFormattedCitation" : "⁶⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }64, which underlines the niche-specific impact of biodiversity on human health. In the respiratory tract, evidence indicates that acute URT infections, such as acute otitis media (AOM)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/infdis/jis024", "ISSN" : "1537-6613", "PMID" : "22351941", "abstract" : "BACKGROUND Interspecies interactions of the nasopharyngeal microbiota are likely to be involved in the pathogenesis of acute otitis media (AOM). Capturing the breadth of microbial interactions requires a detailed description of the microbiota during health and AOM. METHODS The nasopharyngeal microbiota of 163 infants with (n = 153) or without (n = 10) AOM was characterized using nasopharyngeal swabs and multiplexed pyrosequencing of 16S rRNA. Nasopharyngeal swab specimens were collected during 4 winter seasons from 2004 through 2010 for infants with AOM and during 2010 for controls. RESULTS Fifty-eight bacterial families were identified, of which Moraxellaceae, Streptococcaceae, and Pasteurellaceae were the most frequent. Commensal families were less prevalent in infants with AOM than in controls. In infants with AOM, prior exposure to antimicrobials and administration of the heptavalent conjugated pneumococcal polysaccharide vaccine (PCV7) were also associated with reduced prevalence of distinct commensal families (Streptococcaceae and Corynebacteriaceae). In addition, antimicrobial exposure increased the prevalence of Enterobacteriaceae and the abundance of Pasteurellaceae. Other factors, such as age, sex, day care, and a history of recurrent AOM, did not influence the microbiota. CONCLUSIONS Infants' nasopharyngeal microbiota undergoes significant changes during AOM and after exposure to antimicrobials and PCV7, which is mainly attributable to reduced prevalence of commensal bacterial families.", "author" : [ { "dropping-particle" : "", "family" : "Hilty", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qi", "given" : "Weihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brugger", "given" : "Silvio D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frei", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Agyeman", "given" : "Philipp", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frey", "given" : "Pascal M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Aebi", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M\u00fchlemann", "given" : "Kathrin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of infectious diseases", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2012", "4", "1" ] ] }, "page" : "1048-55", "title" : "Nasopharyngeal microbiota in infants with acute otitis media.", "type" : "article-journal", "volume" : "205" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/AEM.01051-12", "ISBN" : "1098-5336 (Electronic)\\n0099-2240 (Linking)", "ISSN" : "00992240", "PMID" : "22752171", "abstract" : "The composition of the upper respiratory tract microbial community may influence the risk for colonization by the acute otitis media (AOM) pathogens Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. We used culture-independent methods to describe upper respiratory tract microbial communities in healthy children and children with upper respiratory tract infection with and without concurrent AOM. Nasal swabs and data were collected in a cross-sectional study of 240 children between 6 months and 3 years of age. Swabs were cultured for S. pneumoniae, and real-time PCR was used to identify S. pneumoniae, H. influenzae, and M. catarrhalis. The V1-V2 16S rRNA gene regions were sequenced using 454 pyrosequencing. Microbial communities were described using a taxon-based approach. Colonization by S. pneumoniae, H. influenzae, and M. catarrhalis was associated with lower levels of diversity in upper respiratory tract flora. We identified commensal taxa that were negatively associated with colonization by each AOM bacterial pathogen and with AOM. The balance of these relationships differed according to the colonizing AOM pathogen and history of antibiotic use. Children with antibiotic use in the past 6 months and a greater abundance of taxa, including Lactococcus and Propionibacterium, were less likely to have AOM than healthy children (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25 to 0.85). Children with no antibiotic use in the past 6 months, a low abundance of Streptococcus and Haemophilus, and a high abundance of Corynebacterium and Dolosigranulum were less likely to have AOM (OR, 0.51; 95% CI, 0.31 to 0.83). An increased understanding of polymicrobial interactions will facilitate the development of effective AOM prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Pettigrew", "given" : "Melinda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laufer", "given" : "Alison S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gent", "given" : "Janneane F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fennie", "given" : "Kristopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metlay", "given" : "Joshua P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Applied and Environmental Microbiology", "id" : "ITEM-2", "issue" : "17", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "6262-6270", "title" : "Upper respiratory tract microbial communities, acute otitis media pathogens, and antibiotic use in healthy and sick children", "type" : "article-journal", "volume" : "78" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^29,65", "plainTextFormattedCitation" : "29,65", "previouslyFormattedCitation" : "^29,65" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }29,65, and mucosal inflammation in chronic rhinosinusitisADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/scitranslmed.3003783", "ISSN" : "1946-6242", "PMID" : "22972842", "abstract" : "Persistent mucosal inflammation and microbial infection are characteristics of chronic rhinosinusitis (CRS). Mucosal microbiota dysbiosis is found in other chronic inflammatory diseases; however, the relationship between sinus microbiota composition and CRS is unknown. Using comparative microbiome profiling of a cohort of CRS patients and healthy subjects, we demonstrate that the sinus microbiota of CRS patients exhibits significantly reduced bacterial diversity compared with that of healthy controls. In our cohort of CRS patients, multiple, phylogenetically distinct lactic acid bacteria were depleted concomitant with an increase in the relative abundance of a single species, Corynebacterium tuberculostearicum. We recapitulated the conditions observed in our human cohort in a murine model and confirmed the pathogenic potential of C. tuberculostearicum and the critical necessity for a replete mucosal microbiota to protect against this species. Moreover, Lactobacillus sakei, which was identified from our comparative microbiome analyses as a potentially protective species, defended against C. tuberculostearicum sinus infection, even in the context of a depleted sinus bacterial community. These studies demonstrate that sinus mucosal health is highly dependent on the composition of the resident microbiota as well as identify both a new sino-pathogen and a strong bacterial candidate for therapeutic intervention.", "author" : [ { "dropping-particle" : "", "family" : "Abreu", "given" : "Nicole A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nagalingam", "given" : "Nabeetha A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Song", "given" : "Yuanlin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roediger", "given" : "Frederick C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pletcher", "given" : "Steven D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldberg", "given" : "Andrew N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Lynch", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science translational medicine", "id" : "ITEM-1", "issue" : "151", "issued" : { "date-parts" : [ [ "2012", "9", "12" ] ] }, "page" : "151ra124", "title" : "Sinus microbiome diversity depletion and Corynebacterium tuberculostearicum enrichment mediates rhinosinusitis.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶⁶", "plainTextFormattedCitation" : "66", "previouslyFormattedCitation" : "⁶⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }66 are associated with decreased diversity of local bacterial communities. Other studies, however, report a less clear association between diversity and respiratory health, which suggests that the bacterial community composition, within a niche-specific ecological context, also impacts respiratory healthADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ismej.2015.99", "ISSN" : "1751-7362", "PMID" : "26151645", "abstract" : "Bacterial pneumonia is a major cause of morbidity and mortality in elderly. We hypothesize that dysbiosis between regular residents of the upper respiratory tract (URT) microbiome, that is balance between commensals and potential pathogens, is involved in pathogen overgrowth and consequently disease. We compared oropharyngeal microbiota of elderly pneumonia patients (n=100) with healthy elderly (n=91) by 16S-rRNA-based sequencing and verified our findings in young adult pneumonia patients (n=27) and young healthy adults (n=187). Microbiota profiles differed significantly between elderly pneumonia patients and healthy elderly (PERMANOVA, P<0.0005). Highly similar differences were observed between microbiota profiles of young adult pneumonia patients and their healthy controls. Clustering resulted in 11 (sub)clusters including 95% (386/405) of samples. We observed three microbiota profiles strongly associated with pneumonia (P<0.05) and either dominated by lactobacilli (n=11), Rothia (n=51) or Streptococcus (pseudo)pneumoniae (n=42). In contrast, three other microbiota clusters (in total n=183) were correlated with health (P<0.05) and were all characterized by more diverse profiles containing higher abundances of especially Prevotella melaninogenica, Veillonella and Leptotrichia. For the remaining clusters (n=99), the association with health or disease was less clear. A decision tree model based on the relative abundance of five bacterial community members in URT microbiota showed high specificity of 95% and sensitivity of 84% (89% and 73%, respectively, after cross-validation) for differentiating pneumonia patients from healthy individuals. These results suggest that pneumonia in elderly and young adults is associated with dysbiosis of the URT microbiome with bacterial overgrowth of single species and absence of distinct anaerobic bacteria. Whether the observed microbiome changes are a cause or a consequence of the development of pneumonia or merely coincide with disease status remains a question for future research.The ISME Journal advance online publication, 7 July 2015; doi:10.1038/ismej.2015.99.", "author" : [ { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter a a", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huijskens", "given" : "Elisabeth G W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wyllie", "given" : "Anne L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergh", "given" : "Menno R", "non-dropping-particle" : "van den", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Xinhui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzci\u0144ski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bonten", "given" : "Marc J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossen", "given" : "John W a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth a M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME Journal", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1", "7" ] ] }, "page" : "97-108", "title" : "Dysbiosis of upper respiratory tract microbiota in elderly pneumonia patients", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵²", "plainTextFormattedCitation" : "52", "previouslyFormattedCitation" : "⁵²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }52. Moreover, certain microbiota members, so called ‘keystone species’, may have exceptionally large beneficial effects on ecosystem balance, function and healthADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2014.09.053", "ISSN" : "1097-4172", "PMID" : "25417156", "abstract" : "Host genetics and the gut microbiome can both influence metabolic phenotypes. However, whether host genetic variation shapes the gut microbiome and interacts with it to affect host phenotype is unclear. Here, we compared microbiotas across >1,000 fecal samples obtained from the TwinsUK population, including 416 twin pairs. We identified many microbial taxa whose abundances were influenced by host genetics. The most heritable taxon, the family Christensenellaceae, formed a co-occurrence network with other heritable Bacteria and with methanogenic Archaea. Furthermore, Christensenellaceae and its partners were enriched in individuals with low body mass index (BMI). An obese-associated microbiome was amended with Christensenella minuta, a cultured member of the Christensenellaceae, and transplanted to germ-free mice. C. minuta amendment reduced weight gain and altered the microbiome of recipient mice. Our findings indicate that host genetics influence the composition of the human gut microbiome and can do so in ways that impact host metabolism.", "author" : [ { "dropping-particle" : "", "family" : "Goodrich", "given" : "Julia K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Waters", "given" : "Jillian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Poole", "given" : "Angela C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sutter", "given" : "Jessica L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koren", "given" : "Omry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blekhman", "given" : "Ran", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beaumont", "given" : "Michelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Treuren", "given" : "William", "non-dropping-particle" : "Van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "Rob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Jordana T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spector", "given" : "Timothy D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clark", "given" : "Andrew G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ley", "given" : "Ruth E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "11", "6" ] ] }, "page" : "789-99", "title" : "Human genetics shape the gut microbiome.", "type" : "article-journal", "volume" : "159" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶⁷", "plainTextFormattedCitation" : "67", "previouslyFormattedCitation" : "⁶⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }67. Potential keystone species among the URT microbiota are Dolosigranulum spp. and Corynebacterium spp. as they have been strongly associated with respiratory health and exclusion of potential pathogens, notably Streptococcus pneumoniae, in multiple epidemiological and mechanistic studiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201407-1240OC", "ISBN" : "2010081269", "ISSN" : "1535-4970", "PMID" : "25329446", "abstract" : "RATIONALE Many bacterial pathogens causing respiratory infections in children are common residents of the respiratory tract. Insight into bacterial colonization patterns and microbiota stability at a young age might elucidate healthy or susceptible conditions for development of respiratory disease. OBJECTIVES To study bacterial succession of the respiratory microbiota in the first 2 years of life and its relation to respiratory health characteristics. METHODS Upper respiratory microbiota profiles of 60 healthy children at the ages of 1.5, 6, 12, and 24 months were characterized by 16S-based pyrosequencing. We determined consecutive microbiota profiles by machine-learning algorithms and validated the findings cross-sectionally in an additional cohort of 140 children per age group. MEASUREMENTS AND MAIN RESULTS Overall, we identified eight distinct microbiota profiles in the upper respiratory tract of healthy infants. Profiles could already be identified at 1.5 months of age and were associated with microbiota stability and change over the first 2 years of life. More stable patterns were marked by early presence and high abundance of Moraxella and Corynebacterium/Dolosigranulum and were positively associated with breastfeeding in the first period of life and with lower rates of parental-reported respiratory infections in the consecutive periods. Less stable profiles were marked by high abundance of Haemophilus or Streptococcus. CONCLUSIONS These findings provide novel insights into microbial succession in the respiratory tract in infancy and link early-life profiles to microbiota stability and respiratory health characteristics. New prospective studies should elucidate potential implications of our findings for early diagnosis and prevention of respiratory infections. Clinical trial registered with (NCT00189020).", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsivtsivadze", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Montijn", "given" : "Roy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "1283-92", "title" : "Early respiratory microbiota composition determines bacterial succession patterns and respiratory health in children.", "type" : "article-journal", "volume" : "190" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/mBio.01725-15", "ISSN" : "2150-7511", "PMID" : "26733066", "abstract" : "UNLABELLED Bacterial interspecies interactions play clinically important roles in shaping microbial community composition. We observed that Corynebacterium spp. are overrepresented in children free of Streptococcus pneumoniae (pneumococcus), a common pediatric nasal colonizer and an important infectious agent. Corynebacterium accolens, a benign lipid-requiring species, inhibits pneumococcal growth during in vitro cocultivation on medium supplemented with human skin surface triacylglycerols (TAGs) that are likely present in the nostrils. This inhibition depends on LipS1, a TAG lipase necessary for C. accolens growth on TAGs such as triolein. We determined that C. accolens hydrolysis of triolein releases oleic acid, which inhibits pneumococcus, as do other free fatty acids (FFAs) that might be released by LipS1 from human skin surface TAGs. Our results support a model in which C. accolens hydrolyzes skin surface TAGS in vivo releasing antipneumococcal FFAs. These data indicate that C. accolens may play a beneficial role in sculpting the human microbiome. IMPORTANCE Little is known about how harmless Corynebacterium species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites. We show that Corynebacterium accolens, a common benign nasal bacterium, modifies its local habitat in vitro as it inhibits growth of Streptococcus pneumoniae by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary C. accolens lipase required for this activity. We postulate a model in which higher numbers of C. accolens cells deter/limit S. pneumoniae nostril colonization, which might partly explain why children without S. pneumoniae colonization have higher levels of nasal Corynebacterium. This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future in vivo studies to determine whether habitat modification by C. accolens could be promoted to control pathogen colonization.", "author" : [ { "dropping-particle" : "", "family" : "Bomar", "given" : "Lindsey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brugger", "given" : "Silvio D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yost", "given" : "Brian H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Sean S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lemon", "given" : "Katherine P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1", "5" ] ] }, "page" : "e01725-15", "publisher" : "American Society for Microbiology (ASM)", "title" : "Corynebacterium accolens Releases Antipneumococcal Free Fatty Acids from Human Nostril and Skin Surface Triacylglycerols.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1128/mBio.00245-10", "ISSN" : "2150-7511", "PMID" : "21285435", "abstract" : "Streptococcus pneumoniae asymptomatically colonizes the upper respiratory tract of children and is a frequent cause of otitis media. Patterns of microbial colonization likely influence S. pneumoniae colonization and otitis media susceptibility. This study compared microbial communities in children with and without otitis media. Nasal swabs and clinical and demographic data were collected in a cross-sectional study of Philadelphia, PA, children (6 to 78 months) (n=108) during the 2008-2009 winter respiratory virus season. Swabs were cultured for S. pneumoniae. DNA was extracted from the swabs; 16S rRNA gene hypervariable regions (V1 and V2) were PCR amplified and sequenced by Roche/454 Life Sciences pyrosequencing. Microbial communities were described using the Shannon diversity and evenness indices. Principal component analysis (PCA) was used to group microbial community taxa into four factors representing correlated taxa. Of 108 children, 47 (44%) were colonized by S. pneumoniae, and 25 (23%) were diagnosed with otitis media. Microbial communities with S. pneumoniae were significantly less diverse and less even. Two PCA factors were associated with a decreased risk of pneumococcal colonization and otitis media, as follows: one factor included potentially protective flora (Corynebacterium and Dolosigranulum), and the other factor included Propionibacterium, Lactococcus, and Staphylococcus. The remaining two PCA factors were associated with an increased risk of otitis media. One factor included Haemophilus, and the final factor included Actinomyces, Rothia, Neisseria, and Veillonella. Generally, these taxa are not considered otitis media pathogens but may be important in the causal pathway. Increased understanding of upper respiratory tract microbial communities will contribute to the development of otitis media treatment and prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Laufer", "given" : "Alison S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metlay", "given" : "Joshua P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gent", "given" : "Janneane F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fennie", "given" : "Kristopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettigrew", "given" : "Melinda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2011", "2", "1" ] ] }, "page" : "e00245-10", "title" : "Microbial communities of the upper respiratory tract and otitis media in children.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1128/AEM.01051-12", "ISBN" : "1098-5336 (Electronic)\\n0099-2240 (Linking)", "ISSN" : "00992240", "PMID" : "22752171", "abstract" : "The composition of the upper respiratory tract microbial community may influence the risk for colonization by the acute otitis media (AOM) pathogens Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. We used culture-independent methods to describe upper respiratory tract microbial communities in healthy children and children with upper respiratory tract infection with and without concurrent AOM. Nasal swabs and data were collected in a cross-sectional study of 240 children between 6 months and 3 years of age. Swabs were cultured for S. pneumoniae, and real-time PCR was used to identify S. pneumoniae, H. influenzae, and M. catarrhalis. The V1-V2 16S rRNA gene regions were sequenced using 454 pyrosequencing. Microbial communities were described using a taxon-based approach. Colonization by S. pneumoniae, H. influenzae, and M. catarrhalis was associated with lower levels of diversity in upper respiratory tract flora. We identified commensal taxa that were negatively associated with colonization by each AOM bacterial pathogen and with AOM. The balance of these relationships differed according to the colonizing AOM pathogen and history of antibiotic use. Children with antibiotic use in the past 6 months and a greater abundance of taxa, including Lactococcus and Propionibacterium, were less likely to have AOM than healthy children (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.25 to 0.85). Children with no antibiotic use in the past 6 months, a low abundance of Streptococcus and Haemophilus, and a high abundance of Corynebacterium and Dolosigranulum were less likely to have AOM (OR, 0.51; 95% CI, 0.31 to 0.83). An increased understanding of polymicrobial interactions will facilitate the development of effective AOM prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Pettigrew", "given" : "Melinda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laufer", "given" : "Alison S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gent", "given" : "Janneane F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fennie", "given" : "Kristopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metlay", "given" : "Joshua P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Applied and Environmental Microbiology", "id" : "ITEM-4", "issue" : "17", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "6262-6270", "title" : "Upper respiratory tract microbial communities, acute otitis media pathogens, and antibiotic use in healthy and sick children", "type" : "article-journal", "volume" : "78" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^21,29,68,69", "plainTextFormattedCitation" : "21,29,68,69", "previouslyFormattedCitation" : "^21,29,68,69" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21,29,68,69. A primary function of any microbial ecosystem is to elicit a state of symbiosis by providing ‘colonization resistance’ against pathogensADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature18849", "ISSN" : "0028-0836", "author" : [ { "dropping-particle" : "", "family" : "B\u00e4umler", "given" : "Andreas J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sperandio", "given" : "Vanessa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7610", "issued" : { "date-parts" : [ [ "2016", "7", "6" ] ] }, "page" : "85-93", "publisher" : "Nature Research", "title" : "Interactions between the microbiota and pathogenic bacteria in the gut", "type" : "article-journal", "volume" : "535" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/ni.2608", "ISSN" : "1529-2916", "PMID" : "23778796", "abstract" : "A dense resident microbial community in the gut, referred as the commensal microbiota, coevolved with the host and is essential for many host physiological processes that include enhancement of the intestinal epithelial barrier, development of the immune system and acquisition of nutrients. A major function of the microbiota is protection against colonization by pathogens and overgrowth of indigenous pathobionts that can result from the disruption of the healthy microbial community. The mechanisms that regulate the ability of the microbiota to restrain pathogen growth are complex and include competitive metabolic interactions, localization to intestinal niches and induction of host immune responses. Pathogens, in turn, have evolved strategies to escape from commensal-mediated resistance to colonization. Thus, the interplay between commensals and pathogens or indigenous pathobionts is critical for controlling infection and disease. Understanding pathogen-commensal interactions may lead to new therapeutic approaches to treating infectious diseases.", "author" : [ { "dropping-particle" : "", "family" : "Kamada", "given" : "Nobuhiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Grace Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Inohara", "given" : "Naohiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "N\u00fa\u00f1ez", "given" : "Gabriel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature immunology", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2013", "7" ] ] }, "page" : "685-90", "title" : "Control of pathogens and pathobionts by the gut microbiota.", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^4,70", "plainTextFormattedCitation" : "4,70", "previouslyFormattedCitation" : "^4,70" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }4,70. The principal mechanism that underlies this is that members of a diverse local microbiome likely use all available nutrients, thereby preventing pathogens to find the resources for colonization. Although cross-sectional surveys have demonstrated associations between decreased diversity and pathogen colonization, no direct evidence exists that demonstrates that increased microbial diversity in the respiratory tract can protect against pathogen acquisition. However, specific microbiota members have been identified that can actively exclude pathogens from the nasopharyngeal niche. For example, Staphylococcus epidermidis has been shown to exclude Staphylococcus aureus and destroy pre-existing biofilms by the secretion of serine proteasesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature09074", "ISSN" : "0028-0836", "author" : [ { "dropping-particle" : "", "family" : "Iwase", "given" : "Tadayuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Uehara", "given" : "Yoshio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shinji", "given" : "Hitomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tajima", "given" : "Akiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seo", "given" : "Hiromi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takada", "given" : "Koji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Agata", "given" : "Toshihiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mizunoe", "given" : "Yoshimitsu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7296", "issued" : { "date-parts" : [ [ "2010", "5", "20" ] ] }, "page" : "346-349", "publisher" : "Nature Research", "title" : "Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization", "type" : "article-journal", "volume" : "465" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷¹", "plainTextFormattedCitation" : "71", "previouslyFormattedCitation" : "⁷¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }71. Furthermore, colonization resistance may be enhanced by interaction with the host immune system. For example, neutrophils appeared more able to kill S. pneumoniae after priming with Haemophilus influenzaeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.ppat.0030118", "ISBN" : "1553-7374 (Electronic)", "ISSN" : "15537366", "PMID" : "17722978", "abstract" : "Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of gamma-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1(-/-) mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo.", "author" : [ { "dropping-particle" : "", "family" : "Lysenko", "given" : "Elena S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Thomas B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shchepetov", "given" : "Mikhail", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ratner", "given" : "Adam J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roper", "given" : "David I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowson", "given" : "Christopher G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiser", "given" : "Jeffrey N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS Pathogens", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2007", "8", "24" ] ] }, "page" : "1073-1081", "title" : "Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷²", "plainTextFormattedCitation" : "72", "previouslyFormattedCitation" : "⁷²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }72.The URT is generally considered a major reservoir for potential pathogens, including S. pneumoniae, to expand and subsequently spread towards the lungs, which potentially leads to a symptomatic infectionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1473-3099(04)00938-7", "ISBN" : "1473-3099 (Print)\\r1473-3099 (Linking)", "ISSN" : "14733099", "PMID" : "14998500", "abstract" : "Streptococcus pneumoniae is an important pathogen causing invasive diseases such as sepsis, meningitis, and pneumonia. The burden of disease is highest in the youngest and oldest sections of the population in both more and less developed countries. The treatment of pneumococcal infections is complicated by the worldwide emergence in pneumococci of resistance to penicillin and other antibiotics. Pneumococcal disease is preceded by asymptomatic colonisation, which is especially high in children. The current seven-valent conjugate vaccine is highly effective against invasive disease caused by the vaccine-type strains. However, vaccine coverage is limited, and replacement by non-vaccine serotypes resulting in disease is a serious threat for the near future. Therefore, the search for new vaccine candidates that elicit protection against a broader range of pneumococcal strains is important. Several surface-associated protein vaccines are currently under investigation. Another important issue is whether the aim should be to prevent pneumococcal disease by eradication of nasopharyngeal colonisation, or to prevent bacterial invasion leaving colonisation relatively unaffected and hence preventing the occurrence of replacement colonisation and disease. To illustrate the importance of pneumococcal colonisation in relation to pneumococcal disease and prevention of disease, we discuss the mechanism and epidemiology of colonisation, the complexity of relations within and between species, and the consequences of the different preventive strategies for pneumococcal colonisation.", "author" : [ { "dropping-particle" : "", "family" : "Bogaert", "given" : "D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "R.", "non-dropping-particle" : "De", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermans", "given" : "P. W M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lancet Infectious Diseases", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "144-154", "title" : "Streptococcus pneumoniae colonisation: The key to pneumococcal disease", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³", "plainTextFormattedCitation" : "3", "previouslyFormattedCitation" : "³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3. Thus, establishing and maintaining a balanced URT microbiota that is resilient to pathogenic expansion and invasion could prove vital to respiratory health. The mechanisms underlying a healthy respiratory microbiota, as well as specific microbiota-host interactions that support this are considered below.[H1] Healthy lungs and their microbiotaThe LRT consists of the conducting airways (trachea, bronchi and bronchioles) and the alveoli, where gas exchange takes place. The conducting airways are paved with a similar respiratory epithelium to the one found in the URT, with the epithelial cells gradually shifting towards a cuboidal shape along the respiratory tree. The alveoli in the lung are lined with functionally distinct alveolar epithelial cells. In contrast to the URT and other human mucosal sites, the LRT has traditionally been considered sterile, however, recent studies using next generation sequencing have discovered a wide range of diverse microbial species in samples from the LRT. Potential contamination of low-density specimens remains a major concern when performing these types of studies and requires caution when interpreting the results (BOX 1). [H3] Source of the lung microbiotaIn healthy individuals, bacteria enter the lung by direct mucosal dispersion and micro-aspiration from the URTADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0002-9343", "PMID" : "645722", "abstract" : "A sensitive technic using indium111 chloride was devised to investigate the occurrence of pharyngeal aspiration. Twenty normal subjects and 10 patients with depressed consciousness were studied. Forty-five per cent of the normal subjects aspirated during deep sleep. Normal subjects who did not aspirate were noted to sleep poorly. Seventy per cent of the patients with depressed consciousness aspirated. Aspiration of pharyngeal secretions occurs frequently in patients with depressed sensorium and also in normal adults during deep sleep. Bacterial pneumonia may result when aspirated bacteria are not effectively cleared. This may result when clearance mechanisms are impaired or when they are overwhelmed by large volumes of aspirated secretions.", "author" : [ { "dropping-particle" : "", "family" : "Huxley", "given" : "E J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Viroslav", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gray", "given" : "W R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pierce", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of medicine", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1978", "4" ] ] }, "page" : "564-8", "title" : "Pharyngeal aspiration in normal adults and patients with depressed consciousness.", "type" : "article-journal", "volume" : "64" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷³", "plainTextFormattedCitation" : "73", "previouslyFormattedCitation" : "⁷³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }73. Culture-independent microbiota studies have confirmed that the lung microbiota largely resembles the URT microbiota when studied in healthy individualsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1186/2049-2618-1-19", "ISSN" : "2049-2618", "PMID" : "24450871", "abstract" : "BACKGROUND: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils.\\n\\nRESULTS: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, \u03b1, or \u03b2 diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022).\\n\\nCONCLUSION: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.", "author" : [ { "dropping-particle" : "", "family" : "Segal", "given" : "Leopoldo N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Alekseyenko", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kulkarni", "given" : "Rohan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Zhan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Hao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berger", "given" : "Kenneth I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldring", "given" : "Roberta M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rom", "given" : "William N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blaser", "given" : "Martin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiden", "given" : "Michael D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "19", "title" : "Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1186/s40168-016-0182-1", "ISSN" : "2049-2618", "abstract" : "Invasive methods requiring general anaesthesia are needed to sample the lung microbiota in young children who do not expectorate. This poses substantial challenges to longitudinal study of paediatric airway microbiota. Non-invasive upper airway sampling is an alternative method for monitoring airway microbiota; however, there are limited data describing the relationship of such results with lung microbiota in young children. In this study, we compared the upper and lower airway microbiota in young children to determine whether non-invasive upper airway sampling procedures provide a reliable measure of either lung microbiota or clinically defined differences. The microbiota in oropharyngeal (OP) swabs, nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) from 78 children (median age 2.2 years) with and without lung disease were characterised using 16S rRNA gene sequencing. Permutational multivariate analysis of variance (PERMANOVA) detected significant differences between the microbiota in BAL and those in both OP swabs (p = 0.0001, Pseudo-F = 12.2, df = 1) and NP swabs (p = 0.0001; Pseudo-F = 21.9, df = 1) with the NP and BAL microbiota more different than the OP and BAL, as indicated by a higher Pseudo-F value. The microbiota in combined OP and NP data (upper airways) provided a more comprehensive representation of BAL microbiota, but significant differences between the upper airway and BAL microbiota remained, albeit with a considerably smaller Pseudo-F (PERMANOVA p = 0.0001; Pseudo-F = 4.9, df = 1). Despite this overall difference, paired BAL and upper airway (OP and NP) microbiota were >50 % similar among 69 % of children. Furthermore, canonical analysis of principal coordinates (CAP analysis) detected significant differences between the microbiota from clinically defined groups when analysing either BAL (eigenvalues >0.8; misclassification rate 26.5 %) or the combined OP and NP data (eigenvalues >0.8; misclassification rate 12.2 %). Upper airway sampling provided an imperfect, but reliable, representation of the BAL microbiota for most children in this study. We recommend inclusion of both OP and NP specimens when non-invasive upper airway sampling is needed to assess airway microbiota in young children who do not expectorate. The results of the CAP analysis suggest lower and upper airway microbiota profiles may differentiate children with chronic suppurative lung disease from those with persistent bacterial bronchitis; however, further resea\u2026", "author" : [ { "dropping-particle" : "", "family" : "Marsh", "given" : "R. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kaestli", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "A. B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Binks", "given" : "M. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pope", "given" : "C. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoffman", "given" : "L. R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith-Vaughan", "given" : "H. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "12", "7" ] ] }, "page" : "37", "publisher" : "BioMed Central", "title" : "The microbiota in bronchoalveolar lavage from young children with chronic lung disease includes taxa present in both the oropharynx and nasopharynx", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^74\u201376", "plainTextFormattedCitation" : "74\u201376", "previouslyFormattedCitation" : "^74\u201376" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }74–76. Whereas the oropharynx seems to be the be the main source of the lung microbiota in adultsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷⁴", "plainTextFormattedCitation" : "74", "previouslyFormattedCitation" : "⁷⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }74, in children the source is more likely to be both the naso- and oropharynxADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s40168-016-0182-1", "ISSN" : "2049-2618", "abstract" : "Invasive methods requiring general anaesthesia are needed to sample the lung microbiota in young children who do not expectorate. This poses substantial challenges to longitudinal study of paediatric airway microbiota. Non-invasive upper airway sampling is an alternative method for monitoring airway microbiota; however, there are limited data describing the relationship of such results with lung microbiota in young children. In this study, we compared the upper and lower airway microbiota in young children to determine whether non-invasive upper airway sampling procedures provide a reliable measure of either lung microbiota or clinically defined differences. The microbiota in oropharyngeal (OP) swabs, nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) from 78 children (median age 2.2 years) with and without lung disease were characterised using 16S rRNA gene sequencing. Permutational multivariate analysis of variance (PERMANOVA) detected significant differences between the microbiota in BAL and those in both OP swabs (p = 0.0001, Pseudo-F = 12.2, df = 1) and NP swabs (p = 0.0001; Pseudo-F = 21.9, df = 1) with the NP and BAL microbiota more different than the OP and BAL, as indicated by a higher Pseudo-F value. The microbiota in combined OP and NP data (upper airways) provided a more comprehensive representation of BAL microbiota, but significant differences between the upper airway and BAL microbiota remained, albeit with a considerably smaller Pseudo-F (PERMANOVA p = 0.0001; Pseudo-F = 4.9, df = 1). Despite this overall difference, paired BAL and upper airway (OP and NP) microbiota were >50 % similar among 69 % of children. Furthermore, canonical analysis of principal coordinates (CAP analysis) detected significant differences between the microbiota from clinically defined groups when analysing either BAL (eigenvalues >0.8; misclassification rate 26.5 %) or the combined OP and NP data (eigenvalues >0.8; misclassification rate 12.2 %). Upper airway sampling provided an imperfect, but reliable, representation of the BAL microbiota for most children in this study. We recommend inclusion of both OP and NP specimens when non-invasive upper airway sampling is needed to assess airway microbiota in young children who do not expectorate. The results of the CAP analysis suggest lower and upper airway microbiota profiles may differentiate children with chronic suppurative lung disease from those with persistent bacterial bronchitis; however, further resea\u2026", "author" : [ { "dropping-particle" : "", "family" : "Marsh", "given" : "R. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kaestli", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "A. B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Binks", "given" : "M. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pope", "given" : "C. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoffman", "given" : "L. R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith-Vaughan", "given" : "H. C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "12", "7" ] ] }, "page" : "37", "publisher" : "BioMed Central", "title" : "The microbiota in bronchoalveolar lavage from young children with chronic lung disease includes taxa present in both the oropharynx and nasopharynx", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷⁶", "plainTextFormattedCitation" : "76", "previouslyFormattedCitation" : "⁷⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }76. This might be due to the difference in anatomy of the URT and the frequent increased production of nasal secretions in children, which both likely enhance dispersal of microorganisms to the lungs. Another potential source of bacteria in the LRT is the direct inhalation of ambient air, albeit to date its direct influence on the lung microbiome is unknown. The contribution of the gastric microbiota to the LRT microbial community through gastric-esophageal reflux has up till now been suggested to be negligibleADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷⁴", "plainTextFormattedCitation" : "74", "previouslyFormattedCitation" : "⁷⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }74.[H3] Composition of the lung microbiotaAs LRT sampling is particularly challenging in young infants (BOX 1) current data on composition and development of the neonatal LRT microbiota is limited to samples from intubated prematurely born infantsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/pr.2014.85", "ISBN" : "1530-0447 (Electronic)\\r0031-3998 (Linking)", "ISSN" : "1530-0447", "PMID" : "24941215", "abstract" : "BACKGROUND: Bronchopulmonary dysplasia (BPD) is associated with perinatal inflammatory triggers. Methods targeting bacterial rRNA may improve detection of microbial colonization in premature infants. We hypothesize that respiratory microbiota differs between preterm infants who develop BPD and those unaffected and correlates with inflammatory mediator concentrations. METHODS: Twenty-five infants, born at \u226432 wk of gestation and intubated in the first 24 h, were enrolled. Tracheal aspirates were obtained at intubation and on days 3, 7, and 28. Bacterial DNA was extracted, and 16S rRNA genes were amplified and sequenced. Concentrations of interleukins (IL-1\u03b2, IL-6, IL-8, IL-10, and IL-12), tumor necrosis factor-\u03b1, interferon-\u03b3, lipopolysaccharide (LPS), and lipoteichoic acid (LTA) were measured. Chorioamnionitis was diagnosed by histology. BPD was defined as an oxygen requirement at 36 wk postmenstrual age. RESULTS: Acinetobacter was the predominant genus in the airways of all infants at birth. Ten infants developed BPD and showed reduced bacterial diversity at birth. No differences were detected in bacterial diversity, cytokines, LPS, and LTA from infants with and without exposure to chorioamnionitis. CONCLUSION: The airways of premature infants are not sterile at birth. Reduced diversity of the microbiome may be an important factor in the development of BPD and is not associated with differences in inflammatory mediators.", "author" : [ { "dropping-particle" : "", "family" : "Lohmann", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luna", "given" : "Ruth A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollister", "given" : "Emily B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Devaraj", "given" : "Sridevi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mistretta", "given" : "Toni-Ann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welty", "given" : "Stephen E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Versalovic", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2014", "9", "18" ] ] }, "note" : "25 infants, born at \u226432 wk of gestation and intubated in the first 24 h \nTracheal aspirates: days 3, 7, and 28. \nMost abundant all infant all timepoints: Acinetobacter (Proteobacteria) + Staphylococcus (Firmicutes)", "page" : "294-301", "publisher" : "Springer Nature", "title" : "The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia.", "type" : "article-journal", "volume" : "76" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1203/PDR.0b013e3181d026c3", "ISSN" : "0031-3998", "author" : [ { "dropping-particle" : "", "family" : "Payne", "given" : "Matthew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goss", "given" : "Kevin C W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Connett", "given" : "Gary J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kollamparambil", "given" : "Tanoj", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legg", "given" : "Julian P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thwaites", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ashton", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puddy", "given" : "Victoria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peacock", "given" : "Janet L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruce", "given" : "Kenneth D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric Research", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "4" ] ] }, "note" : "55 premature infants , less than 1.3 kg \nEndotracheal aspirates (ETA), gel electrophoresis (DGGE) profiling, within the first 5 d of life \nbacterial species in 57%. 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These studies showed that the LRT microbiota of premature infants are dominated by the pathogenic bacteria Staphylococcus spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1203/PDR.0b013e3181d026c3", "ISSN" : "0031-3998", "author" : [ { "dropping-particle" : "", "family" : "Payne", "given" : "Matthew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goss", "given" : "Kevin C W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Connett", "given" : "Gary J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kollamparambil", "given" : "Tanoj", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Legg", "given" : "Julian P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thwaites", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ashton", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Puddy", "given" : "Victoria", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peacock", "given" : "Janet L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruce", "given" : "Kenneth D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric Research", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "4" ] ] }, "note" : "55 premature infants , less than 1.3 kg \nEndotracheal aspirates (ETA), gel electrophoresis (DGGE) profiling, within the first 5 d of life \nbacterial species in 57%. 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Methods targeting bacterial rRNA may improve detection of microbial colonization in premature infants. We hypothesize that respiratory microbiota differs between preterm infants who develop BPD and those unaffected and correlates with inflammatory mediator concentrations. METHODS: Twenty-five infants, born at \u226432 wk of gestation and intubated in the first 24 h, were enrolled. Tracheal aspirates were obtained at intubation and on days 3, 7, and 28. Bacterial DNA was extracted, and 16S rRNA genes were amplified and sequenced. Concentrations of interleukins (IL-1\u03b2, IL-6, IL-8, IL-10, and IL-12), tumor necrosis factor-\u03b1, interferon-\u03b3, lipopolysaccharide (LPS), and lipoteichoic acid (LTA) were measured. Chorioamnionitis was diagnosed by histology. BPD was defined as an oxygen requirement at 36 wk postmenstrual age. RESULTS: Acinetobacter was the predominant genus in the airways of all infants at birth. Ten infants developed BPD and showed reduced bacterial diversity at birth. No differences were detected in bacterial diversity, cytokines, LPS, and LTA from infants with and without exposure to chorioamnionitis. CONCLUSION: The airways of premature infants are not sterile at birth. Reduced diversity of the microbiome may be an important factor in the development of BPD and is not associated with differences in inflammatory mediators.", "author" : [ { "dropping-particle" : "", "family" : "Lohmann", "given" : "Pablo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luna", "given" : "Ruth A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollister", "given" : "Emily B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Devaraj", "given" : "Sridevi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mistretta", "given" : "Toni-Ann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welty", "given" : "Stephen E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Versalovic", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Pediatric research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2014", "9", "18" ] ] }, "note" : "25 infants, born at \u226432 wk of gestation and intubated in the first 24 h \nTracheal aspirates: days 3, 7, and 28. \nMost abundant all infant all timepoints: Acinetobacter (Proteobacteria) + Staphylococcus (Firmicutes)", "page" : "294-301", "publisher" : "Springer Nature", "title" : "The airway microbiome of intubated premature infants: characteristics and changes that predict the development of bronchopulmonary dysplasia.", "type" : "article-journal", "volume" : "76" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷⁷", "plainTextFormattedCitation" : "77", "previouslyFormattedCitation" : "⁷⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }77 highlighting the lack of complexity in these developing bacterial communities. In healthy children and adults, one has found a unique microbial community in the lung that contains many of the bacteria common to the URT. A study in young children reported that, although the lung microbiota was distinct from that of the URT, it was dominated by species also present in the URT, including Moraxella spp., Haemophilus spp., Staphylococcus spp. and Streptococcus spp., but lacked other typical URT species such as Corynebacterium spp. and Dolosigranulum spp.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s40168-016-0182-1", "ISSN" : "2049-2618", "abstract" : "Invasive methods requiring general anaesthesia are needed to sample the lung microbiota in young children who do not expectorate. This poses substantial challenges to longitudinal study of paediatric airway microbiota. Non-invasive upper airway sampling is an alternative method for monitoring airway microbiota; however, there are limited data describing the relationship of such results with lung microbiota in young children. In this study, we compared the upper and lower airway microbiota in young children to determine whether non-invasive upper airway sampling procedures provide a reliable measure of either lung microbiota or clinically defined differences. The microbiota in oropharyngeal (OP) swabs, nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) from 78 children (median age 2.2 years) with and without lung disease were characterised using 16S rRNA gene sequencing. Permutational multivariate analysis of variance (PERMANOVA) detected significant differences between the microbiota in BAL and those in both OP swabs (p = 0.0001, Pseudo-F = 12.2, df = 1) and NP swabs (p = 0.0001; Pseudo-F = 21.9, df = 1) with the NP and BAL microbiota more different than the OP and BAL, as indicated by a higher Pseudo-F value. The microbiota in combined OP and NP data (upper airways) provided a more comprehensive representation of BAL microbiota, but significant differences between the upper airway and BAL microbiota remained, albeit with a considerably smaller Pseudo-F (PERMANOVA p = 0.0001; Pseudo-F = 4.9, df = 1). Despite this overall difference, paired BAL and upper airway (OP and NP) microbiota were >50 % similar among 69 % of children. Furthermore, canonical analysis of principal coordinates (CAP analysis) detected significant differences between the microbiota from clinically defined groups when analysing either BAL (eigenvalues >0.8; misclassification rate 26.5 %) or the combined OP and NP data (eigenvalues >0.8; misclassification rate 12.2 %). Upper airway sampling provided an imperfect, but reliable, representation of the BAL microbiota for most children in this study. We recommend inclusion of both OP and NP specimens when non-invasive upper airway sampling is needed to assess airway microbiota in young children who do not expectorate. The results of the CAP analysis suggest lower and upper airway microbiota profiles may differentiate children with chronic suppurative lung disease from those with persistent bacterial bronchitis; however, further resea\u2026", "author" : [ { "dropping-particle" : "", "family" : "Marsh", "given" : "R. L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kaestli", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "A. B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Binks", "given" : "M. J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pope", "given" : "C. E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoffman", "given" : "L. R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith-Vaughan", "given" : "H. 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The adult lung microbiota appears to be dominated by genera of the phyla Firmicutes (including Streptococcus spp. and Veillonella spp.) and Bacteroidetes (including Prevotella spp.)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201210-1913OC", "ISBN" : "4126922210", "ISSN" : "1073449X", "PMID" : "23491408", "abstract" : "RATIONALE: Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome.\\n\\nOBJECTIVES: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort.\\n\\nMETHODS: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome.\\n\\nMEASUREMENTS AND MAIN RESULTS: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not.\\n\\nCONCLUSIONS: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.", "author" : [ { "dropping-particle" : "", "family" : "Morris", "given" : "Alison", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schloss", "given" : "Patrick D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campbell", "given" : "Thomas B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crothers", "given" : "Kristina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Sonia C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fontenot", "given" : "Andrew P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghedin", "given" : "Elodie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jablonski", "given" : "Kathleen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kleerup", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Lynch", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Twigg", "given" : "Homer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Venkataraman", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1067-1075", "title" : "Comparison of the respiratory microbiome in healthy nonsmokers and smokers", "type" : "article-journal", "volume" : "187" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1186/2049-2618-1-19", "ISSN" : "2049-2618", "PMID" : "24450871", "abstract" : "BACKGROUND: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils.\\n\\nRESULTS: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, \u03b1, or \u03b2 diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022).\\n\\nCONCLUSION: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.", "author" : [ { "dropping-particle" : "", "family" : "Segal", "given" : "Leopoldo N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Alekseyenko", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kulkarni", "given" : "Rohan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Zhan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Hao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berger", "given" : "Kenneth I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldring", "given" : "Roberta M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rom", "given" : "William N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blaser", "given" : "Martin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiden", "given" : "Michael D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "19", "title" : "Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1513/AnnalsATS.201501-029OC", "ISBN" : "3122381397", "ISSN" : "23256621", "PMID" : "25803243", "abstract" : "RATIONALE: The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (\"adapted island model of lung biogeography\"), rather than differences in regional bacterial growth conditions. OBJECTIVES: To determine if the lung microbiome is spatially varied in healthy adults. METHODS: Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage), then in the right upper lobe, left upper lobe and supraglottic space (by protected-specimen brush). Bacterial 16S rRNA-encoding genes were sequenced using Illumina MiSeq. MEASUREMENTS AND MAIN RESULTS: There were no significant differences between specimens collected by bronchoalveolar lavage and protected specimen brush. Spatially separated intrapulmonary sites, when compared to each other, did not contain consistently distinct microbiota. On average, intra-subject variation was significantly less than inter-subject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, inter-subject variability and similarity to source community), right upper lobe microbiota more closely resembled that of the upper respiratory tract than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the upper respiratory tract (P < 0.05). CONCLUSIONS: In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. Bronchoalveolar lavage of a single lung segment is an acceptable method of sampling the healthy lung microbiome. CLINICAL TRIAL REGISTRATION: NCT01099410 Primary Source of Funding: Funding provided by NIH grants T32HL00774921 (RPD), U01HL098961 (JMB, GBH, JLC), R01HL114447 (GBH); and by Merit Review Award 1 I01 BX001389 (CMF) from the Biomedical Laboratory Research & Development Service, and faculty salary support (JM\u2026", "author" : [ { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCloskey", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "821-830", "publisher" : "American Thoracic Society", "title" : "Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^42,75,80", "plainTextFormattedCitation" : "42,75,80", "previouslyFormattedCitation" : "^42,75,80" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }42,75,80. Interestingly, Tropheryma whipplei seems enriched only in the LRT, which suggests that this might be one of the few bacterial species that is not derived by dispersion from the URTADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201210-1913OC", "ISBN" : "4126922210", "ISSN" : "1073449X", "PMID" : "23491408", "abstract" : "RATIONALE: Results from 16S rDNA-encoding gene sequence-based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome.\\n\\nOBJECTIVES: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort.\\n\\nMETHODS: Participants were nonsmokers and smokers without significant comorbidities. Oral washes and bronchoscopic alveolar lavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral model in community ecology was used to identify bacteria that were the most plausible members of a lung microbiome.\\n\\nMEASUREMENTS AND MAIN RESULTS: Sixty-four participants were enrolled. Most bacteria identified in the lung were also in the mouth, but specific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was also in the lung, but not the mouth. Mouth communities differed between nonsmokers and smokers in species such as Porphyromonas, Neisseria, and Gemella, but lung bacterial populations did not.\\n\\nCONCLUSIONS: This study is the largest to examine composition of the lower respiratory tract microbiome in healthy individuals and the first to use the neutral model to compare the lung to the mouth. Specific bacteria appear in significantly higher abundance in the lungs than would be expected if they originated from the mouth, demonstrating that the lung microbiome does not derive entirely from the mouth. The mouth microbiome differs in nonsmokers and smokers, but lung communities were not significantly altered by smoking.", "author" : [ { "dropping-particle" : "", "family" : "Morris", "given" : "Alison", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schloss", "given" : "Patrick D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campbell", "given" : "Thomas B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Crothers", "given" : "Kristina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Sonia C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fontenot", "given" : "Andrew P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghedin", "given" : "Elodie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jablonski", "given" : "Kathleen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kleerup", "given" : "Eric", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V.", "family" : "Lynch", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Twigg", "given" : "Homer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Venkataraman", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "1067-1075", "title" : "Comparison of the respiratory microbiome in healthy nonsmokers and smokers", "type" : "article-journal", "volume" : "187" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1513/AnnalsATS.201501-029OC", "ISBN" : "3122381397", "ISSN" : "23256621", "PMID" : "25803243", "abstract" : "RATIONALE: The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (\"adapted island model of lung biogeography\"), rather than differences in regional bacterial growth conditions. OBJECTIVES: To determine if the lung microbiome is spatially varied in healthy adults. METHODS: Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage), then in the right upper lobe, left upper lobe and supraglottic space (by protected-specimen brush). Bacterial 16S rRNA-encoding genes were sequenced using Illumina MiSeq. MEASUREMENTS AND MAIN RESULTS: There were no significant differences between specimens collected by bronchoalveolar lavage and protected specimen brush. Spatially separated intrapulmonary sites, when compared to each other, did not contain consistently distinct microbiota. On average, intra-subject variation was significantly less than inter-subject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, inter-subject variability and similarity to source community), right upper lobe microbiota more closely resembled that of the upper respiratory tract than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the upper respiratory tract (P < 0.05). CONCLUSIONS: In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. Bronchoalveolar lavage of a single lung segment is an acceptable method of sampling the healthy lung microbiome. CLINICAL TRIAL REGISTRATION: NCT01099410 Primary Source of Funding: Funding provided by NIH grants T32HL00774921 (RPD), U01HL098961 (JMB, GBH, JLC), R01HL114447 (GBH); and by Merit Review Award 1 I01 BX001389 (CMF) from the Biomedical Laboratory Research & Development Service, and faculty salary support (JM\u2026", "author" : [ { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCloskey", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "821-830", "publisher" : "American Thoracic Society", "title" : "Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1186/2049-2618-1-19", "ISSN" : "2049-2618", "PMID" : "24450871", "abstract" : "BACKGROUND: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils.\\n\\nRESULTS: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, \u03b1, or \u03b2 diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022).\\n\\nCONCLUSION: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.", "author" : [ { "dropping-particle" : "", "family" : "Segal", "given" : "Leopoldo N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Alekseyenko", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kulkarni", "given" : "Rohan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Zhan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Hao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berger", "given" : "Kenneth I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldring", "given" : "Roberta M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rom", "given" : "William N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blaser", "given" : "Martin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiden", "given" : "Michael D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "19", "title" : "Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^42,75,80", "plainTextFormattedCitation" : "42,75,80", "previouslyFormattedCitation" : "^42,75,80" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }42,75,80. Studies of the LRT virome revealed a high prevalence of Anelloviridae, in addition to a high frequency of bacteriophagesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/ajt.14076", "ISSN" : "16006135", "PMID" : "27731934", "abstract" : "Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. Thus far, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 month post-transplant and found that levels of Anellovirus, mainly Torque teno viruses (TTV), were significantly higher than in non-transplant healthy controls. Here we used quantitative PCR to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and post-reperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were 100-fold elevated in donor lungs compared with healthy adults (p=0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from pre- to post-transplant than did control recipients (p=0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication, and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung. This article is protected by copyright. All rights reserved.", "author" : [ { "dropping-particle" : "", "family" : "Abbas", "given" : "A A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "J.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chehoud", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chang", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kotzin", "given" : "J.J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "J.C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Imai", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "A.R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cantu", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lederer", "given" : "D.J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meyer", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Milewski", "given" : "R.K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olthoff", "given" : "K.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shaked", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Christie", "given" : "J.D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "F.D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "R.G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Transplantation", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "10", "12" ] ] }, "note" : "22 COPD/interstitial lung disease/CF with Primary Graft Dysfunction and 22 without (controls, but not healthy) + vs their donor lungs (= healthy) \nacellular BAL, shotgun \n105 viral species from 15 family-level groups (2 eukaryotic viruses, 1 plant virus and 12 bacteriophage) \n-\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Anelloviruses, comprising multiple TTV species, were the most abundant eukaryotic virus \n-\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Siphoviridae, Myoviridae and Podoviridae, which infect a broad range of oral and respiratory tract bacteria such as Streptococcus pneumoniae, Staphylococcus aureus, Stenotrophomonas maltophilia and Pseudomonas aeruginosa \n-\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Detection of RNA viruses was limited. The overwhelming majority of viral reads in \n-\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 the cDNA library were annotated as originating from DNA viruses. These reads might represent viral mRNA or incomplete removal of genomic DNA in cDNA preparation. \n-\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 No difference case vs controls", "title" : "The Perioperative Lung Transplant Virome: Torque Teno Viruses are Elevated in Donor Lungs and Show Divergent Dynamics In Primary Graft Dysfunction", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1371/journal.pone.0007370", "ISSN" : "1932-6203", "PMID" : "19816605", "abstract" : "The human respiratory tract is constantly exposed to a wide variety of viruses, microbes and inorganic particulates from environmental air, water and food. Physical characteristics of inhaled particles and airway mucosal immunity determine which viruses and microbes will persist in the airways. Here we present the first metagenomic study of DNA viral communities in the airways of diseased and non-diseased individuals. We obtained sequences from sputum DNA viral communities in 5 individuals with cystic fibrosis (CF) and 5 individuals without the disease. Overall, diversity of viruses in the airways was low, with an average richness of 175 distinct viral genotypes. The majority of viral diversity was uncharacterized. CF phage communities were highly similar to each other, whereas Non-CF individuals had more distinct phage communities, which may reflect organisms in inhaled air. CF eukaryotic viral communities were dominated by a few viruses, including human herpesviruses and retroviruses. Functional metagenomics showed that all Non-CF viromes were similar, and that CF viromes were enriched in aromatic amino acid metabolism. The CF metagenomes occupied two different metabolic states, probably reflecting different disease states. There was one outlying CF virome which was characterized by an over-representation of Guanosine-5'-triphosphate,3'-diphosphate pyrophosphatase, an enzyme involved in the bacterial stringent response. Unique environments like the CF airway can drive functional adaptations, leading to shifts in metabolic profiles. These results have important clinical implications for CF, indicating that therapeutic measures may be more effective if used to change the respiratory environment, as opposed to shifting the taxonomic composition of resident microbiota.", "author" : [ { "dropping-particle" : "", "family" : "Willner", "given" : "Dana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Furlan", "given" : "Mike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haynes", "given" : "Matthew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmieder", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Angly", "given" : "Florent E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Silva", "given" : "Joas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tammadoni", "given" : "Sassan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nosrat", "given" : "Bahador", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conrad", "given" : "Douglas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rohwer", "given" : "Forest", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-2", "issue" : "10", "issued" : { "date-parts" : [ [ "2009", "10", "9" ] ] }, "note" : "5 CF 5 healthy, sputum \nMetagenome sequencing or a priori knowledge of what viruses may be present \nthe majority of sequences (.90%) were unknown when compared to the non-redundant database using BLASTn ( \ndemonstrated spatial heterogeneity in the viral presence within and between lobes, hence limited sampling strategies may underestimate viral presence and diversity within the lower respiratory tract. healthy human lungs, where virome composition is relatively constant (willner 2009) + suggested that there is a core set of 19 phages found in the human respiratory tract, \nThe majority of viral species found in Non-CF viromes were from \na core set of 20 viral genomes,which were shared by allmetagenomes (Table S5; Figure S2). These included a mammalian adenovirus (Bovine adenovirus A), eight mammalian herpesviruses, and three poxviruses.", "page" : "e7370", "publisher" : "Public Library of Science", "title" : "Metagenomic analysis of respiratory tract DNA viral communities in cystic fibrosis and non-cystic fibrosis individuals.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1111/ajt.13031", "ISSN" : "1600-6143", "PMID" : "25403800", "abstract" : "Few studies have examined the lung virome in health and disease. Outcomes of lung transplantation are known to be influenced by several recognized respiratory viruses, but global understanding of the virome of the transplanted lung is incomplete. To define the DNA virome within the respiratory tract following lung transplantation we carried out metagenomic analysis of allograft bronchoalveolar lavage (BAL), and compared with healthy and HIV+ subjects. Viral concentrates were purified from BAL and analyzed by shotgun DNA sequencing. All of the BAL samples contained reads mapping to anelloviruses, with high proportions in lung transplant samples. Anellovirus populations in transplant recipients were complex, with multiple concurrent variants. Quantitative polymerase chain reaction quantification revealed that anellovirus sequences were 56-fold more abundant in BAL from lung transplant recipients compared with healthy controls or HIV+ subjects (p < 0.0001). Anellovirus sequences were also more abundant in upper respiratory tract specimens from lung transplant recipients than controls (p = 0.006). Comparison to metagenomic data on bacterial populations showed that high anellovirus loads correlated with dysbiotic bacterial communities in allograft BAL (p = 0.008). Thus the respiratory tracts of lung transplant recipients contain high levels and complex populations of anelloviruses, warranting studies of anellovirus lung infection and transplant outcome.", "author" : [ { "dropping-particle" : "", "family" : "Young", "given" : "J C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chehoud", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bailey", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cantu", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "A R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abbas", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frye", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Christie", "given" : "J D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "F D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "R G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "1" ] ] }, "page" : "200-9", "publisher" : "NIH Public Access", "title" : "Viral metagenomics reveal blooms of anelloviruses in the respiratory tract of lung transplant recipients.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^81\u201383", "plainTextFormattedCitation" : "81\u201383", "previouslyFormattedCitation" : "^81\u201383" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }81–83. Furthermore, the healthy lung mycobiome was found to be predominantly composed of members of the Eremothecium, Systenostrema, and Malassezia genera and the Davidiellaceae family, with common URT fungi detected only in low abundancesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1471-2334-13-69", "ISBN" : "1471233413", "ISSN" : "1471-2334", "PMID" : "23384395", "abstract" : "BACKGROUND: There is emerging evidence for the presence of an extensive microbiota in human lungs. It is not known whether variations in the prevalence of species of microbiota in the lungs may have aetiological significance in respiratory conditions such as asthma. The aim of the study was to undertake semi-quantitative analysis of the differences in fungal species in pooled sputum samples from asthma patients and controls.\\n\\nMETHODS: Induced sputum samples were collected in a case control study of asthma patients and control subjects drawn from the community in Wandsworth, London. Samples from both groups were pooled and then tested for eukaryotes. DNA was amplified using standard PCR techniques, followed by pyrosequencing and comparison of reads to databases of known sequences to determine in a semi-quantitative way the percentage of DNA from known species in each of the two pooled samples.\\n\\nRESULTS: A total of 136 fungal species were identified in the induced sputum samples, with 90 species more common in asthma patients and 46 species more common in control subjects. Psathyrella candolleana, Malassezia pachydermatis, Termitomyces clypeatus and Grifola sordulenta showed a higher percentage of reads in the sputum of asthma patients and Eremothecium sinecaudum, Systenostrema alba, Cladosporium cladosporioides and Vanderwaltozyma polyspora showed a higher percentage of reads in the sputum of control subjects. A statistically significant difference in the pattern of fungi that were present in the respective samples was demonstrated using the Phylogenetic (P) test (P < 0.0001).\\n\\nCONCLUSION: This study is novel in providing evidence for the widespread nature of fungi in the sputum of healthy and asthmatic individuals. Differences in the pattern of fungi present in asthma patients and controls merit further investigation. Of particular interest was the presence of Malassezia pachydermatis, which is known to be associated with atopic dermatitis.", "author" : [ { "dropping-particle" : "", "family" : "Woerden", "given" : "Hugo Cornelis", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gregory", "given" : "Clive", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brown", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marchesi", "given" : "Julian Roberto", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoogendoorn", "given" : "Bastiaan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Matthews", "given" : "Ian Price", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC infectious diseases", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "12", "5" ] ] }, "page" : "69", "publisher" : "BioMed Central", "title" : "Differences in fungi present in induced sputum samples from asthma patients and non-atopic controls: a community based case control study.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1164/rccm.201204-0693OC", "ISSN" : "1073-449X", "abstract" : "Rationale: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers.Objectives: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing.Methods: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover.Measurements and Main Results: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tra...", "author" : [ { "dropping-particle" : "", "family" : "Charlson", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "Joshua M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Ayannah S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yadav", "given" : "Anjana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "Andrew R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "Frederic D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2012", "9", "15" ] ] }, "page" : "536-545", "publisher" : "American Thoracic Society", "title" : "Lung-enriched Organisms and Aberrant Bacterial and Fungal Respiratory Microbiota after Lung Transplant", "type" : "article-journal", "volume" : "186" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1002/alr.21297", "ISSN" : "20426976", "author" : [ { "dropping-particle" : "", "family" : "Cleland", "given" : "Edward John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bassioni", "given" : "Ahmed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boase", "given" : "Samuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowd", "given" : "Scot", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vreugde", "given" : "Sarah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wormald", "given" : "Peter-John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Forum of Allergy & Rhinology", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "259-265", "title" : "The fungal microbiome in chronic rhinosinusitis: richness, diversity, postoperative changes and patient outcomes", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^57,84,85", "plainTextFormattedCitation" : "57,84,85", "previouslyFormattedCitation" : "^57,84,85" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }57,84,85.Although there are subtle regional variations in physiological parameters of the lungs (for example, in oxygen tension, pH and temperature), which in theory could affect microbial selection and growth, spatial microbial diversity in the lungs of healthy individuals seems almost absentADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1513/AnnalsATS.201501-029OC", "ISBN" : "3122381397", "ISSN" : "23256621", "PMID" : "25803243", "abstract" : "RATIONALE: The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (\"adapted island model of lung biogeography\"), rather than differences in regional bacterial growth conditions. OBJECTIVES: To determine if the lung microbiome is spatially varied in healthy adults. METHODS: Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage), then in the right upper lobe, left upper lobe and supraglottic space (by protected-specimen brush). Bacterial 16S rRNA-encoding genes were sequenced using Illumina MiSeq. MEASUREMENTS AND MAIN RESULTS: There were no significant differences between specimens collected by bronchoalveolar lavage and protected specimen brush. Spatially separated intrapulmonary sites, when compared to each other, did not contain consistently distinct microbiota. On average, intra-subject variation was significantly less than inter-subject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, inter-subject variability and similarity to source community), right upper lobe microbiota more closely resembled that of the upper respiratory tract than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the upper respiratory tract (P < 0.05). CONCLUSIONS: In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. Bronchoalveolar lavage of a single lung segment is an acceptable method of sampling the healthy lung microbiome. CLINICAL TRIAL REGISTRATION: NCT01099410 Primary Source of Funding: Funding provided by NIH grants T32HL00774921 (RPD), U01HL098961 (JMB, GBH, JLC), R01HL114447 (GBH); and by Merit Review Award 1 I01 BX001389 (CMF) from the Biomedical Laboratory Research & Development Service, and faculty salary support (JM\u2026", "author" : [ { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCloskey", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "821-830", "publisher" : "American Thoracic Society", "title" : "Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1164/rccm.201104-0655OC", "ISBN" : "2011040655", "ISSN" : "1535-4970", "PMID" : "21680950", "abstract" : "RATIONALE Defining the biogeography of bacterial populations in human body habitats is a high priority for understanding microbial-host relationships in health and disease. The healthy lung was traditionally considered sterile, but this notion has been challenged by emerging molecular approaches that enable comprehensive examination of microbial communities. However, studies of the lung are challenging due to difficulties in working with low biomass samples. OBJECTIVES Our goal was to use molecular methods to define the bacterial microbiota present in the lungs of healthy individuals and assess its relationship to upper airway populations. METHODS We sampled respiratory flora intensively at multiple sites in six healthy individuals. The upper tract was sampled by oral wash and oro-/nasopharyngeal swabs. Two bronchoscopes were used to collect samples up to the glottis, followed by serial bronchoalveolar lavage and lower airway protected brush. Bacterial abundance and composition were analyzed by 16S rDNA Q-PCR and deep sequencing. MEASUREMENTS AND MAIN RESULTS Bacterial communities from the lung displayed composition indistinguishable from the upper airways, but were 2 to 4 logs lower in biomass. Lung-specific sequences were rare and not shared among individuals. There was no unique lung microbiome. CONCLUSIONS In contrast to other organ systems, the respiratory tract harbors a homogenous microbiota that decreases in biomass from upper to lower tract. The healthy lung does not contain a consistent distinct microbiome, but instead contains low levels of bacterial sequences largely indistinguishable from upper respiratory flora. These findings establish baseline data for healthy subjects and sampling approaches for sequence-based analysis of diseases.", "author" : [ { "dropping-particle" : "", "family" : "Charlson", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "Andrew R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Ayannah S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Frank", "given" : "Ian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yadav", "given" : "Anjana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "Frederic D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-2", "issue" : "8", "issued" : { "date-parts" : [ [ "2011", "10", "15" ] ] }, "page" : "957-63", "publisher" : "American Thoracic Society", "title" : "Topographical continuity of bacterial populations in the healthy human respiratory tract.", "type" : "article-journal", "volume" : "184" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1186/2049-2618-1-19", "ISSN" : "2049-2618", "PMID" : "24450871", "abstract" : "BACKGROUND: The lung microbiome of healthy individuals frequently harbors oral organisms. Despite evidence that microaspiration is commonly associated with smoking-related lung diseases, the effects of lung microbiome enrichment with upper airway taxa on inflammation has not been studied. We hypothesize that the presence of oral microorganisms in the lung microbiome is associated with enhanced pulmonary inflammation. To test this, we sampled bronchoalveolar lavage (BAL) from the lower airways of 29 asymptomatic subjects (nine never-smokers, 14 former-smokers, and six current-smokers). We quantified, amplified, and sequenced 16S rRNA genes from BAL samples by qPCR and 454 sequencing. Pulmonary inflammation was assessed by exhaled nitric oxide (eNO), BAL lymphocytes, and neutrophils.\\n\\nRESULTS: BAL had lower total 16S than supraglottic samples and higher than saline background. Bacterial communities in the lower airway clustered in two distinct groups that we designated as pneumotypes. The rRNA gene concentration and microbial community of the first pneumotype was similar to that of the saline background. The second pneumotype had higher rRNA gene concentration and higher relative abundance of supraglottic-characteristic taxa (SCT), such as Veillonella and Prevotella, and we called it pneumotypeSCT. Smoking had no effect on pneumotype allocation, \u03b1, or \u03b2 diversity. PneumotypeSCT was associated with higher BAL lymphocyte-count (P= 0.007), BAL neutrophil-count (P= 0.034), and eNO (P= 0.022).\\n\\nCONCLUSION: A pneumotype with high relative abundance of supraglottic-characteristic taxa is associated with enhanced subclinical lung inflammation.", "author" : [ { "dropping-particle" : "", "family" : "Segal", "given" : "Leopoldo N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Alekseyenko", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kulkarni", "given" : "Rohan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Zhan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Hao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berger", "given" : "Kenneth I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldring", "given" : "Roberta M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rom", "given" : "William N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blaser", "given" : "Martin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiden", "given" : "Michael D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "19", "title" : "Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^75,80,86", "plainTextFormattedCitation" : "75,80,86", "previouslyFormattedCitation" : "^75,80,86" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }75,80,86. This supports the hypothesis that in health, the lung microbiota is a community of transiently present URT-derived microorganisms, rather than being a thriving, resident community as is commonly found in chronic respiratory diseasesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.02284-14", "ISBN" : "2150-7511 (Electronic)", "ISSN" : "21507511", "PMID" : "25604788", "abstract" : "UNLABELLED: DNA from phylogenetically diverse microbes is routinely recovered from healthy human lungs and used to define the lung microbiome. The proportion of this DNA originating from microbes adapted to the lungs, as opposed to microbes dispersing to the lungs from other body sites and the atmosphere, is not known. We use a neutral model of community ecology to distinguish members of the lung microbiome whose presence is consistent with dispersal from other body sites and those that deviate from the model, suggesting a competitive advantage to these microbes in the lungs. We find that the composition of the healthy lung microbiome is consistent with predictions of the neutral model, reflecting the overriding role of dispersal of microbes from the oral cavity in shaping the microbial community in healthy lungs. In contrast, the microbiome of diseased lungs was readily distinguished as being under active selection. We also assessed the viability of microbes from lung samples by cultivation with a variety of media and incubation conditions. Bacteria recovered by cultivation from healthy lungs represented species that comprised 61% of the 16S rRNA-encoding gene sequences derived from bronchoalveolar lavage samples.\\n\\nIMPORTANCE: Neutral distribution of microbes is a distinguishing feature of the microbiome in healthy lungs, wherein constant dispersal of bacteria from the oral cavity overrides differential growth of bacteria. No bacterial species consistently deviated from the model predictions in healthy lungs, although representatives of many of the dispersed species were readily cultivated. In contrast, bacterial populations in diseased lungs were identified as being under active selection. Quantification of the relative importance of selection and neutral processes such as dispersal in shaping the healthy lung microbiome is a first step toward understanding its impacts on host health.", "author" : [ { "dropping-particle" : "", "family" : "Venkataraman", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "publisher" : "American Society for Microbiology (ASM)", "title" : "Application of a neutral community model to assess structuring of the human lung microbiome", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1513/AnnalsATS.201501-029OC", "ISBN" : "3122381397", "ISSN" : "23256621", "PMID" : "25803243", "abstract" : "RATIONALE: The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (\"adapted island model of lung biogeography\"), rather than differences in regional bacterial growth conditions. OBJECTIVES: To determine if the lung microbiome is spatially varied in healthy adults. METHODS: Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage), then in the right upper lobe, left upper lobe and supraglottic space (by protected-specimen brush). Bacterial 16S rRNA-encoding genes were sequenced using Illumina MiSeq. MEASUREMENTS AND MAIN RESULTS: There were no significant differences between specimens collected by bronchoalveolar lavage and protected specimen brush. Spatially separated intrapulmonary sites, when compared to each other, did not contain consistently distinct microbiota. On average, intra-subject variation was significantly less than inter-subject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, inter-subject variability and similarity to source community), right upper lobe microbiota more closely resembled that of the upper respiratory tract than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the upper respiratory tract (P < 0.05). CONCLUSIONS: In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. Bronchoalveolar lavage of a single lung segment is an acceptable method of sampling the healthy lung microbiome. CLINICAL TRIAL REGISTRATION: NCT01099410 Primary Source of Funding: Funding provided by NIH grants T32HL00774921 (RPD), U01HL098961 (JMB, GBH, JLC), R01HL114447 (GBH); and by Merit Review Award 1 I01 BX001389 (CMF) from the Biomedical Laboratory Research & Development Service, and faculty salary support (JM\u2026", "author" : [ { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCloskey", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-2", "issue" : "6", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "821-830", "publisher" : "American Thoracic Society", "title" : "Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1038/ismej.2011.104", "ISBN" : "1751-7370 (Electronic) 1751-7362 (Linking)", "ISSN" : "1751-7362", "PMID" : "21796216", "abstract" : "Cystic fibrosis (CF) is a common fatal genetic disorder with mortality most often resulting from microbial infections of the lungs. Culture-independent studies of CF-associated microbial communities have indicated that microbial diversity in the CF airways is much higher than suggested by culturing alone. However, these studies have relied on indirect methods to sample the CF lung such as expectorated sputum and bronchoalveolar lavage (BAL). Here, we characterize the diversity of microbial communities in tissue sections from anatomically distinct regions of the CF lung using barcoded 16S amplicon pyrosequencing. Microbial communities differed significantly between different areas of the lungs, and few taxa were common to microbial communities in all anatomical regions surveyed. Our results indicate that CF lung infections are not only polymicrobial, but also spatially heterogeneous suggesting that treatment regimes tailored to dominant populations in sputum or BAL samples may be ineffective against infections in some areas of the lung.", "author" : [ { "dropping-particle" : "", "family" : "Willner", "given" : "Dana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haynes", "given" : "Matthew R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Furlan", "given" : "Mike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmieder", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lim", "given" : "Yan Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rainey", "given" : "Paul B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rohwer", "given" : "Forest", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conrad", "given" : "Douglas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME Journal", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "2" ] ] }, "page" : "471-474", "title" : "Spatial distribution of microbial communities in the cystic fibrosis lung", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^80,87,88", "plainTextFormattedCitation" : "80,87,88", "previouslyFormattedCitation" : "^80,87,88" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }80,87,88. Correspondingly, one recently proposed an ecological model — the adapted island model —, which postulates that the composition of healthy lung microbiota is determined by the balance of microbial immigration and eliminationADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1513/AnnalsATS.201501-029OC", "ISBN" : "3122381397", "ISSN" : "23256621", "PMID" : "25803243", "abstract" : "RATIONALE: The lung microbiome is spatially heterogenous in advanced airway diseases, but whether it varies spatially in health is unknown. We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (\"adapted island model of lung biogeography\"), rather than differences in regional bacterial growth conditions. OBJECTIVES: To determine if the lung microbiome is spatially varied in healthy adults. METHODS: Bronchoscopy was performed on 15 healthy subjects. Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage), then in the right upper lobe, left upper lobe and supraglottic space (by protected-specimen brush). Bacterial 16S rRNA-encoding genes were sequenced using Illumina MiSeq. MEASUREMENTS AND MAIN RESULTS: There were no significant differences between specimens collected by bronchoalveolar lavage and protected specimen brush. Spatially separated intrapulmonary sites, when compared to each other, did not contain consistently distinct microbiota. On average, intra-subject variation was significantly less than inter-subject variation (P = 0.00003). By multiple ecologic parameters (community richness, community composition, inter-subject variability and similarity to source community), right upper lobe microbiota more closely resembled that of the upper respiratory tract than did microbiota from more distal sites. As predicted by the adapted island model, community richness decreased with increasing distance from the source community of the upper respiratory tract (P < 0.05). CONCLUSIONS: In healthy lungs, spatial variation in microbiota within an individual is significantly less than variation across individuals. The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases. Bronchoalveolar lavage of a single lung segment is an acceptable method of sampling the healthy lung microbiome. CLINICAL TRIAL REGISTRATION: NCT01099410 Primary Source of Funding: Funding provided by NIH grants T32HL00774921 (RPD), U01HL098961 (JMB, GBH, JLC), R01HL114447 (GBH); and by Merit Review Award 1 I01 BX001389 (CMF) from the Biomedical Laboratory Research & Development Service, and faculty salary support (JM\u2026", "author" : [ { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCloskey", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Annals of the American Thoracic Society", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "821-830", "publisher" : "American Thoracic Society", "title" : "Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/ismej.2011.104", "ISBN" : "1751-7370 (Electronic) 1751-7362 (Linking)", "ISSN" : "1751-7362", "PMID" : "21796216", "abstract" : "Cystic fibrosis (CF) is a common fatal genetic disorder with mortality most often resulting from microbial infections of the lungs. Culture-independent studies of CF-associated microbial communities have indicated that microbial diversity in the CF airways is much higher than suggested by culturing alone. However, these studies have relied on indirect methods to sample the CF lung such as expectorated sputum and bronchoalveolar lavage (BAL). Here, we characterize the diversity of microbial communities in tissue sections from anatomically distinct regions of the CF lung using barcoded 16S amplicon pyrosequencing. Microbial communities differed significantly between different areas of the lungs, and few taxa were common to microbial communities in all anatomical regions surveyed. Our results indicate that CF lung infections are not only polymicrobial, but also spatially heterogeneous suggesting that treatment regimes tailored to dominant populations in sputum or BAL samples may be ineffective against infections in some areas of the lung.", "author" : [ { "dropping-particle" : "", "family" : "Willner", "given" : "Dana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haynes", "given" : "Matthew R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Furlan", "given" : "Mike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmieder", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lim", "given" : "Yan Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rainey", "given" : "Paul B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rohwer", "given" : "Forest", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Conrad", "given" : "Douglas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME Journal", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "2" ] ] }, "page" : "471-474", "title" : "Spatial distribution of microbial communities in the cystic fibrosis lung", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^80,88", "plainTextFormattedCitation" : "80,88", "previouslyFormattedCitation" : "^80,88" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }80,88. Regardless, to date, the exact function of the lung microbiome in establishing and maintaining respiratory health is not clear, though it likely contributes substantially to mucosal immune homeostasis (BOX 2).[H1] Interbacterial relationshipsNext-generation sequencing studies have revealed valuable information on positive and negative microbial associations. By comparing sequencing data with mechanistic work, ecological interaction networks between microbial community members, or between microbiota and the host or environment, can be partially reconstructed.Associations between microbiota members can signify direct symbiotic or antagonistic relationships. Symbiosis has been described primarily for members of the oropharyngeal microbiota: as such, Veillonella ssp. were shown to induce streptococcal biofilm growth in a species-specific manner, presumably due to shared quorum sensing systemsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.anaerobe.2014.05.003", "ISSN" : "10958274", "PMID" : "24862495", "abstract" : "Oral Veillonella, Veillonella atypica, Veillonella denticariosi, Veillonella dispar, Veillonella parvula, Veillonella rogosae, and Veillonella tobetsuensis are known as early colonizers in oral biofilm formation. To investigate the role of oral Veillonella, biofilms formed by the co-culture of Streptococcus gordonii, Streptococcus mutans, Streptococcus salivarius, or Streptococcus sanguinis, with oral Veillonella were examined at the species level. The amount of biofilm formed by S.mutans, S. gordonii, and S.salivarius in the presence of the six Veillonella species was greater than that formed in the control experiments, with the exception of S.mutans with V.dispar. In contrast, in the case of biofilm formation by S.sanguinis, the presence of Veillonella species reduced the amount of the biofilm, with the exception of V.parvula and V.dispar. The time-dependent changes in the amount of biofilm and the number of planktonic cells were grouped into four patterns over the 24 combinations. Only that of S.gordonii with V.tobetsuensis showed a unique pattern. These results indicate that the mode of action of this combination differed from that of the other combinations with respect to biofilm formation. It is possible that there may be several factors involved in the interaction between Streptococcus and Veillonella species. ?? 2014 Elsevier Ltd.", "author" : [ { "dropping-particle" : "", "family" : "Mashima", "given" : "Izumi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nakazawa", "given" : "Futoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Anaerobe", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "8" ] ] }, "page" : "54-61", "title" : "The influence of oral Veillonella species on biofilms formed by Streptococcus species", "type" : "article-journal", "volume" : "28" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁸⁹", "plainTextFormattedCitation" : "89", "previouslyFormattedCitation" : "⁸⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }89. These communication systems also seem to affect symbiotic interactions between commensal and pathogenic members of the Streptococcus cladeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00382-13", "ISSN" : "2150-7511", "PMID" : "23882015", "abstract" : "UNLABELLED Quorum sensing (QS) regulates diverse and coordinated behaviors in bacteria, including the production of virulence factors, biofilm formation, sporulation, and competence development. It is now established that some streptococci utilize Rgg-type proteins in concert with short hydrophobic peptides (SHPs) to mediate QS, and sequence analysis reveals that several streptococcal species contain highly homologous Rgg/SHP pairs. In group A streptococcus (GAS), two SHPs (SHP2 and SHP3 [SHP2/3]) were previously identified to be important in GAS biofilm formation. SHP2/3 are detected by two antagonistic regulators, Rgg2 and Rgg3, which control expression of the shp genes. In group B streptococcus (GBS), RovS is a known virulence gene regulator and ortholog of Rgg2, whereas no apparent Rgg3 homolog exists. Adjacent to rovS is a gene (shp1520) encoding a peptide nearly identical to SHP2. Using isogenic mutant strains and transcriptional reporters, we confirmed that RovS/SHP1520 comprise a QS circuit in GBS. More important, we performed experiments demonstrating that production and secretion of SHP1520 by GBS can modulate Rgg2/3-regulated gene expression in GAS in trans; likewise, SHP2/3 production by GAS can stimulate RovS-mediated gene regulation in GBS. An isolate of Streptococcus dysgalactiae subsp. equisimilis also produced a secreted factor capable of simulating the QS circuits of both GAS and GBS, and sequencing confirms the presence of an orthologous Rgg2/SHP2 pair in this species as well. To our knowledge, this is the first documented case of bidirectional signaling between streptococcal species in coculture and suggests a role for orthologous Rgg/SHP systems in interspecies communication between important human pathogens. IMPORTANCE Pathogenic streptococci, such as group A (GAS) and group B (GBS) streptococcus, are able to persist in the human body without causing disease but become pathogenic under certain conditions that are not fully characterized. Environmental cues and interspecies signaling between members of the human flora likely play an important role in the transition to a disease state. Since quorum-sensing (QS) peptides have been consistently shown to regulate virulence factor production in pathogenic species, the ability of bacteria to signal via these peptides may prove to be an important link between the carrier and pathogenic states. Here we provide evidence of a bidirectional QS system between GAS, GBS, and Streptococcus dysgala\u2026", "author" : [ { "dropping-particle" : "", "family" : "Cook", "given" : "Laura C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LaSarre", "given" : "Breah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Federle", "given" : "Michael J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "7", "23" ] ] }, "title" : "Interspecies communication among commensal and pathogenic streptococci.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹⁰", "plainTextFormattedCitation" : "90", "previouslyFormattedCitation" : "⁹⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }90, and between the nasopharyngeal community members Moraxella catarrhalis and H. influenzaeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00102-10", "ISSN" : "2150-7511", "PMID" : "20802829", "abstract" : "Otitis media (OM) is among the leading diseases of childhood and is caused by opportunists that reside within the nasopharynx, such as Haemophilus influenzae and Moraxella catarrhalis. As with most airway infections, it is now clear that OM infections involve multiple organisms. This study addresses the hypothesis that polymicrobial infection alters the course, severity, and/or treatability of OM disease. The results clearly show that coinfection with H. influenzae and M. catarrhalis promotes the increased resistance of biofilms to antibiotics and host clearance. Using H. influenzae mutants with known biofilm defects, these phenotypes were shown to relate to biofilm maturation and autoinducer-2 (AI-2) quorum signaling. In support of the latter mechanism, chemically synthesized AI-2 (dihydroxypentanedione [DPD]) promoted increased M. catarrhalis biofilm formation and resistance to antibiotics. In the chinchilla infection model of OM, polymicrobial infection promoted M. catarrhalis persistence beyond the levels seen in animals infected with M. catarrhalis alone. Notably, no such enhancement of M. catarrhalis persistence was observed in animals infected with M. catarrhalis and a quorum signaling-deficient H. influenzae luxS mutant strain. We thus conclude that H. influenzae promotes M. catarrhalis persistence within polymicrobial biofilms via interspecies quorum signaling. AI-2 may therefore represent an ideal target for disruption of chronic polymicrobial infections. Moreover, these results strongly imply that successful vaccination against the unencapsulated H. influenzae strains that cause airway infections may also significantly impact chronic M. catarrhalis disease by removing a reservoir of the AI-2 signal that promotes M. catarrhalis persistence within biofilm.", "author" : [ { "dropping-particle" : "", "family" : "Armbruster", "given" : "Chelsie E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hong", "given" : "Wenzhou", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pang", "given" : "Bing", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weimer", "given" : "Kristin E D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Juneau", "given" : "Richard A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turner", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Swords", "given" : "W Edward", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2010" ] ] }, "publisher" : "American Society for Microbiology (ASM)", "title" : "Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling.", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹¹", "plainTextFormattedCitation" : "91", "previouslyFormattedCitation" : "⁹¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }91. Other symbiotic interactions in the nasopharyngeal microbiota exist, as illustrated by the interaction between Corynebacterium spp. and Staphylococcus spp. Their relationship is complex and its directionality is likely species- or even strain-specific; Corynebacterium accolens and S. aureus mutually induce each other’s growth through an unknown molecular mechanismADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.chom.2013.11.005", "ISBN" : "2122633255", "ISSN" : "19313128", "PMID" : "24331461", "abstract" : "The indigenous microbiota of the nasal cavity plays important roles in human health and disease. Patterns of spatial variation in microbiota composition may help explain Staphylococcus aureus colonization and reveal interspecies and species-host interactions. To assess the biogeography of the nasal microbiota, we sampled healthy subjects, representing both S. aureus carriers and noncarriers at three nasal sites (anterior naris, middle meatus, and sphenoethmoidal recess). Phylogenetic compositional and sparse linear discriminant analyses revealed communities that differed according to site epithelium type and S. aureus culture-based carriage status. Corynebacterium accolens and C. pseudodiphtheriticum were identified as the most important microbial community determinants of S. aureus carriage, and competitive interactions were only evident at sites with ciliated pseudostratified columnar epithelium. In vitro cocultivation experiments provided supporting evidence of interactions among these species. These results highlight spatial variation in nasal microbial communities and differences in community composition between S. aureus carriers and noncarriers. ?? 2013 Elsevier Inc.", "author" : [ { "dropping-particle" : "", "family" : "Yan", "given" : "Miling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pamp", "given" : "S\u00fcnje J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukuyama", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hwang", "given" : "Peter H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Do Yeon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holmes", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Relman", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell Host and Microbe", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "12", "11" ] ] }, "page" : "631-640", "title" : "Nasal microenvironments and interspecific interactions influence nasal microbiota complexity and S. aureus carriage", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵⁰", "plainTextFormattedCitation" : "50", "previouslyFormattedCitation" : "⁵⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }50, whereas mixed reports exist on the interactions between Corynebacterium pseudodiptheriticum and S. aureusADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0010598", "ISSN" : "1932-6203", "PMID" : "20498722", "abstract" : "BACKGROUND Colonization of humans with Staphylococcus aureus is a critical prerequisite of subsequent clinical infection of the skin, blood, lung, heart and other deep tissues. S. aureus persistently or intermittently colonizes the nares of approximately 50% of healthy adults, whereas approximately 50% of the general population is rarely or never colonized by this pathogen. Because microbial consortia within the nasal cavity may be an important determinant of S. aureus colonization we determined the composition and dynamics of the nasal microbiota and correlated specific microorganisms with S. aureus colonization. METHODOLOGY/PRINCIPAL FINDINGS Nasal specimens were collected longitudinally from five healthy adults and a cross-section of hospitalized patients (26 S. aureus carriers and 16 non-carriers). Culture-independent analysis of 16S rRNA sequences revealed that the nasal microbiota of healthy subjects consists primarily of members of the phylum Actinobacteria (e.g., Propionibacterium spp. and Corynebacterium spp.), with proportionally less representation of other phyla, including Firmicutes (e.g., Staphylococcus spp.) and Proteobacteria (e.g. Enterobacter spp). In contrast, inpatient nasal microbiotas were enriched in S. aureus or Staphylococcus epidermidis and diminished in several actinobacterial groups, most notably Propionibacterium acnes. Moreover, within the inpatient population S. aureus colonization was negatively correlated with the abundances of several microbial groups, including S. epidermidis (p = 0.004). CONCLUSIONS/SIGNIFICANCE The nares environment is colonized by a temporally stable microbiota that is distinct from other regions of the integument. Negative association between S. aureus, S. epidermidis, and other groups suggests microbial competition during colonization of the nares, a finding that could be exploited to limit S. aureus colonization.", "author" : [ { "dropping-particle" : "", "family" : "Frank", "given" : "Daniel N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Feazel", "given" : "Leah M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bessesen", "given" : "Mary T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Price", "given" : "Connie S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Janoff", "given" : "Edward N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pace", "given" : "Norman R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2010", "5", "17" ] ] }, "page" : "e10598", "title" : "The human nasal microbiota and Staphylococcus aureus carriage.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/ismej.2010.15", "ISBN" : "1751-7370 (Electronic)\\r1751-7362 (Linking)", "ISSN" : "1751-7362", "PMID" : "20182526", "abstract" : "The anterior nares are the major reservoir for Staphylococcus aureus in humans, where nasal carriage has a crucial function as a source for invasive infections. Despite various investigations on aerobic community members based on traditional cultivation methods, little is known on the overall microbial composition and complex in situ interactions, but such knowledge is highly warranted for effective S. aureus control strategies. As assessed using advanced culture-independent approaches, this study provides a comprehensive survey of the anterior nare bacterial community of 40 individuals. Previously undiscovered co-colonization patterns and natural variations in species composition were revealed and provide insights for future intervention strategies for the control of health-care- and community-associated S. aureus infections.", "author" : [ { "dropping-particle" : "", "family" : "Wos-Oxley", "given" : "Melissa L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Plumeier", "given" : "Iris", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eiff", "given" : "Christof", "non-dropping-particle" : "von", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Taudien", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Platzer", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vilchez-Vargas", "given" : "Ramiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Becker", "given" : "Karsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pieper", "given" : "Dietmar H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME Journal", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2010", "7" ] ] }, "page" : "839-851", "title" : "A poke into the diversity and associations within human anterior nare microbial communities", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.chom.2013.11.005", "ISBN" : "2122633255", "ISSN" : "19313128", "PMID" : "24331461", "abstract" : "The indigenous microbiota of the nasal cavity plays important roles in human health and disease. Patterns of spatial variation in microbiota composition may help explain Staphylococcus aureus colonization and reveal interspecies and species-host interactions. To assess the biogeography of the nasal microbiota, we sampled healthy subjects, representing both S. aureus carriers and noncarriers at three nasal sites (anterior naris, middle meatus, and sphenoethmoidal recess). Phylogenetic compositional and sparse linear discriminant analyses revealed communities that differed according to site epithelium type and S. aureus culture-based carriage status. Corynebacterium accolens and C. pseudodiphtheriticum were identified as the most important microbial community determinants of S. aureus carriage, and competitive interactions were only evident at sites with ciliated pseudostratified columnar epithelium. In vitro cocultivation experiments provided supporting evidence of interactions among these species. These results highlight spatial variation in nasal microbial communities and differences in community composition between S. aureus carriers and noncarriers. ?? 2013 Elsevier Inc.", "author" : [ { "dropping-particle" : "", "family" : "Yan", "given" : "Miling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pamp", "given" : "S\u00fcnje J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukuyama", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hwang", "given" : "Peter H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cho", "given" : "Do Yeon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holmes", "given" : "Susan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Relman", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell Host and Microbe", "id" : "ITEM-3", "issue" : "6", "issued" : { "date-parts" : [ [ "2013", "12", "11" ] ] }, "page" : "631-640", "title" : "Nasal microenvironments and interspecific interactions influence nasal microbiota complexity and S. aureus carriage", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^46,50,92", "plainTextFormattedCitation" : "46,50,92", "previouslyFormattedCitation" : "^46,50,92" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }46,50,92. Furthermore, antagonistic relationships have been identified, such as between S. aureus and S. pneumoniaeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140-6736(04)16357-5", "ISBN" : "1474-547X (Electronic)\\r0140-6736 (Linking)", "ISSN" : "01406736", "PMID" : "15183627", "abstract" : "A trial with a 7-valent pneumococcal-conjugate vaccine in children with recurrent acute otitis media showed a shift in pneumococcal colonisation towards non-vaccine serotypes and an increase in Staphylococcus aureus-related acute otitis media after vaccination. We investigated prevalence and determinants of nasopharyngeal carriage of Streptococcus pneumoniae and S aureus in 3198 healthy children aged 1-19 years. Nasopharyngeal carriage of S pneumoniae was detected in 598 (19%) children, and was affected by age (peak incidence at 3 years) and day-care attendance (odds ratio [OR] 2.14, 95% CI 1.44-3.18). S aureus carriage was affected by age (peak incidence at 10 years) and male sex (OR 1.46, 1.25-1.70). Serotyping showed 42% vaccine type pneumococci. We noted a negative correlation for co-colonisation of S aureus and vaccine-type pneumococci (OR 0.68, 0.48-0.94), but not for S aureus and non-vaccine serotypes. These findings suggest a natural competition between colonisation with vaccine-type pneumococci and S aureus, which might explain the increase in S aureus-related otitis media after vaccination.", "author" : [ { "dropping-particle" : "", "family" : "Bogaert", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Belkum", "given" : "A", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sluijter", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luijendijk", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "R", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "R\u00fcmke", "given" : "HC", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Verbrugh", "given" : "HA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermans", "given" : "PWM", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet", "id" : "ITEM-1", "issue" : "9424", "issued" : { "date-parts" : [ [ "2004", "6" ] ] }, "page" : "1871-1872", "title" : "Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children", "type" : "article-journal", "volume" : "363" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³²", "plainTextFormattedCitation" : "32", "previouslyFormattedCitation" : "³²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }32, which may in part be explained by the production of pneumococcal hydrogen peroxide, which results in lethal bacteriophage induction in S. aureusADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/JB.00317-06", "ISBN" : "0021-9193 (Print)\\r0021-9193 (Linking)", "ISSN" : "00219193", "PMID" : "16788209", "abstract" : "The bactericidal activity of Streptococcus pneumoniae toward Staphylococcus aureus is mediated by hydrogen peroxide. Catalase eliminated this activity. Pneumococci grown anaerobically or genetically lacking pyruvate oxidase (SpxB) were not bactericidal, nor were nonpneumococcal streptococci. These results provide a possible mechanistic explanation for the interspecies interference observed in epidemiologic studies", "author" : [ { "dropping-particle" : "", "family" : "Regev-Yochay", "given" : "Gili", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzci\u0144ski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thompson", "given" : "Claudette M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Malley", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lipsitch", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Bacteriology", "id" : "ITEM-1", "issue" : "13", "issued" : { "date-parts" : [ [ "2006", "7" ] ] }, "page" : "4996-5001", "title" : "Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae", "type" : "article-journal", "volume" : "188" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1073/pnas.0809600106", "ISBN" : "1091-6490 (Electronic)\\n0027-8424 (Linking)", "ISSN" : "0027-8424", "PMID" : "19141630", "abstract" : "A surprising example of interspecies competition is the production by certain bacteria of hydrogen peroxide at concentrations that are lethal for others. A case in point is the displacement of Staphylococcus aureus by Streptococcus pneumoniae in the nasopharynx, which is of considerable clinical significance. How it is accomplished, however, has been a great mystery, because H(2)O(2) is a very well known disinfectant whose lethality is largely due to the production of hyperoxides through the abiological Fenton reaction. In this report, we have solved the mystery by showing that H(2)O(2) at the concentrations typically produced by pneumococci kills lysogenic but not nonlysogenic staphylococci by inducing the SOS response. The SOS response, a stress response to DNA damage, not only invokes DNA repair mechanisms but also induces resident prophages, and the resulting lysis is responsible for H(2)O(2) lethality. Because the vast majority of S. aureus strains are lysogenic, the production of H(2)O(2) is a very widely effective antistaphylococcal strategy. Pneumococci, however, which are also commonly lysogenic and undergo SOS induction in response to DNA-damaging agents such as mitomycin C, are not SOS-induced on exposure to H(2)O(2). This is apparently because they are resistant to the DNA-damaging effects of the Fenton reaction. The production of an SOS-inducing signal to activate prophages in neighboring organisms is thus a rather unique competitive strategy, which we suggest may be in widespread use for bacterial interference. However, this strategy has as a by-product the release of active phage, which can potentially spread mobile genetic elements carrying virulence genes", "author" : [ { "dropping-particle" : "", "family" : "Selva", "given" : "Laura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Viana", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Regev-Yochay", "given" : "Gili", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzcinski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Corpa", "given" : "Juan Manuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lasa", "given" : "I\u00f1igo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Novick", "given" : "Richard P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Penades", "given" : "J. R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2009", "1", "27" ] ] }, "page" : "1234-1238", "title" : "Killing niche competitors by remote-control bacteriophage induction", "type" : "article-journal", "volume" : "106" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^93,94", "plainTextFormattedCitation" : "93,94", "previouslyFormattedCitation" : "^93,94" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }93,94. Human experimental colonization with the commensal Neisseria lactamica reduces existing Neisseria meningitidis colonization and even protects against new meningococcal acquisition, underlying involvement of host (adaptive) immunity although the exact mechanisms underlying this antagonistic relationship are unknownADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/cid/civ098", "ISSN" : "1537-6591", "PMID" : "25814628", "abstract" : "BACKGROUND Herd protection by meningococcal vaccines is conferred by population-level reduction of meningococcal nasopharyngeal colonization. Given the inverse epidemiological association between colonization by commensal Neisseria lactamica and meningococcal disease, we investigated whether controlled infection of human volunteers with N. lactamica prevents colonization by Neisseria meningitidis. METHODS In a block-randomized human challenge study, 310 university students were inoculated with 10(4) colony-forming units of N. lactamica or were sham-inoculated, and carriage was monitored for 26 weeks, after which all participants were reinoculated with N. lactamica and resampled 2 weeks later. RESULTS At baseline, natural N. meningitidis carriage in the control group was 22.4% (36/161), which increased to 33.6% (48/143) by week 26. Two weeks after inoculation of N. lactamica, 33.6% (48/143) of the challenge group became colonized with N. lactamica. In this group, meningococcal carriage reduced from 24.2% (36/149) at inoculation to 14.7% (21/143) 2 weeks after inoculation (-9.5%; P = .006). The inhibition of meningococcal carriage was only observed in carriers of N. lactamica, was due both to displacement of existing meningococci and to inhibition of new acquisition, and persisted over at least 16 weeks. Crossover inoculation of controls with N. lactamica replicated the result. Genome sequencing showed that inhibition affected multiple meningococcal sequence types. CONCLUSIONS The inhibition of meningococcal carriage by N. lactamica is even more potent than after glycoconjugate meningococcal vaccination. Neisseria lactamica or its components could be a novel bacterial medicine to suppress meningococcal outbreaks. This observation explains the epidemiological observation of natural immunity conferred by carriage of N. lactamica. CLINICAL TRIALS REGISTRATION NCT02249598.", "author" : [ { "dropping-particle" : "", "family" : "Deasy", "given" : "Alice M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guccione", "given" : "Ed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dale", "given" : "Adam P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Andrews", "given" : "Nick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "Cariad M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bennett", "given" : "Julia S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bratcher", "given" : "Holly B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maiden", "given" : "Martin C J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gorringe", "given" : "Andrew R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Read", "given" : "Robert C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2015", "5", "15" ] ] }, "page" : "1512-20", "title" : "Nasal Inoculation of the Commensal Neisseria lactamica Inhibits Carriage of Neisseria meningitidis by Young Adults: A Controlled Human Infection Study.", "type" : "article-journal", "volume" : "60" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹⁵", "plainTextFormattedCitation" : "95", "previouslyFormattedCitation" : "⁹⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }95. One might postulate that, especially in early life, the human host may nourish and promote specific members of the microbiota, such as S. aureus, to benefit from the wide range of antimicrobial molecules that it produces. This could aid the human host in its defense against invading pathogensADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.ppat.1005812", "ISSN" : "1553-7374", "author" : [ { "dropping-particle" : "", "family" : "Janek", "given" : "Daniela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zipperer", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kulik", "given" : "Andreas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krismer", "given" : "Bernhard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peschel", "given" : "Andreas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLOS Pathogens", "editor" : [ { "dropping-particle" : "", "family" : "Zhang", "given" : "Gongyi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2016", "8", "4" ] ] }, "page" : "e1005812", "publisher" : "Public Library of Science", "title" : "High Frequency and Diversity of Antimicrobial Activities Produced by Nasal Staphylococcus Strains against Bacterial Competitors", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹⁶", "plainTextFormattedCitation" : "96", "previouslyFormattedCitation" : "⁹⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }96. The fact that S. aureus is present in almost all infants though only sporadically causes disease, could in turn be related to specific microbial interactions: for example, co-occurrence with Corynebacterium striatum was shown to increase the commensal behaviour of S. aureus and reduced its virulence in an in vivo infection modelADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3389/fmicb.2016.01230", "ISSN" : "1664-302X (Electronic)", "PMID" : "27582729", "abstract" : "Staphylococcus aureus-human interactions result in a continuum of outcomes from commensalism to pathogenesis. S. aureus is a clinically important pathogen that asymptomatically colonizes ~25% of humans as a member of the nostril and skin microbiota, where it resides with other bacteria including commensal Corynebacterium species. Commensal Corynebacterium spp. are also positively correlated with S. aureus in chronic polymicrobial diabetic foot infections, distinct from acute monomicrobial S. aureus infections. Recent work by our lab and others indicates that microbe-microbe interactions between S. aureus and human skin/nasal commensals, including Corynebacterium species, affect S. aureus behavior and fitness. Thus, we hypothesized that S. aureus interactions with Corynebacterium spp. diminish S. aureus virulence. We tested this by assaying for changes in S. aureus gene expression during in vitro mono- versus coculture with Corynebacterium striatum, a common skin and nasal commensal. We observed a broad shift in S. aureus gene transcription during in vitro growth with C. striatum, including increased transcription of genes known to exhibit increased expression during human nasal colonization and decreased transcription of virulence genes. S. aureus uses several regulatory pathways to transition between commensal and pathogenic states. One of these, the quorum signal accessory gene regulator (agr) system, was strongly inhibited in response to Corynebacterium spp. Phenotypically, S. aureus exposed to C. striatum exhibited increased adhesion to epithelial cells, reflecting a commensal state, and decreased hemolysin activity, reflecting an attenuation of virulence. Consistent with this, S. aureus displayed diminished fitness in experimental in vivo coinfection with C. striatum when compared to monoinfection. These data support a model in which S. aureus shifts from virulence toward a commensal state when exposed to commensal Corynebacterium species.", "author" : [ { "dropping-particle" : "", "family" : "Ramsey", "given" : "Matthew M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freire", "given" : "Marcelo O.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gabrilska", "given" : "Rebecca A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rumbaugh", "given" : "Kendra P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lemon", "given" : "Katherine P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Frontiers in microbiology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "8", "17" ] ] }, "page" : "1230", "publisher" : "Frontiers", "title" : "Staphylococcus aureus Shifts toward Commensalism in Response to Corynebacterium Species.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹⁷", "plainTextFormattedCitation" : "97", "previouslyFormattedCitation" : "⁹⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }97. Furthermore, interactions within the Staphylococcus genus might help to keep S. aureus from overgrowing as well; for example, its colonization is hindered by serine protease activity from Staphylococcus epidermidisADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature09074", "ISSN" : "0028-0836", "author" : [ { "dropping-particle" : "", "family" : "Iwase", "given" : "Tadayuki", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Uehara", "given" : "Yoshio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shinji", "given" : "Hitomi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tajima", "given" : "Akiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seo", "given" : "Hiromi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takada", "given" : "Koji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Agata", "given" : "Toshihiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mizunoe", "given" : "Yoshimitsu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7296", "issued" : { "date-parts" : [ [ "2010", "5", "20" ] ] }, "page" : "346-349", "publisher" : "Nature Research", "title" : "Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization", "type" : "article-journal", "volume" : "465" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷¹", "plainTextFormattedCitation" : "71", "previouslyFormattedCitation" : "⁷¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }71 and by lugdunin production from S. lugdunensis, which is a natural antibiotic that is also active against other potential pathogensADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature18634", "ISSN" : "0028-0836", "PMID" : "27466123", "abstract" : "The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.", "author" : [ { "dropping-particle" : "", "family" : "Zipperer", "given" : "Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Konnerth", "given" : "Martin C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Laux", "given" : "Claudia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berscheid", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Janek", "given" : "Daniela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weidenmaier", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burian", "given" : "Marc", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schilling", "given" : "Nadine A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Slavetinsky", "given" : "Christoph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marschal", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Willmann", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalbacher", "given" : "Hubert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schittek", "given" : "Birgit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Br\u00f6tz-Oesterhelt", "given" : "Heike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grond", "given" : "Stephanie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peschel", "given" : "Andreas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Krismer", "given" : "Bernhard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7613", "issued" : { "date-parts" : [ [ "2016", "7", "27" ] ] }, "page" : "511-516", "title" : "Human commensals producing a novel antibiotic impair pathogen colonization", "type" : "article-journal", "volume" : "535" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹⁸", "plainTextFormattedCitation" : "98", "previouslyFormattedCitation" : "⁹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }98. Microbiota members might also modulate one another’s growth in an indirect manner, for example, through outer membrane vesicle (OMV)-mediated immune evasionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1086/517611", "ISBN" : "0022-1899 (Print)\\r0022-1899 (Linking)", "ISSN" : "0022-1899, 1537-6613", "PMID" : "17471436", "abstract" : "Moraxella catarrhalis causes respiratory tract infections in children and in adults with chronic obstructive pulmonary disease. It is often isolated as a copathogen with Haemophilus influenzae. The underlying mechanism for this cohabitation is unclear. Here, in clinical specimens from a patient with M. catarrhalis infection, we document that outer membrane vesicles (OMVs) carrying ubiquitous surface protein (Usp) A1 and UspA2 (hereafter, UspA1/A2) were secreted. Further analyses revealed that OMVs isolated in vitro also contained UspA1/A2, which mediate interactions with, among other proteins, the third component of the complement system (C3). OMVs from M. catarrhalis wild-type clinical strains bound to C3 and counteracted the complement cascade to a larger extent than did OMVs without UspA1/A2. In contrast, UspA1/A2-deficient OMVs were significantly weaker inhibitors of complement-dependent killing of H. influenzae. Thus, our results suggest that a novel strategy exists in which pathogens collaborate to conquer innate immunity and that the M. catarrhalis vaccine candidates UspA1/A2 play a major role in this interaction.", "author" : [ { "dropping-particle" : "", "family" : "Tong", "given" : "Tan Thuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M\u00f6rgelin", "given" : "Matthias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsgren", "given" : "Arne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Riesbeck", "given" : "Kristian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Infectious Diseases", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2007", "6", "1" ] ] }, "page" : "1661-1670", "title" : "Haemophilus influenzae Survival during Complement-Mediated Attacks Is Promoted by Moraxella catarrhalis Outer Membrane Vesicles", "type" : "article-journal", "volume" : "195" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁹⁹", "plainTextFormattedCitation" : "99", "previouslyFormattedCitation" : "⁹⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }99, or by utilizing specific properties of the local environment, as shown for Corynebacterium accolens, which converts host triacylglycerols into free fatty acids (FFAs) that in turn limit pneumococcal growthADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.01725-15", "ISSN" : "2150-7511", "PMID" : "26733066", "abstract" : "UNLABELLED Bacterial interspecies interactions play clinically important roles in shaping microbial community composition. We observed that Corynebacterium spp. are overrepresented in children free of Streptococcus pneumoniae (pneumococcus), a common pediatric nasal colonizer and an important infectious agent. Corynebacterium accolens, a benign lipid-requiring species, inhibits pneumococcal growth during in vitro cocultivation on medium supplemented with human skin surface triacylglycerols (TAGs) that are likely present in the nostrils. This inhibition depends on LipS1, a TAG lipase necessary for C. accolens growth on TAGs such as triolein. We determined that C. accolens hydrolysis of triolein releases oleic acid, which inhibits pneumococcus, as do other free fatty acids (FFAs) that might be released by LipS1 from human skin surface TAGs. Our results support a model in which C. accolens hydrolyzes skin surface TAGS in vivo releasing antipneumococcal FFAs. These data indicate that C. accolens may play a beneficial role in sculpting the human microbiome. IMPORTANCE Little is known about how harmless Corynebacterium species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites. We show that Corynebacterium accolens, a common benign nasal bacterium, modifies its local habitat in vitro as it inhibits growth of Streptococcus pneumoniae by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary C. accolens lipase required for this activity. We postulate a model in which higher numbers of C. accolens cells deter/limit S. pneumoniae nostril colonization, which might partly explain why children without S. pneumoniae colonization have higher levels of nasal Corynebacterium. This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future in vivo studies to determine whether habitat modification by C. accolens could be promoted to control pathogen colonization.", "author" : [ { "dropping-particle" : "", "family" : "Bomar", "given" : "Lindsey", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brugger", "given" : "Silvio D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yost", "given" : "Brian H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "Sean S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lemon", "given" : "Katherine P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "1", "5" ] ] }, "page" : "e01725-15", "publisher" : "American Society for Microbiology (ASM)", "title" : "Corynebacterium accolens Releases Antipneumococcal Free Fatty Acids from Human Nostril and Skin Surface Triacylglycerols.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶⁸", "plainTextFormattedCitation" : "68", "previouslyFormattedCitation" : "⁶⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }68. A second example of such mechanisms is the frequent co-occurrence of Corynebacterium spp. and Dolosigranulum spp. in the nasopharynxADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. Infants born by Caesarian section showed a delay in overall development of respiratory microbiota profiles with specifically reduced colonization with health-associated commensals like Corynebacterium and Dolosigranulum, thereby possibly influencing respiratory health later in life.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levin", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houten", "given" : "Marlies A.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalkman", "given" : "Gino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A.A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "Pieter-Kees C.M.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pernet", "given" : "Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EBioMedicine", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "336-345", "title" : "Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/mBio.00245-10", "ISSN" : "2150-7511", "PMID" : "21285435", "abstract" : "Streptococcus pneumoniae asymptomatically colonizes the upper respiratory tract of children and is a frequent cause of otitis media. Patterns of microbial colonization likely influence S. pneumoniae colonization and otitis media susceptibility. This study compared microbial communities in children with and without otitis media. Nasal swabs and clinical and demographic data were collected in a cross-sectional study of Philadelphia, PA, children (6 to 78 months) (n=108) during the 2008-2009 winter respiratory virus season. Swabs were cultured for S. pneumoniae. DNA was extracted from the swabs; 16S rRNA gene hypervariable regions (V1 and V2) were PCR amplified and sequenced by Roche/454 Life Sciences pyrosequencing. Microbial communities were described using the Shannon diversity and evenness indices. Principal component analysis (PCA) was used to group microbial community taxa into four factors representing correlated taxa. Of 108 children, 47 (44%) were colonized by S. pneumoniae, and 25 (23%) were diagnosed with otitis media. Microbial communities with S. pneumoniae were significantly less diverse and less even. Two PCA factors were associated with a decreased risk of pneumococcal colonization and otitis media, as follows: one factor included potentially protective flora (Corynebacterium and Dolosigranulum), and the other factor included Propionibacterium, Lactococcus, and Staphylococcus. The remaining two PCA factors were associated with an increased risk of otitis media. One factor included Haemophilus, and the final factor included Actinomyces, Rothia, Neisseria, and Veillonella. Generally, these taxa are not considered otitis media pathogens but may be important in the causal pathway. Increased understanding of upper respiratory tract microbial communities will contribute to the development of otitis media treatment and prevention strategies.", "author" : [ { "dropping-particle" : "", "family" : "Laufer", "given" : "Alison S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metlay", "given" : "Joshua P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gent", "given" : "Janneane F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fennie", "given" : "Kristopher P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Yong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pettigrew", "given" : "Melinda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2011", "2", "1" ] ] }, "page" : "e00245-10", "title" : "Microbial communities of the upper respiratory tract and otitis media in children.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.chom.2015.03.008", "ISSN" : "1934-6069", "PMID" : "25865368", "abstract" : "The nasopharynx (NP) is a reservoir for microbes associated with acute respiratory infections (ARIs). Lung inflammation resulting from ARIs during infancy is linked to asthma development. We examined the NP microbiome during the critical first year of life in a prospective cohort of 234 children, capturing both the viral and bacterial communities and documenting all incidents of ARIs. Most infants were initially colonized with Staphylococcus or Corynebacterium before stable colonization with Alloiococcus or Moraxella. Transient incursions of Streptococcus, Moraxella, or Haemophilus marked virus-associated ARIs. Our data identify the NP microbiome as a determinant for infection spread to the lower airways, severity of accompanying inflammatory symptoms, and risk for future asthma development. Early asymptomatic colonization with Streptococcus was a strong asthma predictor, and antibiotic usage disrupted asymptomatic colonization patterns. In the absence of effective anti-viral therapies, targeting pathogenic bacteria within the NP microbiome could represent a prophylactic approach to asthma.", "author" : [ { "dropping-particle" : "", "family" : "Teo", "given" : "Shu Mei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mok", "given" : "Danny", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pham", "given" : "Kym", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kusel", "given" : "Merci", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Serralha", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Troy", "given" : "Niamh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Barbara J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hales", "given" : "Belinda J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "Michael L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hollams", "given" : "Elysia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bochkov", "given" : "Yury A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grindle", "given" : "Kristine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnston", "given" : "Sebastian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gern", "given" : "James E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sly", "given" : "Peter D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Patrick G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Kathryn E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Inouye", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell host & microbe", "id" : "ITEM-3", "issue" : "5", "issued" : { "date-parts" : [ [ "2015", "5", "13" ] ] }, "page" : "704-15", "publisher" : "Elsevier Inc.", "title" : "The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^20,22,69", "plainTextFormattedCitation" : "20,22,69", "previouslyFormattedCitation" : "^20,22,69" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20,22,69, where Dolosigranulum spp. might be responsible for the acidification of the local environment which in turn may facilitate Corynebacterium spp. expansion. However, a direct, symbiotic interaction between these species cannot be ruled out. Given the low density and presumably transient microbiota in the LRT, one could speculate that the diversity of this microbiota is shaped to a lesser extent by interbacterial relationships compared to the URT bacterial communities although little is known about level of proximity and likelihood of interbacterial effects.Bacterial associations that are detected in epidemiological surveys may also indicate the existence of joint host or environmental drivers, and not the presence of direct or indirect microbial interactions per se. For example, the co-occurrence of Corynebacterium accolens and Propionibacterium spp. on the lipid-rich mucosa of the anterior naresADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/gb-2014-15-5-r66", "ISBN" : "1465-6914 (Electronic)\\n1465-6906 (Linking)", "ISSN" : "1465-6914", "PMID" : "24887286", "abstract" : "BACKGROUND: Determining bacterial abundance variation is the first step in understanding bacterial similarity between individuals. Categorization of bacterial communities into groups or community classes is the subsequent step in describing microbial distribution based on abundance patterns. Here, we present an analysis of the groupings of bacterial communities in stool, nasal, skin, vaginal and oral habitats in a healthy cohort of 236 subjects from the Human Microbiome Project. RESULTS: We identify distinct community group patterns in the anterior nares, four skin sites, and vagina at the genus level. We also confirm three enterotypes previously identified in stools. We identify two clusters with low silhouette values in most oral sites, in which bacterial communities are more homogeneous. Subjects sharing a community class in one habitat do not necessarily share a community class in another, except in the three vaginal sites and the symmetric habitats of the left and right retroauricular creases. Demographic factors, including gender, age, and ethnicity, significantly influence community composition in several habitats. Community classes in the vagina, retroauricular crease and stool are stable over approximately 200 days. CONCLUSION: The community composition, association of demographic factors with community classes, and demonstration of community stability deepen our understanding of the variability and dynamics of human microbiomes. This also has significant implications for experimental designs that seek microbial correlations with clinical phenotypes.", "author" : [ { "dropping-particle" : "", "family" : "Zhou", "given" : "Yanjiao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mihindukulasuriya", "given" : "Kathie a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Hongyu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosa", "given" : "Patricio S", "non-dropping-particle" : "La", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wylie", "given" : "Kristine M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "John C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kota", "given" : "Karthik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shannon", "given" : "William D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mitreva", "given" : "Makedonka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Genome biology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "R66", "publisher" : "BioMed Central", "title" : "Exploration of bacterial community classes in major human habitats.", "type" : "article-journal", "volume" : "15" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴⁸", "plainTextFormattedCitation" : "48", "previouslyFormattedCitation" : "⁴⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }48 could be explained by their joint lipophilic nature only. Furthermore, epidemiological data suggest positive associations between Moraxella catarrhalis, Haemophilus influenzae and Streptococcus pneumoniae, which could be mediated by biological interactions, be based on their shared association with crowding conditions (e.g. the presence of young siblings and daycare attendance) and/or more frequent asymptomatic co-presence of respiratory virusesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0047711", "ISBN" : "1932-6203", "ISSN" : "1932-6203", "PMID" : "23082199", "abstract" : "BACKGROUND: High rates of potentially pathogenic bacteria and respiratory viruses can be detected in the upper respiratory tract of healthy children. Investigating presence of and associations between these pathogens in healthy individuals is still a rather unexplored field of research, but may have implications for interpreting findings during disease.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: We selected 986 nasopharyngeal samples from 433 6- to 24-month-old healthy children that had participated in a randomized controlled trial. We determined the presence of 20 common respiratory viruses using real-time PCR. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus were identified by conventional culture methods. Information on risk factors was obtained by questionnaires. We performed multivariate logistic regression analyses followed by partial correlation analysis to identify the overall pattern of associations. S. pneumoniae colonization was positively associated with the presence of H. influenzae (adjusted odds ratio 1.60, 95% confidence interval 1.18-2.16), M. catarrhalis (1.78, 1.29-2.47), human rhinoviruses (1.63, 1.19-2.22) and enteroviruses (1.97, 1.26-3.10), and negatively associated with S. aureus presence (0.59, 0.35-0.98). H. influenzae was positively associated with human rhinoviruses (1.63, 1.22-2.18) and respiratory syncytial viruses (2.78, 1.06-7.28). M. catarrhalis colonization was positively associated with coronaviruses (1.99, 1.01-3.93) and adenoviruses (3.69, 1.29-10.56), and negatively with S. aureus carriage (0.42, 0.25-0.69). We observed a strong positive association between S. aureus and influenza viruses (4.87, 1.59-14.89). In addition, human rhinoviruses and enteroviruses were positively correlated (2.40, 1.66-3.47), as were enteroviruses and human bocavirus, WU polyomavirus, parainfluenza viruses, and human parechovirus. A negative association was observed between human rhinoviruses and coronaviruses.\\n\\nCONCLUSIONS/SIGNIFICANCE: Our data revealed high viral and bacterial prevalence rates and distinct bacterial-bacterial, viral-bacterial and viral-viral associations in healthy children, hinting towards the complexity and potential dynamics of microbial communities in the upper respiratory tract. This warrants careful consideration when associating microbial presence with specific respiratory diseases.", "author" : [ { "dropping-particle" : "", "family" : "Bergh", "given" : "Menno R", "non-dropping-particle" : "van den", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rossen", "given" : "John W A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A A", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A T M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gils", "given" : "Elske J M", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Xinhui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Boonacker", "given" : "Chantal W B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veenhoven", "given" : "Reinier H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruin", "given" : "Jacob P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "e47711", "title" : "Associations between pathogens in the upper respiratory tract of young children: interplay between viruses and bacteria.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1098/rstb.2014.0294", "ISSN" : "0962-8436", "PMID" : "26150660", "abstract" : "Respiratory tract infections are a major global health concern, accounting for high morbidity and mortality, especially in young children and elderly individuals. Traditionally, highly common bacterial respiratory tract infections, including otitis media and pneumonia, were thought to be caused by a limited number of pathogens including Streptococcus pneumoniae and Haemophilus influenzae. However, these pathogens are also frequently observed commensal residents of the upper respiratory tract (URT) and form-together with harmless commensal bacteria, viruses and fungi-intricate ecological networks, collectively known as the 'microbiome'. Analogous to the gut microbiome, the respiratory microbiome at equilibrium is thought to be beneficial to the host by priming the immune system and providing colonization resistance, while an imbalanced ecosystem might predispose to bacterial overgrowth and development of respiratory infections. We postulate that specific ecological perturbations of the bacterial communities in the URT can occur in response to various lifestyle or environmental effectors, leading to diminished colonization resistance, loss of containment of newly acquired or resident pathogens, preluding bacterial overgrowth, ultimately resulting in local or systemic bacterial infections. Here, we review the current body of literature regarding niche-specific upper respiratory microbiota profiles within human hosts and the changes occurring within these profiles that are associated with respiratory infections.", "author" : [ { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A. A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Philosophical Transactions of the Royal Society B: Biological Sciences", "id" : "ITEM-2", "issue" : "1675", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "20140294", "title" : "The role of the local microbial ecosystem in respiratory health and disease", "type" : "article-journal", "volume" : "370" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^53,100", "plainTextFormattedCitation" : "53,100", "previouslyFormattedCitation" : "^53,100" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }53,100.[H1] Impact of virome and mycobiome[H3] Bidirectional viral-bacterial interactionsPerhaps the best known historical example is of viral-bacterial interactions in the respiratory tract comes from the Spanish flu pandemic in 1918-1919, when millions of individuals died from a secondary bacterial pneumonia after initial influenza A virus infectionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1006/viro.2000.0495", "ISSN" : "00426822", "author" : [ { "dropping-particle" : "", "family" : "Taubenberger", "given" : "Jeffery K.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reid", "given" : "Ann H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fanning", "given" : "Thomas G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Virology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2000", "9" ] ] }, "page" : "241-245", "title" : "The 1918 Influenza Virus: A Killer Comes into View", "type" : "article-journal", "volume" : "274" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰¹", "plainTextFormattedCitation" : "101", "previouslyFormattedCitation" : "¹⁰¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }101. Also in the absence of disease, epidemiological studies have suggested the presence of viral-bacterial interactions (reviewed in ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.ppat.1003057", "ISBN" : "1553-7374 (Electronic) 1553-7366 (Linking)", "ISSN" : "1553-7374", "PMID" : "23326226", "abstract" : "Respiratory infectious diseases are mainly caused by viruses or bacteria that often interact with one another. Although their presence is a prerequisite for subsequent infections, viruses and bacteria may be present in the nasopharynx without causing any respiratory symptoms. The upper respiratory tract hosts a vast range of commensals and potential pathogenic bacteria, which form a complex microbial community. This community is assumed to be constantly subject to synergistic and competitive interspecies interactions. Disturbances in the equilibrium, for instance due to the acquisition of new bacteria or viruses, may lead to overgrowth and invasion. A better understanding of the dynamics between commensals and pathogens in the upper respiratory tract may provide better insight into the pathogenesis of respiratory diseases. Here we review the current knowledge regarding specific bacterial-bacterial and viral-bacterial interactions that occur in the upper respiratory niche, and discuss mechanisms by which these interactions might be mediated. Finally, we propose a theoretical model to summarize and illustrate these mechanisms.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A T M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzcinski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS pathogens", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e1003057", "title" : "Viral and bacterial interactions in the upper respiratory tract.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰²", "plainTextFormattedCitation" : "102", "previouslyFormattedCitation" : "¹⁰²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }102). The biological mechanisms underlying these bidirectional interactions have been extensively studied, though mostly for viruses and bacteria that are known to cause respiratory diseasesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.ppat.1003057", "ISBN" : "1553-7374 (Electronic) 1553-7366 (Linking)", "ISSN" : "1553-7374", "PMID" : "23326226", "abstract" : "Respiratory infectious diseases are mainly caused by viruses or bacteria that often interact with one another. Although their presence is a prerequisite for subsequent infections, viruses and bacteria may be present in the nasopharynx without causing any respiratory symptoms. The upper respiratory tract hosts a vast range of commensals and potential pathogenic bacteria, which form a complex microbial community. This community is assumed to be constantly subject to synergistic and competitive interspecies interactions. Disturbances in the equilibrium, for instance due to the acquisition of new bacteria or viruses, may lead to overgrowth and invasion. A better understanding of the dynamics between commensals and pathogens in the upper respiratory tract may provide better insight into the pathogenesis of respiratory diseases. Here we review the current knowledge regarding specific bacterial-bacterial and viral-bacterial interactions that occur in the upper respiratory niche, and discuss mechanisms by which these interactions might be mediated. Finally, we propose a theoretical model to summarize and illustrate these mechanisms.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A T M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzcinski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS pathogens", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "e1003057", "title" : "Viral and bacterial interactions in the upper respiratory tract.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰²", "plainTextFormattedCitation" : "102", "previouslyFormattedCitation" : "¹⁰²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }102.One of the main modes of action by which respiratory viruses are thought to predispose to bacterial disease is by disrupting the airway-epithelial barrier, which facilitates the adhesion of bacterial pathogensADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.200801-136OC", "ISBN" : "1535-4970 (Electronic) 1073-449X (Linking)", "ISSN" : "1073449X", "PMID" : "18787220", "abstract" : "RATIONALE: Secondary bacterial infection following rhinovirus (RV) infection has been recognized in chronic obstructive pulmonary disease.\\n\\nOBJECTIVES: We sought to understand mechanisms by which RV infection facilitates secondary bacterial infection.\\n\\nMETHODS: Primary human airway epithelial cells grown at air-liquid interface and human bronchial epithelial (16HBE14o-) cells grown as polarized monolayers were infected apically with RV. Transmigration of bacteria (nontypeable Haemophilus influenzae and others) was assessed by colony counting and transmission electron microscopy. Transepithelial resistance (R(T)) was measured by using a voltmeter. The distribution of zona occludins (ZO)-1 was determined by immunohistochemistry and immunoblotting.\\n\\nMEASUREMENTS AND MAIN RESULTS: Epithelial cells infected with RV showed 2-log more bound bacteria than sham-infected cultures, and bacteria were recovered from the basolateral media of RV- but not sham-infected cells. Infection of polarized airway epithelial cell cultures with RV for 24 hours caused a significant decrease in R(T) without causing cell death or apoptosis. Ultraviolet-treated RV did not decrease R(T), suggesting a requirement for viral replication. Reduced R(T) was associated with increased paracellular permeability, as determined by flux of fluorescein isothiocyanate (FITC)-inulin. Neutralizing antibodies to tumor necrosis factor (TNF)-alpha, IFN-gamma and IL-1beta reversed corresponding cytokine-induced reductions in R(T) but not that induced by RV, indicating that the RV effect is independent of these proinflammatory cytokines. Confocal microscopy and immunoblotting revealed the loss of ZO-1 from tight junction complexes in RV-infected cells. Intranasal inoculation of mice with RV1B also caused the loss of ZO-1 from the bronchial epithelium tight junctions in vivo.\\n\\nCONCLUSIONS: RV facilitates binding, translocation, and persistence of bacteria by disrupting airway epithelial barrier function.", "author" : [ { "dropping-particle" : "", "family" : "Sajjan", "given" : "Umadevi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Qiong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhao", "given" : "Ying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruenert", "given" : "Dieter C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hershenson", "given" : "Marc B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2008", "12", "15" ] ] }, "page" : "1271-1281", "publisher" : "American Thoracic Society", "title" : "Rhinovirus disrupts the barrier function of polarized airway epithelial cells", "type" : "article-journal", "volume" : "178" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/JVI.80.4.1629-1636.2006", "ISSN" : "0022-538X", "PMID" : "16439519", "abstract" : "Secondary bacterial infections often complicate respiratory viral infections, but the mechanisms whereby viruses predispose to bacterial disease are not completely understood. We determined the effects of infection with respiratory syncytial virus (RSV), human parainfluenza virus 3 (HPIV-3), and influenza virus on the abilities of nontypeable Haemophilus influenzae and Streptococcus pneumoniae to adhere to respiratory epithelial cells and how these viruses alter the expression of known receptors for these bacteria. All viruses enhanced bacterial adhesion to primary and immortalized cell lines. RSV and HPIV-3 infection increased the expression of several known receptors for pathogenic bacteria by primary bronchial epithelial cells and A549 cells but not by primary small airway epithelial cells. Influenza virus infection did not alter receptor expression. Paramyxoviruses augmented bacterial adherence to primary bronchial epithelial cells and immortalized cell lines by up-regulating eukaryotic cell receptors for these pathogens, whereas this mechanism was less significant in primary small airway epithelial cells and in influenza virus infections. Respiratory viruses promote bacterial adhesion to respiratory epithelial cells, a process that may increase bacterial colonization and contribute to disease. These studies highlight the distinct responses of different cell types to viral infection and the need to consider this variation when interpreting studies of the interactions between respiratory cells and viral pathogens.", "author" : [ { "dropping-particle" : "", "family" : "Avadhanula", "given" : "Vasanthi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rodriguez", "given" : "Carina A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Devincenzo", "given" : "John P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Webby", "given" : "Richard J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ulett", "given" : "Glen C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Adderson", "given" : "Elisabeth E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of virology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2006", "2" ] ] }, "page" : "1629-36", "publisher" : "American Society for Microbiology (ASM)", "title" : "Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner.", "type" : "article-journal", "volume" : "80" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISBN" : "0019-9567 (Print)\\r0019-9567 (Linking)", "ISSN" : "00199567", "PMID" : "6769805", "abstract" : "Adherence of Pseudomonas aeruginosa to normal, injured, and regenerating tracheal mucosa was examined by scanning electron microscopy. Uninfected and influenza-infected murine tracheas were exposed to six strains of P. aeruginosa isolated from human sources and one strain of platn origin. All of the strains tested adhered to desquamating cells of the infected tracheas, but not to normal mucosa, the basal cell layer, or the regenerating epithelium. Adherence increased when the incubation time of the bacteria with the trachea was prolonged. Strains isolated from human tracheas appeared to adhere better than strains derived from the urinary tract. After endotracheal intubation of ferrets, P. aeruginosa adhered only to the injured cells and to areas of exposed basement membrane. We call this phenomenon \"opportunistic adherence\" and propose that alteration of the cell surfaces or cell injury facilitates the adherence of this bacterium and that adherence to injured cells may be a key to the pathogenesis of opportunistic Pseudomonas infections.", "author" : [ { "dropping-particle" : "", "family" : "Ramphal", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Small", "given" : "P M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shands", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fischlschweiger", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Small", "given" : "P A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Infection and Immunity", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "1980", "2" ] ] }, "page" : "614-619", "title" : "Adherence of Pseudomonas aeruginosa to tracheal cells injured by influenza infection or by endotracheal intubation", "type" : "article-journal", "volume" : "27" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^103\u2013105", "plainTextFormattedCitation" : "103\u2013105", "previouslyFormattedCitation" : "^103\u2013105" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }103–105. Furthermore, it was demonstrated that influenza virus infection enhances especially pneumococcal colonization by liberating host-derived nutrientsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.chom.2014.06.005", "ISSN" : "19313128", "abstract" : "Much of the mortality attributed to influenza virus is due to secondary bacterial pneumonia, particularly from Streptococcus pneumoniae. However, mechanisms underlying this coinfection are incompletely understood. We find that prior influenza infection enhances pneumococcal colonization of the murine nasopharynx, which in turn promotes bacterial spread to the lungs. Influenza accelerates bacterial replication in\u00a0vivo, and sialic acid, a major component of airway glycoconjugates, is identified as the host-derived metabolite that stimulates pneumococcal proliferation. Influenza infection increases sialic acid and sialylated mucin availability and enhances desialylation of host glycoconjugates. Pneumococcal genes for sialic acid catabolism are required for influenza to promote bacterial growth. Decreasing sialic acid availability in\u00a0vivo by genetic deletion of the major airway mucin Muc5ac or mucolytic treatment limits influenza-induced pneumococcal replication. Our findings suggest that higher rates of disease during coinfection could stem from influenza-provided sialic acid, which increases pneumococcal proliferation, colonization, and aspiration.", "author" : [ { "dropping-particle" : "", "family" : "Siegel", "given" : "Steven\u00a0J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roche", "given" : "Aoife\u00a0M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiser", "given" : "Jeffrey\u00a0N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell Host & Microbe", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "55-67", "title" : "Influenza Promotes Pneumococcal Growth during Coinfection by Providing Host Sialylated Substrates as a Nutrient Source", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰⁶", "plainTextFormattedCitation" : "106", "previouslyFormattedCitation" : "¹⁰⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }106 and by decreasing mucociliary clearanceADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1165/rcmb.2007-0417OC", "ISSN" : "1535-4989", "PMID" : "19520922", "abstract" : "Influenza virus infections increase susceptibility to secondary bacterial infections, such as pneumococcal pneumonia, resulting in increased morbidity and mortality. Influenza-induced tissue damage is hypothesized to increase susceptibility to Streptococcus pneumoniae infection by increasing adherence to the respiratory epithelium. Using a mouse model of influenza infection followed by S. pneumoniae infection, we found that an influenza infection does not increase the number of pneumococci initially present within the trachea, but does inhibit pneumococcal clearance by 2 hours after infection. To determine whether influenza damage increases pneumococcal adherence, we developed a novel murine tracheal explant system to determine influenza-induced tissue damage and subsequent pneumococcal adherence. Murine tracheas were kept viable ex vivo as shown by microscopic examination of ciliary beating and cellular morphology using continuous media flow for up to 8 days. Tracheas were infected with influenza virus for 0.5-5 days ex vivo, and influenza-induced tissue damage and the early stages of repair to the epithelium were assessed histologically. A prior influenza infection did not increase pneumococcal adherence, even when the basement membrane was maximally denuded or during the repopulation of the basement membrane with undifferentiated epithelial cells. We measured mucociliary clearance in vivo and found it was decreased in influenza-infected mice. Together, our results indicate that exposure of the tracheal basement membrane contributes minimally to pneumococcal adherence. Instead, an influenza infection results in decreased tracheal mucociliary velocity and initial clearance of pneumococci, leading to an increased pneumococcal burden as early as 2 hours after pneumococcal infection.", "author" : [ { "dropping-particle" : "", "family" : "Pittet", "given" : "Lynnelle A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall-Stoodley", "given" : "Luanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rutkowski", "given" : "Melanie R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harmsen", "given" : "Allen G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory cell and molecular biology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2010", "4" ] ] }, "page" : "450-60", "title" : "Influenza virus infection decreases tracheal mucociliary velocity and clearance of Streptococcus pneumoniae.", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰⁷", "plainTextFormattedCitation" : "107", "previouslyFormattedCitation" : "¹⁰⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }107. Additionally, respiratory viruses can modulate host innate and adaptive immune responses, thereby promoting bacterial colonization and infection, for example by impairing monocyte activityADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1099/0022-1317-49-3-227", "ISSN" : "0022-2615", "PMID" : "10707942", "abstract" : "Non-typable Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis and respiratory syncytial virus (RSV) are commonly isolated from patients during the course of chronic obstructive pulmonary disease (COPD). Earlier studies found that virus infection enhanced binding of bacterial respiratory pathogens to epithelial cells in vitro. The objective of the present study was to assess the effect of RSV infection of a human monocytic cell line on bactericidal activity and cytokine production in response to these bacterial respiratory pathogens. The effect of RSV infection on binding, uptake and intracellular killing of bacteria by a human monocytic leukaemia cell line, THP-1, was assessed. Cell culture supernates were examined with a mouse fibroblast cell assay for tumour necrosis factor-alpha (TNF-alpha) bioactivity. Expression of CD14, CD11a, CD18, CD15 and CD29 on uninfected and RSV-infected THP-1 cells was assessed by flow cytometry in relation to differences in bacterial binding. RSV infection of THP-1 cells significantly decreased their ability to bind and kill bacteria. Compared with uninfected cells, fewer bacteria bound to RSV-infected THP-1 cells and the surface antigens that have been reported to bind bacteria were expressed at lower levels on RSV-infected cells. RSV-infected cells incubated with bacteria exhibited less TNF-alpha bioactivity than uninfected cell incubated with bacteria. The results elucidate some of the mechanisms involved in the increased susceptibility of virus-infected patients to secondary bacterial infection. Reduced bacterial killing by virus-infected monocytes might contribute to reduced clearance of bacteria from the respiratory tract and damage elicited by the bacteria or cytokine response in COPD patients.", "author" : [ { "dropping-particle" : "", "family" : "Raza", "given" : "M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blackwell", "given" : "C C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Elton", "given" : "R A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weir", "given" : "D M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of medical microbiology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2000", "3" ] ] }, "page" : "227-33", "title" : "Bactericidal activity of a monocytic cell line (THP-1) against common respiratory tract bacterial pathogens is depressed after infection with respiratory syncytial virus.", "type" : "article-journal", "volume" : "49" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰⁸", "plainTextFormattedCitation" : "108", "previouslyFormattedCitation" : "¹⁰⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }108, extended desensitization of alveolar macrophages for Toll-like receptor (TLR)-ligandsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1084/jem.20070891", "ISSN" : "1540-9538", "PMID" : "18227219", "abstract" : "The World Health Organization estimates that lower respiratory tract infections (excluding tuberculosis) account for approximately 35% of all deaths caused by infectious diseases. In many cases, the cause of death may be caused by multiple pathogens, e.g., the life-threatening bacterial pneumonia observed in patients infected with influenza virus. The ability to evolve more efficient immunity on each successive encounter with antigen is the hallmark of the adaptive immune response. However, in the absence of cross-reactive T and B cell epitopes, one lung infection can modify immunity and pathology to the next for extended periods of time. We now report for the first time that this phenomenon is mediated by a sustained desensitization of lung sentinel cells to Toll-like receptor (TLR) ligands; this is an effect that lasts for several months after resolution of influenza or respiratory syncytial virus infection and is associated with reduced chemokine production and NF-kappaB activation in alveolar macrophages. Although such desensitization may be beneficial in alleviating overall immunopathology, the reduced neutrophil recruitment correlates with heightened bacterial load during secondary respiratory infection. Our data therefore suggests that post-viral desensitization to TLR signals may be one possible contributor to the common secondary bacterial pneumonia associated with pandemic and seasonal influenza infection.", "author" : [ { "dropping-particle" : "", "family" : "Didierlaurent", "given" : "Arnaud", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goulding", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patel", "given" : "Seema", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snelgrove", "given" : "Robert", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Low", "given" : "Lionel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bebien", "given" : "Magali", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawrence", "given" : "Toby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rijt", "given" : "Leonie S", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lambrecht", "given" : "Bart N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sirard", "given" : "Jean-Claude", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hussell", "given" : "Tracy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of experimental medicine", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008", "2", "18" ] ] }, "page" : "323-9", "title" : "Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection.", "type" : "article-journal", "volume" : "205" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁰⁹", "plainTextFormattedCitation" : "109", "previouslyFormattedCitation" : "¹⁰⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }109, suppressed phagocytic capacity of alveolar macrophagesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm1765", "ISSN" : "1078-8956", "PMID" : "18438414", "abstract" : "Secondary bacterial infection often occurs after pulmonary virus infection and is a common cause of severe disease in humans, yet the mechanisms responsible for this viral-bacterial synergy in the lung are only poorly understood. We now report that pulmonary interferon-gamma (IFN-gamma) produced during T cell responses to influenza infection in mice inhibits initial bacterial clearance from the lung by alveolar macrophages. This suppression of phagocytosis correlates with lung IFN-gamma abundance, but not viral burden, and leads to enhanced susceptibility to secondary pneumococcal infection, which can be prevented by IFN-gamma neutralization after influenza infection. Direct inoculation of IFN-gamma can mimic influenza infection and downregulate the expression of the class A scavenger receptor MARCO on alveolar macrophages. Thus, IFN-gamma, although probably facilitating induction of specific anti-influenza adaptive immunity, suppresses innate protection against extracellular bacterial pathogens in the lung.", "author" : [ { "dropping-particle" : "", "family" : "Sun", "given" : "Keer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Metzger", "given" : "Dennis W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Medicine", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2008", "5", "27" ] ] }, "page" : "558-564", "title" : "Inhibition of pulmonary antibacterial defense by interferon-\u03b3 during recovery from influenza infection", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹⁰", "plainTextFormattedCitation" : "110", "previouslyFormattedCitation" : "¹¹⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }110, and inhibition of T-helper 17 cell induced antimicrobial peptide productionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/infdis/jit527", "ISBN" : "0022-1899, 1537-6613", "ISSN" : "00221899", "PMID" : "24072844", "abstract" : "Influenza A represents a significant cause of morbidity and mortality worldwide. Bacterial complications of influenza A confer the greatest risk to patients. TH17 pathway inhibition has been implicated as a mechanism by which influenza A alters bacterial host defense. Here we show that preceding influenza causes persistent Staphylococcus aureus infection and suppression of TH17 pathway activation in mice. Influenza does not inhibit S. aureus binding and uptake by phagocytic cells but instead attenuates S. aureus induced TH17 related antimicrobial peptides necessary for bacterial clearance in the lung. Importantly, exogenous lipocalin 2 rescued viral exacerbation of S. aureus infection and decreased free iron levels in the bronchoalveolar lavage from mice coinfected with S. aureus and influenza. These findings indicate a novel mechanism by which influenza A inhibits TH17 immunity and increases susceptibility to secondary bacterial pneumonia. Identification of new mechanisms in the pathogenesis of bacterial pneumonia could lead to future therapeutic targets.", "author" : [ { "dropping-particle" : "", "family" : "Robinson", "given" : "Keven M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McHugh", "given" : "Kevin J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mandalapu", "given" : "Sivanarayana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clay", "given" : "Michelle E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Benjamin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Scheller", "given" : "Erich", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Enelow", "given" : "Richard I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chan", "given" : "Yvonne R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kolls", "given" : "Jay K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alcorn", "given" : "John F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Infectious Diseases", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2014", "3" ] ] }, "page" : "865-875", "title" : "Influenza a virus exacerbates staphylococcus aureus pneumonia in mice by attenuating antimicrobial peptide production", "type" : "article-journal", "volume" : "209" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹¹", "plainTextFormattedCitation" : "111", "previouslyFormattedCitation" : "¹¹¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }111. Vice versa, respiratory bacteria can also promote viral infection by a myriad of pathwaysADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0041104", "ISBN" : "1932-6203 (Electronic)\\r1932-6203 (Linking)", "ISSN" : "19326203", "PMID" : "22844430", "abstract" : "BACKGROUND: Regulatory T cells (Treg cells), which are essential for regulation of immune response to respiratory syncytial virus (RSV) infection, are promoted by pharyngeal commensal pneumococcus. The effects of pharyngeal microflora disruption by antibiotics on airway responsiveness and relative immune responses after RSV infection have not been clarified.\\n\\nMETHODS: Female BALB/c mice (aged 3 weeks) were infected with RSV and then treated with either oral antibiotics or oral double distilled water (ddH(2)O) from 1 d post infection (pi). Changes in pharyngeal microflora were analyzed after antibiotic treatment for 7 d and 14 d. At 8 d pi and 15 d pi, the inflammatory cells in bronchoalveolar lavage fluid (BALF) were investigated in combination with tests of pulmonary histopathology, airway hyperresponsiveness (AHR), pulmonary and splenic Treg cells responses. Pulmonary Foxp3 mRNA expression, IL-10 and TGF-\u03b21 in BALF and lung homogenate were investigated at 15 d pi. Ovalbumin (OVA) challenge was used to induce AHR after RSV infection.\\n\\nRESULTS: The predominant pharyngeal commensal, Streptococcus, was cleared by antibiotic treatment for 7 d. Same change also existed after antibiotic treatment for 14 d. After RSV infection, AHR was promoted by antibiotic treatment at 15 d pi. Synchronous decreases of pulmonary Treg cells, Foxp3 mRNA and TGF-\u03b21 were detected. Similar results were observed under OVA challenge.\\n\\nCONCLUSIONS: After RSV infection, antibiotic treatment cleared pharyngeal commensal bacteria such as Streptococcus, which consequently, might induce AHR and decrease pulmonary Treg cells.", "author" : [ { "dropping-particle" : "", "family" : "Ni", "given" : "Ke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Simin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xia", "given" : "Qiuling", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zang", "given" : "Na", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deng", "given" : "Yu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xie", "given" : "Xiaohong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Zhengxiu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Luo", "given" : "Yan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Lijia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fu", "given" : "Zhou", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Enmei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS ONE", "editor" : [ { "dropping-particle" : "", "family" : "Cormier", "given" : "Stephania Ann", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2012", "7", "26" ] ] }, "page" : "e41104", "publisher" : "Public Library of Science", "title" : "Pharyngeal microflora disruption by antibiotics promotes airway hyperresponsiveness after respiratory syncytial virus infection", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISBN" : "0732-6580 (Print)\\r0732-6580 (Linking)", "ISSN" : "0732-6580", "PMID" : "2319263", "abstract" : "Muramyl dipeptide (MDP), murabutide (a derivative of MDP), mouse alpha-interferon (MoIFN), and polyinosinic-polycytodylic acid (poly (I-C) were tested in a mouse-influenza virus model for anti-influenza virus activity. None of these compounds administered alone prior to virus challenge had more than minimal ability to protect mice from influenza virus infection. In contrast, mice given either MDP or murabutide 2 days prior to challenge with influenza A/Hong Kong/68 virus and poly I-C 1 day prior to virus challenge had significantly reduced pulmonary virus titers and mortality compared to comparably challenged control mice. No significant reductions in pulmonary virus titers or mortality were seen if MoIFN was given in place of poly I-C in this sequence.", "author" : [ { "dropping-particle" : "", "family" : "Wyde", "given" : "P R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Six", "given" : "H R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ambrose", "given" : "M W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Throop", "given" : "B J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of biological response modifiers", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "1990", "2" ] ] }, "page" : "98-102", "title" : "Muramyl peptides and polyinosinic-polycytodylic acid given to mice prior to influenza virus challenge reduces pulmonary disease and mortality.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1096/fj.06-5806fje", "ISBN" : "1530-6860 (Electronic)\\r0892-6638 (Linking)", "ISSN" : "0892-6638", "PMID" : "16914605", "abstract" : "Rhinovirus (RV) is an important trigger of chronic obstructive pulmonary disease (COPD) exacerbations. In addition, respiratory viruses are more likely to be isolated in patients with a history of frequent exacerbations, suggesting that these patients are more susceptible to viral infection. To examine potential mechanisms for cooperative effects between bacterial and viral infection in COPD, we studied the responses of cultured human airway epithelial cells to nontypeable Hemophilus influenzae and RV. In both 16HBE14o- and primary mucociliary-differentiated cells, preincubation with H. influenzae enhanced RV serotype 39-induced protein expression of interleukin (IL)-8, epithelial-derived neutrophil attractant-78, and growth-related oncogene-alpha. H. influenzae infection also increased the binding of RV39 to cultured cells, as well as expression of intercellular adhesion molecule (ICAM)-1 and Toll-like receptor (TLR)-3, receptors for RV and dsRNA, respectively. Neutralizing antibody against tumor necrosis factor-alpha inhibited IL-8 expression induced by H. influenzae and RV39. Finally, siRNA against TLR3 attenuated RV-induced IL-8 expression. We conclude that H. influenzae infection increases airway epithelial cell ICAM-1 and TLR3 expression, leading to enhanced binding of RV and a potentiation of RV-induced chemokine release. These data provide a cellular mechanism by which H. influenzae infection may increase the susceptibility of COPD patients to RV-induced exacerbations.", "author" : [ { "dropping-particle" : "", "family" : "Sajjan", "given" : "Umadevi S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The FASEB Journal", "id" : "ITEM-3", "issue" : "12", "issued" : { "date-parts" : [ [ "2006", "10", "1" ] ] }, "page" : "2121-2123", "title" : "H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1096/fj.14-254359", "ISSN" : "0892-6638", "PMID" : "25411435", "abstract" : "Nontypeable Haemophilus influenzae (NTHI), a common colonizer of lungs of patients with chronic obstructive pulmonary disease (COPD), can enhance expression of the cellular receptor intercellular adhesion molecule 1 (ICAM-1), which in turn can be used by major group human rhinoviruses (HRVs) for attachment. Here, we evaluated the effect of NTHI-induced up-regulation of ICAM-1 on viral replication and inflammatory responses toward different respiratory viruses. Therefore, human bronchial epithelial cells were pretreated with heat-inactivated NTHI (hi-NTHI) and subsequently infected with either HRV16 (major group), HRV1B (minor group), or respiratory syncytial virus (RSV). Pretreatment with hi-NTHI significantly up-regulated ICAM-1 in BEAS-2B cells and primary bronchial epithelial cells. Concomitantly, release of infectious HRV16 particles was increased in cells pretreated with hi-NTHI. Pretreatment with hi-NTHI also caused a significant increase in HRV16 RNA, whereas replication of HRV1B and RSV were increased to a far lesser extent and only at later time points. Interestingly, release of IL-6 and IL-8 after RSV, but not HRV, infection was synergistically increased in hi-NTHI-pretreated BEAS-2B cells. In summary, exposure to hi-NTHI significantly enhanced sensitivity toward HRV16 but not HRV1B or RSV, probably through ICAM-1 up-regulation. Furthermore, hi-NTHI pretreatment may enhance the inflammatory response to RSV infection, suggesting that preexisting bacterial infections might exaggerate inflammation during secondary viral infection.", "author" : [ { "dropping-particle" : "", "family" : "Gulraiz", "given" : "Fahad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bellinghausen", "given" : "Carla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruggeman", "given" : "Cathrien A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stassen", "given" : "Frank R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The FASEB Journal", "id" : "ITEM-4", "issue" : "3", "issued" : { "date-parts" : [ [ "2015", "3", "1" ] ] }, "page" : "849-858", "title" : "Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelial cells to viral infections", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1186/s12931-016-0382-z", "ISSN" : "1465-993X", "author" : [ { "dropping-particle" : "", "family" : "Bellinghausen", "given" : "Carla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gulraiz", "given" : "Fahad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heinzmann", "given" : "Alexandra C. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dentener", "given" : "Mieke A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savelkoul", "given" : "Paul H. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wouters", "given" : "Emiel F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rohde", "given" : "Gernot G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stassen", "given" : "Frank R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Respiratory Research", "id" : "ITEM-5", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "12", "3" ] ] }, "page" : "68", "publisher" : "BioMed Central", "title" : "Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^112\u2013116", "plainTextFormattedCitation" : "112\u2013116", "previouslyFormattedCitation" : "^112\u2013116" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }112–116. For example, up-regulation of adhesion receptors such as ICAM-1 (intercellular adhesion molecule 1) has been shown to increase binding of HRV and respiratory syncytial virus (RSV), and amplify pro-inflammatory responsesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1096/fj.06-5806fje", "ISBN" : "1530-6860 (Electronic)\\r0892-6638 (Linking)", "ISSN" : "0892-6638", "PMID" : "16914605", "abstract" : "Rhinovirus (RV) is an important trigger of chronic obstructive pulmonary disease (COPD) exacerbations. In addition, respiratory viruses are more likely to be isolated in patients with a history of frequent exacerbations, suggesting that these patients are more susceptible to viral infection. To examine potential mechanisms for cooperative effects between bacterial and viral infection in COPD, we studied the responses of cultured human airway epithelial cells to nontypeable Hemophilus influenzae and RV. In both 16HBE14o- and primary mucociliary-differentiated cells, preincubation with H. influenzae enhanced RV serotype 39-induced protein expression of interleukin (IL)-8, epithelial-derived neutrophil attractant-78, and growth-related oncogene-alpha. H. influenzae infection also increased the binding of RV39 to cultured cells, as well as expression of intercellular adhesion molecule (ICAM)-1 and Toll-like receptor (TLR)-3, receptors for RV and dsRNA, respectively. Neutralizing antibody against tumor necrosis factor-alpha inhibited IL-8 expression induced by H. influenzae and RV39. Finally, siRNA against TLR3 attenuated RV-induced IL-8 expression. We conclude that H. influenzae infection increases airway epithelial cell ICAM-1 and TLR3 expression, leading to enhanced binding of RV and a potentiation of RV-induced chemokine release. These data provide a cellular mechanism by which H. influenzae infection may increase the susceptibility of COPD patients to RV-induced exacerbations.", "author" : [ { "dropping-particle" : "", "family" : "Sajjan", "given" : "Umadevi S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The FASEB Journal", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2006", "10", "1" ] ] }, "page" : "2121-2123", "title" : "H. influenzae potentiates airway epithelial cell responses to rhinovirus by increasing ICAM-1 and TLR3 expression", "type" : "article-journal", "volume" : "20" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1096/fj.14-254359", "ISSN" : "0892-6638", "PMID" : "25411435", "abstract" : "Nontypeable Haemophilus influenzae (NTHI), a common colonizer of lungs of patients with chronic obstructive pulmonary disease (COPD), can enhance expression of the cellular receptor intercellular adhesion molecule 1 (ICAM-1), which in turn can be used by major group human rhinoviruses (HRVs) for attachment. Here, we evaluated the effect of NTHI-induced up-regulation of ICAM-1 on viral replication and inflammatory responses toward different respiratory viruses. Therefore, human bronchial epithelial cells were pretreated with heat-inactivated NTHI (hi-NTHI) and subsequently infected with either HRV16 (major group), HRV1B (minor group), or respiratory syncytial virus (RSV). Pretreatment with hi-NTHI significantly up-regulated ICAM-1 in BEAS-2B cells and primary bronchial epithelial cells. Concomitantly, release of infectious HRV16 particles was increased in cells pretreated with hi-NTHI. Pretreatment with hi-NTHI also caused a significant increase in HRV16 RNA, whereas replication of HRV1B and RSV were increased to a far lesser extent and only at later time points. Interestingly, release of IL-6 and IL-8 after RSV, but not HRV, infection was synergistically increased in hi-NTHI-pretreated BEAS-2B cells. In summary, exposure to hi-NTHI significantly enhanced sensitivity toward HRV16 but not HRV1B or RSV, probably through ICAM-1 up-regulation. Furthermore, hi-NTHI pretreatment may enhance the inflammatory response to RSV infection, suggesting that preexisting bacterial infections might exaggerate inflammation during secondary viral infection.", "author" : [ { "dropping-particle" : "", "family" : "Gulraiz", "given" : "Fahad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bellinghausen", "given" : "Carla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruggeman", "given" : "Cathrien A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stassen", "given" : "Frank R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The FASEB Journal", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2015", "3", "1" ] ] }, "page" : "849-858", "title" : "Haemophilus influenzae increases the susceptibility and inflammatory response of airway epithelial cells to viral infections", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1186/s12931-016-0382-z", "ISSN" : "1465-993X", "author" : [ { "dropping-particle" : "", "family" : "Bellinghausen", "given" : "Carla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gulraiz", "given" : "Fahad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heinzmann", "given" : "Alexandra C. A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dentener", "given" : "Mieke A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Savelkoul", "given" : "Paul H. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wouters", "given" : "Emiel F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rohde", "given" : "Gernot G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stassen", "given" : "Frank R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Respiratory Research", "id" : "ITEM-3", "issue" : "1", "issued" : { "date-parts" : [ [ "2016", "12", "3" ] ] }, "page" : "68", "publisher" : "BioMed Central", "title" : "Exposure to common respiratory bacteria alters the airway epithelial response to subsequent viral infection", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^114\u2013116", "plainTextFormattedCitation" : "114\u2013116", "previouslyFormattedCitation" : "^114\u2013116" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }114–116. These findings were substantiated by a recent clinical study, showing that nasopharyngeal colonization with S. pneumoniae and H. influenzae in infants is associated with an amplified systemic RSV-induced host immune response, plausibly resulting in more severe RSV infectionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201602-0220OC", "ISSN" : "1535-4970", "PMID" : "27135599", "abstract" : "RATIONALE Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and hospitalizations in infants worldwide. Known risk factors, however, incompletely explain the variability of RSV disease severity, especially among healthy children. We postulate that severity of RSV infection is influenced by modulation of the host immune response by the local bacterial ecosystem. OBJECTIVES To assess whether specific nasopharyngeal microbiota (clusters) are associated with distinct host transcriptome profiles and disease severity in children under two years of age with RSV infection. METHODS We characterized the nasopharyngeal microbiota profiles of young children with mild and severe RSV disease and healthy children by 16S-rRNA sequencing. In parallel, using multivariable models, we analyzed whole blood transcriptiome profiles to study the relationship between microbial community composition, the RSV-induced host transcriptional response and clinical disease severity. MEASUREMENTS AND MAIN RESULTS We identified five nasopharyngeal microbiota clusters characterized by enrichment of either H. influenzae, Streptococcus, Corynebacterium, Moraxella or S. aureus. RSV infection and RSV hospitalization were positively associated with H. influenzae and Streptococcus, and negatively associated with S. aureus abundance, independent of age. RSV infected children showed overexpression of interferon-related genes, independent of the microbiota cluster. In addition, transcriptome profiles of children with RSV infection and H. influenzae and Streptococcus-dominated microbiota were characterized by greater overexpression of genes linked to toll-like receptor, neutrophil and macrophage activation and signaling. CONCLUSIONS Our data suggest that interactions between RSV and nasopharyngeal microbiota might modulate the host immune response, potentially affecting clinical disease severity.", "author" : [ { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A A", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heinonen", "given" : "Santtu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bunsow", "given" : "Eleonora", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Bennett", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suarez-Arrabal", "given" : "Maria-Carmen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaussabel", "given" : "Damien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cohen", "given" : "Daniel M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramilo", "given" : "Octavio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mejias", "given" : "Asuncion", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "5", "2" ] ] }, "page" : "rccm.201602-0220OC", "title" : "Nasopharyngeal Microbiota, Host Transcriptome and Disease Severity in Children with Respiratory Syncytial Virus Infection.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹⁷", "plainTextFormattedCitation" : "117", "previouslyFormattedCitation" : "¹¹⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }117. Conversely, the presence of specific bacterial species within the respiratory microbiota may impede viral infections. These interactions can be either directADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-1899", "PMID" : "1527412", "abstract" : "Different proteases from various microorganisms present in the respiratory tract were capable of enhancing influenza virus infectivity and pathogenicity in mice by proteolytic activation of hemagglutinin (HA). Aerococcus viridans, isolated from a patient with pneumonia, secreted a protease that could activate HA directly, similarly to some Staphylococcus aureus strains. The protease of Pseudomonas aeruginosa could not activate HA directly, but combined application of P. aeruginosa protease and virus into mice enhanced virus titers and pathogenicity. Generation of trypsin-like activity in bronchoalveolar lavage fluids resulting from this combination treatment may be responsible for HA activation. A similar indirect effect on HA activation was induced by streptokinase and staphylokinase, which are known to generate plasmin by plasminogen activation. It was concluded that plasminogen-activating streptococci and staphylococci facilitate viral replication and pathogenicity of plasmin-sensitive influenza virus strains by amplification of the plasminogen/plasmin system.", "author" : [ { "dropping-particle" : "", "family" : "Scheiblauer", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reinacher", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tashiro", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rott", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of infectious diseases", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1992", "10" ] ] }, "page" : "783-91", "title" : "Interactions between bacteria and influenza A virus in the development of influenza pneumonia.", "type" : "article-journal", "volume" : "166" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/325536a0", "ISSN" : "0028-0836", "PMID" : "3543690", "abstract" : "In influenza the combined virus-bacterial pneumonia is approximately three times more common than primary viral pneumonia. The bacteria most commonly involved are Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae. S. aureus co-infection is reported to have a fatality rate of up to 42% (ref. 2). It is thought that virus infection in the respiratory tract favours growth conditions for bacteria. In this letter data are presented which show that some S. aureus strains secrete a protease which exerts a decisive influence on the outcome of influenza virus infection in mice by cleavage activation of the virus haemagglutinin.", "author" : [ { "dropping-particle" : "", "family" : "Tashiro", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ciborowski", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Klenk", "given" : "H.-D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pulverer", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rott", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-2", "issue" : "6104", "issued" : { "date-parts" : [ [ "1987", "2", "5" ] ] }, "page" : "536-537", "title" : "Role of Staphylococcus protease in the development of influenza pneumonia", "type" : "article-journal", "volume" : "325" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^118,119", "plainTextFormattedCitation" : "118,119", "previouslyFormattedCitation" : "^118,119" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }118,119 or indirect through the host immune system. For example, influenza virus infection was shown to be less efficient following immune priming by lipopolysaccharide (LPS)-mediated TLR4 receptor activation of innate immune cellsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1159/000353905", "ISSN" : "1662-8128", "PMID" : "23970306", "abstract" : "It is well established that infection with influenza A virus (IAV) facilitates secondary bacterial disease. However, there is a growing body of evidence that the microbial context in which IAV infection occurs can affect both innate and adaptive responses to the virus. To date, these studies have been restricted to murine models of disease and the relevance of these findings in primary human cells remains to be elucidated. Here, we show that pre-stimulation of primary human monocyte-derived macrophages (MDMs) with the bacterial ligand lipopolysaccharide (LPS) reduces the ability of IAV to infect these cells. The inhibition of IAV infection was associated with a reduced transcription of viral RNA and the ability of LPS to induce an anti-viral/type I interferon response in human MDMs. We demonstrated that this reduced rate of viral infection is associated with a reduced ability to present a model antigen to autologous CD8+ T cells. Taken together, these data provide the first evidence that exposure to bacterial ligands like LPS can play an important role in modulating the immune response of primary human immune cells towards IAV infection, which may then have important consequences for the development of the host's adaptive immune response.", "author" : [ { "dropping-particle" : "", "family" : "Short", "given" : "Kirsty R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vissers", "given" : "Marloes", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kleijn", "given" : "Stan", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zomer", "given" : "Aldert L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kedzierska", "given" : "Katherine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grant", "given" : "Emma", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reading", "given" : "Patrick C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hermans", "given" : "Peter W.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ferwerda", "given" : "Gerben", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diavatopoulos", "given" : "Dimitri A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Innate Immunity", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "129-139", "publisher" : "Karger Publishers", "title" : "Bacterial Lipopolysaccharide Inhibits Influenza Virus Infection of Human Macrophages and the Consequent Induction of CD8+ T Cell Immunity", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1073/pnas.1019378108", "ISBN" : "1091-6490 (Electronic)\\r0027-8424 (Linking)", "ISSN" : "1091-6490", "PMID" : "21402903", "abstract" : "Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, the role of commensal bacteria in immune responses at other mucosal surfaces remains less clear. Here, we show that commensal microbiota composition critically regulates the generation of virus-specific CD4 and CD8 T cells and antibody responses following respiratory influenza virus infection. By using various antibiotic treatments, we found that neomycin-sensitive bacteria are associated with the induction of productive immune responses in the lung. Local or distal injection of Toll-like receptor (TLR) ligands could rescue the immune impairment in the antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for pro-IL-1\u03b2 and pro-IL-18 at steady state. Following influenza virus infection, inflammasome activation led to migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cell priming. Our results reveal the importance of commensal microbiota in regulating immunity in the respiratory mucosa through the proper activation of inflammasomes.", "author" : [ { "dropping-particle" : "", "family" : "Ichinohe", "given" : "Takeshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pang", "given" : "Iris K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kumamoto", "given" : "Yosuke", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peaper", "given" : "David R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ho", "given" : "John H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murray", "given" : "Thomas S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Iwasaki", "given" : "Akiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Proceedings of the National Academy of Sciences of the United States of America", "id" : "ITEM-2", "issue" : "13", "issued" : { "date-parts" : [ [ "2011", "3", "29" ] ] }, "page" : "5354-9", "title" : "Microbiota regulates immune defense against respiratory tract influenza A virus infection.", "type" : "article-journal", "volume" : "108" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^120,121", "plainTextFormattedCitation" : "120,121", "previouslyFormattedCitation" : "^120,121" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }120,121. In fact, some studies suggest that LPS-signaling is necessary for proper immune crosstalk and immune ‘readiness’ for future viral encountersADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.1179050", "ISBN" : "1095-9203 (Electronic) 0036-8075 (Linking)", "ISSN" : "1095-9203", "PMID" : "19729616", "abstract" : "Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells.", "author" : [ { "dropping-particle" : "", "family" : "Amit", "given" : "Ido", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garber", "given" : "Manuel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chevrier", "given" : "Nicolas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leite", "given" : "Ana Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Donner", "given" : "Yoni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eisenhaure", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Guttman", "given" : "Mitchell", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grenier", "given" : "Jennifer K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Weibo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zuk", "given" : "Or", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schubert", "given" : "Lisa A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Birditt", "given" : "Brian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shay", "given" : "Tal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goren", "given" : "Alon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhang", "given" : "Xiaolan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Zachary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deering", "given" : "Raquel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McDonald", "given" : "Rebecca C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cabili", "given" : "Moran", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bernstein", "given" : "Bradley E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rinn", "given" : "John L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Meissner", "given" : "Alex", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Root", "given" : "David E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hacohen", "given" : "Nir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Regev", "given" : "Aviv", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science", "id" : "ITEM-1", "issue" : "5950", "issued" : { "date-parts" : [ [ "2009", "10", "9" ] ] }, "page" : "257-263", "title" : "Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses", "type" : "article-journal", "volume" : "326" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.immuni.2012.04.011", "ISSN" : "10747613", "PMID" : "22705104", "abstract" : "Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.", "author" : [ { "dropping-particle" : "", "family" : "Abt", "given" : "Michael C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Osborne", "given" : "Lisa C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Monticelli", "given" : "Laurel A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doering", "given" : "Travis A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alenghat", "given" : "Theresa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sonnenberg", "given" : "Gregory F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paley", "given" : "Michael A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Antenus", "given" : "Marcelo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "Katie L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erikson", "given" : "Jan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wherry", "given" : "E. John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Artis", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Immunity", "id" : "ITEM-2", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "7", "27" ] ] }, "page" : "158-170", "publisher" : "Elsevier", "title" : "Commensal Bacteria Calibrate the Activation Threshold of Innate Antiviral Immunity", "type" : "article-journal", "volume" : "37" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^122,123", "plainTextFormattedCitation" : "122,123", "previouslyFormattedCitation" : "^122,123" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }122,123. In general, bacteriophage infection of bacteria appears to be omnipresent. This phenomenon has even resulted in the evolution of a diverse array of antiviral defense mechanisms in commensal bacteriaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1462-2920.2012.02775.x", "ISSN" : "1462-2920", "PMID" : "22583485", "abstract" : "Explorations of human microbiota have provided substantial insight into microbial community composition; however, little is known about interactions between various microbial components in human ecosystems. In response to the powerful impact of viral predation, bacteria have acquired potent defences, including an adaptive immune response based on the clustered regularly interspaced short palindromic repeats (CRISPRs)/Cas system. To improve our understanding of the interactions between bacteria and their viruses in humans, we analysed 13\u2003977 streptococcal CRISPR sequences and compared them with 2\u2003588\u2003172 virome reads in the saliva of four human subjects over 17 months. We found a diverse array of viruses and CRISPR spacers, many of which were specific to each subject and time point. There were numerous viral sequences matching CRISPR spacers; these matches were highly specific for salivary viruses. We determined that spacers and viruses coexist at the same time, which suggests that streptococcal CRISPR/Cas systems are under constant pressure from salivary viruses. CRISPRs in some subjects were just as likely to match viral sequences from other subjects as they were to match viruses from the same subject. Because interactions between bacteria and viruses help to determine the structure of bacterial communities, CRISPR-virus analyses are likely to provide insight into the forces shaping the human microbiome.", "author" : [ { "dropping-particle" : "", "family" : "Pride", "given" : "David T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Salzman", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Relman", "given" : "David A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Environmental microbiology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2012", "9" ] ] }, "page" : "2564-76", "title" : "Comparisons of clustered regularly interspaced short palindromic repeats and viromes in human saliva reveal bacterial adaptations to salivary viruses.", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²⁴", "plainTextFormattedCitation" : "124", "previouslyFormattedCitation" : "¹²⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }124. As a consequence, selective infection of specific bacterial strains may regulate the bacterial community composition and may facilitate the adaptation of the bacterial community to novel environments by preserving its diversityADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/1471-2148-13-17", "ISSN" : "1471-2148", "PMID" : "23339571", "abstract" : "BACKGROUND Bacteriophage (viruses that infect bacteria) are of key importance in ecological processes at scales from biofilms to biogeochemical cycles. Close interaction can lead to antagonistic coevolution of phage and their hosts. Selection pressures imposed by phage are often frequency-dependent, such that rare phenotypes are favoured; this occurs when infection depends on some form of genetic matching. Also, resistance to phage often affects host fitness by pleiotropy (whereby mutations conferring resistance affect the function of other traits) and/or direct costs of resistance mechanisms. RESULTS Here a simple model of bacteria and bacteriophage coevolving in a resource-limited chemostat is used to study the effect of coevolving phage on the evolution of bacterial hosts. Density-dependent mortality from phage predation limits the density of any single bacterial strain, preventing competitive exclusion by faster-growing strains. Thus multiple strains can coexist by partitioning resources and stable high diversity is created by negative frequency-dependent selection from phage. Standing bacterial diversity promotes adaptation in dynamic environments, since it increases the likelihood of a pre-existing genotype being suited to altered conditions. In addition, frequency-dependent selection for resistance creates transient local trade-offs between growth rate and resistance that allow bacterial strains to adapt across fitness valleys. Thus bacterial populations that (in the absence of phage) would have been trapped at sub-optimal local peaks in the adaptive landscape are able (in the presence of phage) to reach alternate higher peaks than could have been reached by mutation alone. CONCLUSIONS This study shows that reasonable assumptions for coevolution of bacteria and phage create conditions in which phage increase the evolutionary potential of their hosts. Thus phage, in contrast to their deleterious effects on individual host cells, can confer an evolutionary benefit to bacterial populations. These findings have implications for the role of phage in ecosystem processes, where they have mainly been considered as a mortality factor; these results suggest that on long timescales phage may actually increase bacterial productivity by aiding the evolution of faster-growing strains. Furthermore, these results suggest that the therapeutic use of phage to treat bacterial infections (phage therapy) could have unintended negative side-effects.", "author" : [ { "dropping-particle" : "", "family" : "Williams", "given" : "Hywel T P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC evolutionary biology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "1", "22" ] ] }, "page" : "17", "title" : "Phage-induced diversification improves host evolvability.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²⁵", "plainTextFormattedCitation" : "125", "previouslyFormattedCitation" : "¹²⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }125. A recent study also reported a broad overlap between species-specific bacteriophages and the bacterial community diversity in the lungs, suggesting that substantial interactions between the microbiota and bacteriophages exist in the healthy respiratory tract as wellADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nmicrobiol.2016.31", "ISSN" : "2058-5276", "author" : [ { "dropping-particle" : "", "family" : "Segal", "given" : "Leopoldo N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clemente", "given" : "Jose C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsay", "given" : "Jun-Chieh J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koralov", "given" : "Sergei B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keller", "given" : "Brian C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Benjamin G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Yonghua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shen", "given" : "Nan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ghedin", "given" : "Elodie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morris", "given" : "Alison", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diaz", "given" : "Phillip", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "Laurence", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wikoff", "given" : "William R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ubeda", "given" : "Carles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Artacho", "given" : "Alejandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rom", "given" : "William N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sterman", "given" : "Daniel H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blaser", "given" : "Martin J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiden", "given" : "Michael D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Microbiology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2016", "4", "4" ] ] }, "page" : "16031", "publisher" : "Nature Publishing Group", "title" : "Enrichment of the lung microbiome with oral taxa is associated with lung inflammation of a Th17 phenotype", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹²⁶", "plainTextFormattedCitation" : "126", "previouslyFormattedCitation" : "¹²⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }126.[H3] Fungal-bacterial interactionsMechanistic insight into the interactions between fungi, bacteria, and the host during health is scarce. It has been demonstrated in vitro and in vivo, however, that biofilm formation by S. aureus, Streptococcus spp. and P. aeruginosa damages respiratory epithelia, which allows fungal biofilms to developADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/alr.21138", "ISSN" : "20426976", "author" : [ { "dropping-particle" : "", "family" : "Boase", "given" : "Sam", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jervis-Bardy", "given" : "Joshua", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cleland", "given" : "Edward", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pant", "given" : "Harshita", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tan", "given" : "Lorwai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wormald", "given" : "Peter-John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "International Forum of Allergy & Rhinology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2013", "5" ] ] }, "page" : "341-348", "title" : "Bacterial-induced epithelial damage promotes fungal biofilm formation in a sheep model of sinusitis", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/IAI.05896-11", "ISSN" : "1098-5522", "PMID" : "22104105", "abstract" : "Candida albicans is a commensal colonizer of the gastrointestinal tract of humans, where it coexists with highly diverse bacterial communities. It is not clear whether this interaction limits or promotes the potential of C. albicans to become an opportunistic pathogen. Here we investigate the interaction between C. albicans and three species of streptococci from the viridans group, which are ubiquitous and abundant oral commensal bacteria. The ability of C. albicans to form biofilms with Streptococcus oralis, Streptococcus sanguinis, or Streptococcus gordonii was investigated using flow cell devices that allow abiotic biofilm formation under salivary flow. In addition, we designed a novel flow cell system that allows mucosal biofilm formation under conditions that mimic the environment in the oral and esophageal mucosae. It was observed that C. albicans and streptococci formed a synergistic partnership where C. albicans promoted the ability of streptococci to form biofilms on abiotic surfaces or on the surface of an oral mucosa analogue. The increased ability of streptococci to form biofilms in the presence of C. albicans could not be explained by a growth-stimulatory effect since the streptococci were unaffected in their growth in planktonic coculture with C. albicans. Conversely, the presence of streptococci increased the ability of C. albicans to invade organotypic models of the oral and esophageal mucosae under conditions of salivary flow. Moreover, characterization of mucosal invasion by the biofilm microorganisms suggested that the esophageal mucosa is more permissive to invasion than the oral mucosa. In summary, C. albicans and commensal oral streptococci display a synergistic interaction with implications for the pathogenic potential of C. albicans in the upper gastrointestinal tract.", "author" : [ { "dropping-particle" : "", "family" : "Diaz", "given" : "Patricia I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xie", "given" : "Zhihong", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sobue", "given" : "Takanori", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thompson", "given" : "Angela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biyikoglu", "given" : "Basak", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ricker", "given" : "Austin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ikonomou", "given" : "Laertis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dongari-Bagtzoglou", "given" : "Anna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Infection and immunity", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2012", "2" ] ] }, "page" : "620-32", "publisher" : "American Society for Microbiology (ASM)", "title" : "Synergistic interaction between Candida albicans and commensal oral streptococci in a novel in vitro mucosal model.", "type" : "article-journal", "volume" : "80" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1111/cmi.12216", "ISBN" : "1462-5822 (Electronic)\\r1462-5814 (Linking)", "ISSN" : "14625814", "PMID" : "24079976", "abstract" : "Mitis-group streptococci are ubiquitous oral commensals that can promote polybacterial biofilm virulence. Using a novel murine oral mucosal co-infection model we sought to determine for the first time whether these organisms promote the virulence of C. albicans mucosal biofilms in oropharyngeal infection and explored mechanisms of pathogenic synergy. We found that Streptococcus oralis colonization of the oral and gastrointestinal tract was augmented in the presence of C. albicans. S. oralis and C. albicans co-infection significantly augmented the frequency and size of oral thrush lesions. Importantly, S. oralis promoted deep organ dissemination of C. albicans. Whole mouse genome tongue microarray analysis showed that when compared with animals infected with one organism, the doubly infected animals had genes in the major categories of neutrophilic response/chemotaxis/inflammation significantly upregulated, indicative of an exaggerated inflammatory response. This response was dependent on TLR2 signalling since oral lesions, transcription of pro-inflammatory genes and neutrophil infiltration, were attenuated in TLR2(-/-) animals. Furthermore, S. oralis activated neutrophils in a TLR2-dependent manner in vitro. In summary, this study identifies a previously unrecognized pathogenic synergy between oral commensal bacteriaand C. albicans. This is the first report of the ability of mucosal commensal bacteria to modify the virulence of an opportunistic fungal pathogen.", "author" : [ { "dropping-particle" : "", "family" : "Xu", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sobue", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thompson", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xie", "given" : "Z", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Poon", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ricker", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cervantes", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diaz", "given" : "P I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dongari-Bagtzoglou", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cellular Microbiology", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2014", "2" ] ] }, "page" : "214-231", "publisher" : "Wiley-Blackwell", "title" : "Streptococcal co-infection augments candida pathogenicity by amplifying the mucosal inflammatory response", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^127\u2013129", "plainTextFormattedCitation" : "127\u2013129", "previouslyFormattedCitation" : "^127\u2013129" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }127–129. Furthermore, P. aeruginosa stimulates the growth of Aspergillus fumigatus through sensing of volatile metabolites at a distanceADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00219-16", "ISSN" : "2150-7511", "PMID" : "26980832", "abstract" : "UNLABELLED Chronic lung infections with opportunistic bacterial and fungal pathogens are a major cause of morbidity and mortality especially in patients with cystic fibrosis. Pseudomonas aeruginosa is the most frequently colonizing bacterium in these patients, and it is often found in association with the filamentous fungus Aspergillus fumigatus. P.\u00a0aeruginosa is known to inhibit the growth of A.\u00a0fumigatus in situations of direct contact, suggesting the existence of interspecies communication that may influence disease outcome. Our study shows that the lung pathogens P.\u00a0aeruginosa and A.\u00a0fumigatus can interact at a distance via volatile-mediated communication and expands our understanding of interspecific signaling in microbial communities. IMPORTANCE Microbiota studies have shown that pathogens cannot be studied individually anymore and that the establishment and progression of a specific disease are due not to a single microbial species but are the result of the activity of many species living together. To date, the interaction between members of the human microbiota has been analyzed in situations of direct contact or liquid-mediated contact between organisms. This study showed unexpectedly that human opportunistic pathogens can interact at a distance after sensing volatiles emitted by another microbial species. This finding will open a new research avenue for the understanding of microbial communities.", "author" : [ { "dropping-particle" : "", "family" : "Briard", "given" : "Benoit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heddergott", "given" : "Christoph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Latg\u00e9", "given" : "Jean-Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2016", "3", "15" ] ] }, "page" : "e00219", "title" : "Volatile Compounds Emitted by Pseudomonas aeruginosa Stimulate Growth of the Fungal Pathogen Aspergillus fumigatus.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³⁰", "plainTextFormattedCitation" : "130", "previouslyFormattedCitation" : "¹³⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }130. Conversely, Candida albicans has shown to increase P. aeruginosa prevalence in mice by impeding reactive oxygen species (ROS) production of alveolar macrophagesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/CCM.0b013e31819629d2", "ISBN" : "1530-0293 (Electronic)\\r0090-3493 (Linking)", "ISSN" : "0090-3493", "PMID" : "19237918", "abstract" : "OBJECTIVE: To determine whether Candida albicans airway colonization influences Pseudomonas aeruginosa pneumonia prevalence in rats and by which mechanism. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory of a university. SUBJECTS: Male adult Wistar rats weighing 275-300 g. INTERVENTIONS: In vivo: P. aeruginosa pneumonia was induced by bronchial instillation of P. aeruginosa in rats previously instilled or not with live or ethanol-killed C. albicans. In vitro: Alveolar macrophages were incubated with or without live or ethanol-killed C. albicans. MEASUREMENTS AND MAIN RESULTS: Quantitative cultures of lung were done. Lung tumor necrosis factor alpha, interferon gamma, and interleukin-6 levels were measured along with reactive oxygen species (ROS) production by alveolar macrophages. P. aeruginosa pneumonia prevalence was higher in rats given live but not ethanol-killed C. albicans. Instilling live C. albicans alone increased lung tumor necrosis factor-alpha and interferon-gamma but not interleukin-6, and was not associated with clinical or histologic signs of infection. These three cytokines were more abundant in lungs instilled with live C. albicans and P. aeruginosa than in those instilled with P. aeruginosa alone or with ethanol-killed C. albicans and P. aeruginosa. Alveolar macrophages incubated with live C. albicans had decreased ROS production. CONCLUSIONS: C. albicans impedes alveolar macrophage ROS production and is correlated with an increase of P. aeruginosa pneumonia prevalence in rats. These results highlight the previously overlooked impact of airway fungal colonization on lung bacterial infection, and indicate the need for studies on the potential for antifungal therapy to prevent the onset of ventilator-associated pneumonia caused by P. aeruginosa.", "author" : [ { "dropping-particle" : "", "family" : "Roux", "given" : "Damien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaudry", "given" : "St\u00e9phane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dreyfuss", "given" : "Didier", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "El-Benna", "given" : "Jamel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prost", "given" : "Nicolas", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Denamur", "given" : "Erick", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Saumon", "given" : "Georges", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ricard", "given" : "Jean-Damien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Critical care medicine", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009", "3" ] ] }, "page" : "1062-1067", "title" : "Candida albicans impairs macrophage function and facilitates Pseudomonas aeruginosa pneumonia in rat.", "type" : "article-journal", "volume" : "37" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³¹", "plainTextFormattedCitation" : "131", "previouslyFormattedCitation" : "¹³¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }131. To date, the exact role and breadth of mechanisms by which fungi contribute to a healthy equilibrium at the respiratory tract have until now unfortunately remained unstudied. Although studies suggest the importance of both the respiratory virome and mycobiome in respiratory health, there is a considerable knowledge gap in their exact contributions to health compared to the role of the bacterial microbiome. However, current evidence provides an important basis for further in depth analyses of the interactions that exist between bacteria, viruses and fungi, as well as the impact of host and environmental factors on these interactions.[H1] Host-bacterial interactionsWith a vast number of commensals and potential pathogens inhabiting the respiratory tract mucosa, a delicate equilibrium has to be maintained between immune sensing and tolerance of non-pathogenic commensals on the one hand and the containment of resident pathogens and new invaders on the other. This fine balance is of specific importance to the LRT, as gaseous exchange is absolutely essential for human life, and the lungs are exceptionally susceptible to damage from inflammatory responses. In this section, we will give an overview of the immune components that have a role in immune homeostasis in the URT and lungs. A detailed discussion of host-bacterial interactions and their role in immune homeostasis, organogenesis and immune education is given in BOX 2 and 3, respectively. In addition to bacteria, viruses may also symbiotically influence host immune homeostasis, which is discussed in BOX 4.The respiratory tract is exposed to large quantities of airborne particles from the environment. The first line of defense is the mucus layer of the nasopharynx and conducting airways. The mucus traps these particles, including microbial pathogens, which are then cleared through ciliary action towards the oral cavity. Additionally, the glycoproteins in the mucus accommodate resident microorganisms and prevent infectionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mi.2008.5", "ISSN" : "1933-0219", "PMID" : "19079178", "abstract" : "The mucosal tissues of the gastrointestinal, respiratory, reproductive, and urinary tracts, and the surface of the eye present an enormous surface area to the exterior environment. All of these tissues are covered with resident microbial flora, which vary considerably in composition and complexity. Mucosal tissues represent the site of infection or route of access for the majority of viruses, bacteria, yeast, protozoa, and multicellular parasites that cause human disease. Mucin glycoproteins are secreted in large quantities by mucosal epithelia, and cell surface mucins are a prominent feature of the apical glycocalyx of all mucosal epithelia. In this review, we highlight the central role played by mucins in accommodating the resident commensal flora and limiting infectious disease, interplay between underlying innate and adaptive immunity and mucins, and the strategies used by successful mucosal pathogens to subvert or avoid the mucin barrier, with a particular focus on bacteria.", "author" : [ { "dropping-particle" : "", "family" : "Linden", "given" : "S K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sutton", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Karlsson", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Korolik", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McGuckin", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Mucosal Immunology", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "5", "5" ] ] }, "page" : "183-197", "title" : "Mucins in the mucosal barrier to infection", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³²", "plainTextFormattedCitation" : "132", "previouslyFormattedCitation" : "¹³²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }132, as evidenced by the decrease in anti-bacterial cytokines and presence of phagocytosis-impaired macrophages in lungs of mucin-deficient miceADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature12807", "ISBN" : "1476-4687 (Electronic)\\r0028-0836 (Linking)", "ISSN" : "1476-4687", "PMID" : "24317696", "abstract" : "Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.", "author" : [ { "dropping-particle" : "", "family" : "Roy", "given" : "Michelle G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Livraghi-Butrico", "given" : "Alessandra", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fletcher", "given" : "Ashley A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McElwee", "given" : "Melissa M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "Scott E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { 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NALT has an important role in the induction of mucosal immune responses, including the generation of T helper 1 and T helper 2 cells, and IgA-committed B cells. Moreover, intranasal immunization can lead to the induction of antigen-specific protective immunity in both the mucosal and systemic immune compartments. Therefore, a greater understanding of the differences between NALT and other organized lymphoid tissues, such as Peyer's patches, should facilitate the development of nasal vaccines.", "author" : [ { "dropping-particle" : "", "family" : "Kiyono", "given" : "Hiroshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukuyama", "given" : "Satoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature reviews. Immunology", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2004", "9" ] ] }, "page" : "699-710", "title" : "NALT- versus Peyer's-patch-mediated mucosal immunity.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³⁴", "plainTextFormattedCitation" : "134", "previouslyFormattedCitation" : "¹³⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }134 and can preclude pathogens from inhabiting the mucosal surface and interacting with epithelial surface receptors. IgA is also hypothesized to be involved in the regulation and selection of commensal microorganisms and establishing symbiotic host-microorganisms interactionsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.immuni.2014.05.016", "ISSN" : "10747613", "PMID" : "25017466", "abstract" : "Foxp3(+) T cells play a critical role for the maintenance of immune tolerance. Here we show that in mice, Foxp3(+) T cells contributed to diversification of gut microbiota, particularly of species belonging to Firmicutes. The control of indigenous bacteria by Foxp3(+) T cells involved regulatory functions both outside and inside germinal centers (GCs), consisting of suppression of inflammation and regulation of immunoglobulin A (IgA) selection in Peyer's patches, respectively. Diversified and selected IgAs contributed to maintenance of diversified and balanced microbiota, which in turn facilitated the expansion of Foxp3(+) T cells, induction of GCs, and IgA responses in the gut through a symbiotic regulatory loop. 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IgA continues to maintain dynamic interactions with the gut microbiota throughout life and this influences immune system homeostasis as well as other physiological processes. The secretory IgA produced independently of T-cell selection are commonly referred to as natural or innate antibodies. Our studies have shown that innate-IgA, while effective at excluding microorganisms from the gut, does not promote mutualism with the microbiota in the same way as adaptive-IgA that is selected in T cell-dependent germinal center reactions. Adaptive-IgA fosters more advanced mutualism with the microbiota than innate-IgA by selecting and diversifying beneficial microbial communities. 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In parallel, alveolar surfactant has an important role in lung innate immunity as a deficiency in surfactant protein A has been associated with diminished bacterial phagocytosis and killing by alveolar macrophagesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-1767", "PMID" : "11034401", "abstract" : "Mice lacking surfactant protein (SP)-A (SP-A-/-) or SP-D (SP-D-/-) and wild-type mice were infected with group B streptococcus or Haemophilus influenzae by intratracheal instillation. Although decreased killing of group B streptococcus and H. influenzae was observed in SP-A-/- mice but not in SP-D-/- mice, deficiency of either SP-A or SP-D was associated with increased inflammation and inflammatory cell recruitment in the lung after infection. Deficient uptake of bacteria by alveolar macrophages was observed in both SP-A- and SP-D-deficient mice. Isolated alveolar macrophages from SP-A-/- mice generated significantly less, whereas those from SP-D-/- mice generated significantly greater superoxide and hydrogen peroxide compared with wild-type alveolar macrophages. In SP-D-/- mice, bacterial killing was associated with increased lung inflammation, increased oxidant production, and decreased macrophage phagocytosis. In contrast, in the absence of SP-A, bacterial killing was decreased and associated with increased lung inflammation, decreased oxidant production, and decreased macrophage phagocytosis. Increased oxidant production likely contributes to effective bacterial killing in the lungs of SP-D-/- mice. 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The airway epithelium produces various antimicrobial substances that contribute to barrier function, including human beta-defensin-2ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.molimm.2007.02.007", "ISSN" : "01615890", "PMID" : "17403538", "abstract" : "Epithelial cells may form the first barrier of defense against bacteria in human tissues. We recently revealed that oral epithelial cells generated anti-bacterial factors, such as peptidoglycan recognition proteins (PGRPs) and beta-defensin 2, but not proinflammatory cytokines, such as interleukin-8 (IL-8), upon stimulation with bacterial cell-surface components. In this study, we found clear expressions of Toll-like receptor (TLR)2, TLR3, TLR4, TLR7, NOD1 and NOD2 in oral, tongue, salivary gland, pharyngeal, esophageal, intestinal, cervical, breast, lung, and kidney epithelial cells. However, tongue, salivary gland, pharyngeal, esophageal, intestinal, cervical, breast, lung, and kidney epithelial cells, as well as oral epithelial cells, did not secrete IL-6, IL-8 or monocyte chemoattractant protein-1 in response to chemically synthesized TLR and NOD agonists mimicking microbial components: TLR2 agonistic lipopeptide (Pam3CSSNA), TLR3 agonistic Poly I:C, TLR4 agonistic lipid A (LA-15-PP), TLR7 agonistic single stranded RNA (ssPoly U), NOD1 agonistic iE-DAP (gamma-D-glumtamyl-meso-diaminopimelic acid), and NOD2 agonistic muramyldipeptide (MDP). Although PGRPs on oral epithelial cells were significantly up-regulated upon stimulation with these synthetic components, PGRPs on pharyngeal epithelial cells were only slightly up-regulated, and PGRPs on esophageal, intestinal and cervical epithelial cells were not up-regulated upon stimulation with the components. 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Pharyngeal and lung epithelial cells, as well as macrophages and dendritic cells (DCs), possess various receptors to sense the microbiota, including innate pattern recognition receptors (PRRs) such as TLRs and nucleotide-binding oligomerization domain (NOD)-like receptorsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.molimm.2007.02.007", "ISSN" : "01615890", "PMID" : "17403538", "abstract" : "Epithelial cells may form the first barrier of defense against bacteria in human tissues. We recently revealed that oral epithelial cells generated anti-bacterial factors, such as peptidoglycan recognition proteins (PGRPs) and beta-defensin 2, but not proinflammatory cytokines, such as interleukin-8 (IL-8), upon stimulation with bacterial cell-surface components. 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Although PGRPs on oral epithelial cells were significantly up-regulated upon stimulation with these synthetic components, PGRPs on pharyngeal epithelial cells were only slightly up-regulated, and PGRPs on esophageal, intestinal and cervical epithelial cells were not up-regulated upon stimulation with the components. In contrast, stimulation with synthetic TLRs and NODs ligands induced beta-defensin 2 generation in all epithelial cells examined. These findings indicate that TLR and NOD in various epithelial cells are functional receptors that induce anti-bacterial responses in general without being accompanied by inflammatory responses.", "author" : [ { "dropping-particle" : "", "family" : "Uehara", "given" : "Akiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fujimoto", "given" : "Yukari", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukase", "given" : "Koichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takada", "given" : "Haruhiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular Immunology", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2007", "5" ] ] }, "page" : "3100-3111", "title" : "Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³⁸", "plainTextFormattedCitation" : "138", "previouslyFormattedCitation" : "¹³⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }138, which are central to balancing the activation of downstream inflammatory signaling with maintenance of immune tolerance. The epithelium in the URT is supported by mucosa-associated lymphoid tissue (MALT) tissue, which is populated with microfold (M) cells that transport micro-organisms from the epithelium to the lamina propria, where they can activate DCsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4049/jimmunol.0903794", "ISSN" : "0022-1767", "PMID" : "21357262", "abstract" : "In this study, we demonstrated a new airway Ag sampling site by analyzing tissue sections of the murine nasal passages. We revealed the presence of respiratory M cells, which had the ability to take up OVA and recombinant Salmonella typhimurium expressing GFP, in the turbinates covered with single-layer epithelium. These M cells were also capable of taking up respiratory pathogen group A Streptococcus after nasal challenge. Inhibitor of DNA binding/differentiation 2 (Id2)-deficient mice, which are deficient in lymphoid tissues, including nasopharynx-associated lymphoid tissue, had a similar frequency of M cell clusters in their nasal epithelia to that of their littermates, Id2(+/-) mice. The titers of Ag-specific Abs were as high in Id2(-/-) mice as in Id2(+/-) mice after nasal immunization with recombinant Salmonella-ToxC or group A Streptococcus, indicating that respiratory M cells were capable of sampling inhaled bacterial Ag to initiate an Ag-specific immune response. Taken together, these findings suggest that respiratory M cells act as a nasopharynx-associated lymphoid tissue-independent alternative gateway for Ag sampling and subsequent induction of Ag-specific immune responses in the upper respiratory tract.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "D.-Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sato", "given" : "A.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukuyama", "given" : "Satoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sagara", "given" : "Hiroshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nagatake", "given" : "Takahiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kong", "given" : "Il Gyu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goda", "given" : "Kaoru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nochi", "given" : "Tomonori", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kunisawa", "given" : "Jun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sato", "given" : "Shintaro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yokota", "given" : "Yoshifumi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Chul Hee", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kiyono", "given" : "Hiroshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Immunology", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "4", "1" ] ] }, "page" : "4253-4262", "title" : "The Airway Antigen Sampling System: Respiratory M Cells as an Alternative Gateway for Inhaled Antigens", "type" : "article-journal", "volume" : "186" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³⁹", "plainTextFormattedCitation" : "139", "previouslyFormattedCitation" : "¹³⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }139. In the lung, DCs are located within and directly below the alveolar epithelium, where they continuously sample the alveolar spaceADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-1767", "PMID" : "17056510", "abstract" : "An increase in the tempo of local dendritic cell (DC)-mediated immune surveillance is a recognized feature of the response to acute inflammation at airway mucosal surfaces, and transient up-regulation of the APC functions of these DC preceding their emigration to regional lymph nodes has recently been identified as an important trigger for T cell-mediated airway tissue damage in diseases such as asthma. In this study, using a rat model, we demonstrate that the kinetics of the airway mucosal DC (AMDC) response to challenge with heat-killed bacteria is considerably more rapid and as a consequence more effectively compartmentalized than that in recall responses to soluble Ag. Notably, Ag-bearing AMDC expressing full APC activity reach regional lymph nodes within 30 min of cessation of microbial exposure, and in contrast to recall responses to nonpathogenic Ags, there is no evidence of local expression of APC activity within the airway mucosa preceding DC emigration. We additionally demonstrate that, analogous to that reported in the gut, a subset of airway intraepithelial DC extend their processes into the airway lumen. This function is constitutively expressed within the AMDC population, providing a mechanism for continuous immune surveillance of the airway luminal surface in the absence of \"danger\" signals.", "author" : [ { "dropping-particle" : "", "family" : "Jahnsen", "given" : "Frode L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Strickland", "given" : "Deborah H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thomas", "given" : "Jennifer A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tobagus", "given" : "Iriani T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Napoli", "given" : "Sylvia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zosky", "given" : "Graeme R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turner", "given" : "Debra J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sly", "given" : "Peter D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stumbles", "given" : "Philip A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holt", "given" : "Patrick G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of immunology (Baltimore, Md. : 1950)", "id" : "ITEM-1", "issue" : "9", "issued" : { "date-parts" : [ [ "2006", "11", "1" ] ] }, "page" : "5861-7", "title" : "Accelerated antigen sampling and transport by airway mucosal dendritic cells following inhalation of a bacterial stimulus.", "type" : "article-journal", "volume" : "177" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴⁰", "plainTextFormattedCitation" : "140", "previouslyFormattedCitation" : "¹⁴⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }140. Subsequently they present processed antigen to different subsets of T-cells in the lung-draining lymph node, which initiates adaptive immune responses. Anti-inflammatory alveolar macrophages are central in lung immune homeostasis and for regulating the cross-talk between epithelial cells, DCs and T-cells (reviewed in ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ni.3052", "ISSN" : "1529-2908", "author" : [ { "dropping-particle" : "", "family" : "Kopf", "given" : "Manfred", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schneider", "given" : "Christoph", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nobs", "given" : "Samuel P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Immunology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "12", "18" ] ] }, "page" : "36-44", "publisher" : "Nature Research", "title" : "The development and function of lung-resident macrophages and dendritic cells", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴¹", "plainTextFormattedCitation" : "141", "previouslyFormattedCitation" : "¹⁴¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }141 and ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nri3600", "ISSN" : "1474-1733", "author" : [ { "dropping-particle" : "", "family" : "Hussell", "given" : "Tracy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bell", "given" : "Thomas J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Reviews Immunology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2014", "1", "21" ] ] }, "page" : "81-93", "publisher" : "Nature Research", "title" : "Alveolar macrophages: plasticity in a tissue-specific context", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴²", "plainTextFormattedCitation" : "142", "previouslyFormattedCitation" : "¹⁴²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }142). These cells dampen TLR-induced inflammatory signals in epithelial cellsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature12902", "ISBN" : "1476-4687 (Electronic)\\n0028-0836 (Linking)", "ISSN" : "1476-4687", "PMID" : "24463523", "abstract" : "The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca(2+) waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca(2+)-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.", "author" : [ { "dropping-particle" : "", "family" : "Westphalen", "given" : "Kristin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gusarova", "given" : "Galina A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Islam", "given" : "Mohammad N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Subramanian", "given" : "Manikandan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cohen", "given" : "Taylor S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Prince", "given" : "Alice S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhattacharya", "given" : "Jahar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7489", "issued" : { "date-parts" : [ [ "2014", "2", "27" ] ] }, "page" : "503-506", "title" : "Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity.", "type" : "article-journal", "volume" : "506" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴³", "plainTextFormattedCitation" : "143", "previouslyFormattedCitation" : "¹⁴³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }143, suppress inflammation by inhibiting DC-medicated activation of T-cellsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0022-1007", "PMID" : "8426110", "abstract" : "Class II major histocompatibility complex (Ia)-bearing dendritic cells (DC) from airway epithelium and lung parenchyma express low-moderate antigen presenting cell (APC) activity when freshly isolated. However, this function is markedly upregulated during overnight culture in a manner analogous to epidermal Langerhans cells. The in vitro \"maturation\" process is inhibited by coculture with pulmonary alveolar macrophages (PAM) across a semipermeable membrane, and the degree of inhibition achieved can be markedly increased by the presence of tumor necrosis factor alpha. In addition, PAM-mediated suppression of DC function is abrogated via inhibition of the nitric oxide synthetase pathway. Functional maturation of the DC is accompanied by increased expression of surface Ia, which is also inhibited in the presence of PAM. Prior elimination of PAM from DC donors via intratracheal administration of the cytotoxic drug dichloromethylene diphosphonate in liposomes, 24-72 h before lung DC preparation, achieves a comparable upregulation of APC activity, suggesting that (consistent with the in vitro data) the resident PAM population actively suppresses the APC function of lung DC in situ. In support of the feasibility of such a regulatory mechanism, electron microscopic examination of normal lung fixed by intravascular perfusion in the inflated state (which optimally preserves PAM in situ), revealed that the majority are preferentially localized in recesses at the alveolar septal junctions. In this position, the PAM are in intimate association with the alveolar epithelial surface, and are effectively separated by as little as 0.2 microns from underlying interstitial spaces which contain the peripheral lung DC population. A similar juxtaposition of airway intraepithelial DC is demonstrated with underlying submucosal tissue macrophages, where the separation between the two cell populations is effectively the width of the basal lamina.", "author" : [ { "dropping-particle" : "", "family" : "Holt", "given" : "P G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliver", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bilyk", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McMenamin", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McMenamin", "given" : "P G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kraal", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thepen", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of experimental medicine", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "1993", "2", "1" ] ] }, "page" : "397-407", "title" : "Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages.", "type" : "article-journal", "volume" : "177" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0022-1007", "PMID" : "3162253", "abstract" : "Collagenase digestion of tissue slices from perfused, lavaged SPF rat lung released approximately 10(8) viable mononuclear cells per gram tissue, which comprised 35% T lymphocytes and up to 26% macrophages. A subset of these cells that were Ia+, surface Ig-, nonadherent, FcR- and of ultra low density (putative dendritic cells [DC]), presented protein antigen to immune T cells in vitro, and this function was inhibited by the presence of low numbers of endogenous adherent, FcR+ cells (putative macrophages). APCs were also identified in digests from tracheal epithelium, and were shown to bind antigen in immunogenic form as a result of natural (inhalation) exposure in vivo. Immunoperoxidase staining of frozen sections revealed populations of strongly Ia+ cells with prominent DC-like morphology within the alveolar septal walls and the tracheal epithelium; in both areas, they were closely associated with pleiomorphic cells that expressed macrophage surface markers. We accordingly postulate that interactions between Ia+ antigen-presenting DCs and endogenous tissue macrophages play an important role in regulating T cell activity in the respiratory tract.", "author" : [ { "dropping-particle" : "", "family" : "Holt", "given" : "P G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schon-Hegrad", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oliver", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of experimental medicine", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "1988", "2", "1" ] ] }, "page" : "262-74", "title" : "MHC class II antigen-bearing dendritic cells in pulmonary tissues of the rat. Regulation of antigen presentation activity by endogenous macrophage populations.", "type" : "article-journal", "volume" : "167" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^144,145", "plainTextFormattedCitation" : "144,145", "previouslyFormattedCitation" : "^144,145" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }144,145, and induction of regulatory cellsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1084/jem.20121849", "ISBN" : "1540-9538 (Electronic)\\r0022-1007 (Linking)", "ISSN" : "0022-1007", "PMID" : "23547101", "abstract" : "Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (M\u00d8s), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3(+) iTreg cells is unclear. Here, we show that lung-resident tissue M\u00d8s coexpress TGF-\u03b2 and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3(+) Treg cells. Treg cell induction in this model depended on both TGF-\u03b2 and retinoic acid. Transfer of the antigen-pulsed tissue M\u00d8s into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue M\u00d8s to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue M\u00d8s have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma.", "author" : [ { "dropping-particle" : "", "family" : "Soroosh", "given" : "Pejman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doherty", "given" : "Taylor A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Duan", "given" : "Wei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mehta", "given" : "Amit Kumar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Choi", "given" : "Heonsik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Adams", "given" : "Yan Fei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mikulski", "given" : "Zbigniew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khorram", "given" : "Naseem", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosenthal", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Broide", "given" : "David H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Croft", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Experimental Medicine", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4", "8" ] ] }, "page" : "775-788", "title" : "Lung-resident tissue macrophages generate Foxp3 + regulatory T cells and promote airway tolerance", "type" : "article-journal", "volume" : "210" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴⁶", "plainTextFormattedCitation" : "146", "previouslyFormattedCitation" : "¹⁴⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }146.In conclusion, host-microbiota interactions influence different aspects of immune system development and contribute to immune maturation, immune tolerance and resistance to bacterial infection.[H1] Conclusions and perspectivesThe advent of massive parallel sequencingADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature03959", "ISBN" : "1476-4687 (Electronic)", "ISSN" : "1476-4687", "PMID" : "16056220", "abstract" : "The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. 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Studies show that different ecological niches within the respiratory tract are occupied by diverse microbial communities that could act as gatekeepers to respiratory health. Further studies will be required to understand the pressures shaping these communities, their precise functions and contributions to human health. Efforts should focus on reductionist approaches to understand the underlying mechanisms of environment-microorganism, microorganism-microorganism and microorganism-host interactions within their authentic ecological context. The use of in vitro models that allow for the manipulation of specific bacterial and host or environmental factors could substantially advance our understanding of the respiratory microbiota. In addition, in vivo optical imaging techniques will help to visualize host-microbiota or intra-microbiota interactions in their spatial context in health and diseaseADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s40336-016-0180-0", "ISSN" : "2281-5872", "PMID" : "27340649", "abstract" : "The rise in multidrug resistant (MDR) bacteria has become a global crisis. Rapid and accurate diagnosis of infection will facilitate antibiotic stewardship and preserve our ability to treat and cure patients from bacterial infection. Direct in situ imaging of bacteria offers the prospect of accurately diagnosing disease and monitoring patient outcomes and response to treatment in real-time. There have been many recent advances in the field of optical imaging of infection; namely in specific probe and fluorophore design. This combined with the advances in imaging device technology render direct optical imaging of infection a feasible approach for accurate diagnosis in the clinic. Despite this, there are currently no licensed molecular probes for clinical optical imaging of infection. Here we report some of the most promising and interesting probes and approaches under development for this purpose, which have been evaluated in in vivo models within the laboratory setting.", "author" : [ { "dropping-particle" : "", "family" : "Mills", "given" : "Bethany", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bradley", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dhaliwal", "given" : "Kevin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical and Translational Imaging", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2016", "6", "4" ] ] }, "page" : "163-174", "title" : "Optical imaging of bacterial infections", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴⁸", "plainTextFormattedCitation" : "148", "previouslyFormattedCitation" : "¹⁴⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }148. Data derived from these approaches could be utilized in mathematical models to reconstruct bacterial interactions and study host and environmental forces that govern microbial behaviourADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.chom.2016.02.021", "ISBN" : "1934-6069 (Electronic)\\r1931-3128 (Linking)", "ISSN" : "19346069", "PMID" : "27053168", "abstract" : "The host epithelium is the critical interface with microbial communities, but the mechanisms by which the host regulates these communities are poorly understood. Here we develop the hypothesis that hosts use differential adhesion to select for and against particular members of their microbiota. We use an established computational, individual-based model to study the impact of host factors that regulate adhesion at the epithelial surface. Our simulations predict that host-mediated adhesion can increase the competitive advantage of microbes and create ecological refugia for slow-growing species. We show how positive selection via adhesion can be transformed into negative selection if the host secretes large quantities of a matrix such as mucus. Our work predicts that adhesion is a powerful mechanism for both positive and negative selection within the microbiota. We discuss molecules - mucus glycans and IgA - that affect microbe adhesion and identify testable predictions of the adhesion-as-selection model.", "author" : [ { "dropping-particle" : "", "family" : "McLoughlin", "given" : "Kirstie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schluter", "given" : "Jonas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rakoff-Nahoum", "given" : "Seth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Adrian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "Kevin R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell Host and Microbe", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2016", "4", "13" ] ] }, "page" : "550-559", "title" : "Host Selection of Microbiota via Differential Adhesion", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁴⁹", "plainTextFormattedCitation" : "149", "previouslyFormattedCitation" : "¹⁴⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }149.In addition to the in-depth studies of highly complex and context-dependent interspecies and host-microbiota interaction networks, holistic approaches remain important. Although studies on the respiratory tract microbiota composition did not show substantial differences between different developed countries, the question as to whether comparable host and environmental factors regulate the respiratory microbiota of individuals living in low-middle-income countries remains an important open question. The high burden of infectious and inflammation-related diseases in developing areas of the world might at least in part be related to compositional changes in the respiratory microbiota composition, and vice versaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S0140-6736(12)60560-1", "ISBN" : "1474-547X", "ISSN" : "01406736", "PMID" : "22579125", "abstract" : "Background: Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. Methods: Updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1-59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. Findings: Of 7??6 million deaths in children younger than 5 years in 2010, 64??0 (4??879 million) were attributable to infectious causes and 40??3 (3??072 million) occurred in neonates. Preterm birth complications (14??1; 1??078 million, uncertainty range [UR] 0??916-1??325), intrapartum-related complications (9??4; 0??717 million, 0??610-0??876), and sepsis or meningitis (5??2; 0??393 million, 0??252-0??552) were the leading causes of neonatal death. In older children, pneumonia (14??1; 1??071 million, 0??977-1??176), diarrhoea (9??9; 0??751 million, 0??538-1??031), and malaria (7??4; 0??564 million, 0??432-0??709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2??7 (0??205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0??451 million [0??339-0??547], 0??363 million [0??283-0??419], and 0??359 million [0??215- 0??476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. Interpretation: Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010-15 will need accelerated reduction for the most common causes of death, notabl\u2026", "author" : [ { "dropping-particle" : "", "family" : "Liu", "given" : "Li", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "Hope L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cousens", "given" : "Simon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Perin", "given" : "Jamie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Scott", "given" : "Susana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lawn", "given" : "Joy E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rudan", "given" : "Igor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Campbell", "given" : "Harry", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cibulskis", "given" : "Richard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Mengying", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mathers", "given" : "Colin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Black", "given" : "Robert E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Lancet", "id" : "ITEM-1", "issue" : "9832", "issued" : { "date-parts" : [ [ "2012", "6", "9" ] ] }, "page" : "2151-2161", "title" : "Global, regional, and national causes of child mortality: An updated systematic analysis for 2010 with time trends since 2000", "type" : "article-journal", "volume" : "379" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵⁰", "plainTextFormattedCitation" : "150", "previouslyFormattedCitation" : "¹⁵⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }150. Most progress can be expected from large cohort studies, in which the microbiota of healthy individuals and individuals at an increased risk of infectious respiratory diseases is longitudinally characterized. In parallel, (host) transcriptomics and metabolomics data, and metadata (crowding conditions, social and medical context) should be collected to study the cross-talk between host and microorganism, microbiota function, and impact of environmental factors on microbiota composition. Consequently, advances in bioinformatics will be required to appropriately combine and analyze multiple high-dimensional datasets. Methods to analyze complex combinatorial data sets are sparse, yet the field is rapidly progressing by applying machine learning algorithms and time-resolved data modeling. A multi-disciplinary approach to extract patterns and associations from these studies could culminate in individualized risk assessment and preventive personalized medicine, as illustrated by a study in which dietary interventions were made based on the gut microbiota led to improved control of post-meal glucose levelsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2015.11.001", "ISBN" : "00928674", "ISSN" : "10974172", "PMID" : "26590418", "abstract" : "Summary Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences. 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Microbiota-based interventions are likely to be most beneficial in young children, as a ‘window of opportunity’ within which the local microbiota primes specific features of the immune system appears to exist. Interventions during this impressionable period could redirect an aberrant developmental route, potentially influencing long-term respiratory health.Box 1 | Technical challenges in respiratory microbiome researchRespiratory microbiome research faces general and niche-specific challenges. The absence of uniform laboratory practices (sample storage, DNA isolation and choice of 16S rRNA variable region) and bioinformatics and data analysis pipelines limit the potential to perform accurate comparative or meta-analyses. Although different research questions require different approaches, more energy should be put into the development of standardized operating procedures, comparable to, for example, the Earth Microbiome project protocolADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ismej.2012.8", "ISSN" : "1751-7370", "PMID" : "22402401", "abstract" : "DNA sequencing continues to decrease in cost with the Illumina HiSeq2000 generating up to 600 Gb of paired-end 100 base reads in a ten-day run. Here we present a protocol for community amplicon sequencing on the HiSeq2000 and MiSeq Illumina platforms, and apply that protocol to sequence 24 microbial communities from host-associated and free-living environments. A critical question as more sequencing platforms become available is whether biological conclusions derived on one platform are consistent with what would be derived on a different platform. We show that the protocol developed for these instruments successfully recaptures known biological results, and additionally that biological conclusions are consistent across sequencing platforms (the HiSeq2000 versus the MiSeq) and across the sequenced regions of amplicons.", "author" : [ { "dropping-particle" : "", "family" : "Caporaso", "given" : "J Gregory", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lauber", "given" : "Christian L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walters", "given" : "William A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Berg-Lyons", "given" : "Donna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huntley", "given" : "James", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fierer", "given" : "Noah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Owens", "given" : "Sarah M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Betley", "given" : "Jason", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fraser", "given" : "Louise", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bauer", "given" : "Markus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gormley", "given" : "Niall", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gilbert", "given" : "Jack A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Geoff", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "Rob", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The ISME journal", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2012", "8" ] ] }, "page" : "1621-4", "title" : "Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms.", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵²", "plainTextFormattedCitation" : "152", "previouslyFormattedCitation" : "¹⁵²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }152.A specific challenge in microbiota surveys of the respiratory tract is the low density of bacterial communities found there, particularly in healthy individuals; densities as low as 102-103 bacteria per mL have been reported in bronchial alveolar lavages (BALs) of healthy individualsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1164/rccm.201304-0775OC", "ISSN" : "1535-4970", "PMID" : "24024497", "abstract" : "RATIONALE The role of airway microbiome in corticosteroid response in asthma is unknown. OBJECTIVES To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. METHODS 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. MEASUREMENTS AND MAIN RESULTS Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-\u03b2-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. CONCLUSIONS A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.", "author" : [ { "dropping-particle" : "", "family" : "Goleva", "given" : "Elena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Leisa P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harris", "given" : "J Kirk", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robertson", "given" : "Charles E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sutherland", "given" : "E Rand", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall", "given" : "Clifton F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Good", "given" : "James T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gelfand", "given" : "Erwin W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "Richard J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leung", "given" : "Donald Y M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-2", "issue" : "10", "issued" : { "date-parts" : [ [ "2013", "11", "15" ] ] }, "page" : "1193-201", "title" : "The effects of airway microbiome on corticosteroid responsiveness in asthma.", "type" : "article-journal", "volume" : "188" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^74,153", "plainTextFormattedCitation" : "74,153", "previouslyFormattedCitation" : "^74,153" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }74,153. Such low quantities of DNA preclude whole-genome sequencing, resulting in hampered taxonomic resolution and functional interpretation of microbiome data. Furthermore, sampling of the lower airways is cumbersome and typically based on BAL or collection of expectorated sputum. Both sampling methods carry a high risk of cross-contamination of the LRT samples with resident bacterial communities in the URT. Discrimination between authentic LRT communities and URT contamination is complicated because of the anatomical link between both niches. Once bacterial DNA has been extracted, the quantity can be so low that environmental DNA contamination invalidates the resultsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s12915-014-0087-z", "ISBN" : "1741-7007 (Electronic)\\r1741-7007 (Linking)", "ISSN" : "1741-7007", "PMID" : "25387460", "abstract" : "BACKGROUND:The study of microbial communities has been revolutionised in recent years by the widespread adoption of culture independent analytical techniques such as 16S rRNA gene sequencing and metagenomics. One potential confounder of these sequence-based approaches is the presence of contamination in DNA extraction kits and other laboratory reagents.RESULTS:In this study we demonstrate that contaminating DNA is ubiquitous in commonly used DNA extraction kits and other laboratory reagents, varies greatly in composition between different kits and kit batches, and that this contamination critically impacts results obtained from samples containing a low microbial biomass. Contamination impacts both PCR-based 16S rRNA gene surveys and shotgun metagenomics. We provide an extensive list of potential contaminating genera, and guidelines on how to mitigate the effects of contamination.CONCLUSIONS:These results suggest that caution should be advised when applying sequence-based techniques to the study of microbiota present in low biomass environments. Concurrent sequencing of negative control samples is strongly advised.", "author" : [ { "dropping-particle" : "", "family" : "Salter", "given" : "Susannah J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "Michael J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turek", "given" : "Elena M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Calus", "given" : "Szymon T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cookson", "given" : "William O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moffatt", "given" : "Miriam F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Turner", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parkhill", "given" : "Julian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loman", "given" : "Nicholas J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walker", "given" : "Alan W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC Biology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2014", "11", "12" ] ] }, "language" : "En", "page" : "87", "publisher" : "BioMed Central", "title" : "Reagent and laboratory contamination can critically impact sequence-based microbiome analyses", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵⁴", "plainTextFormattedCitation" : "154", "previouslyFormattedCitation" : "¹⁵⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }154,ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0032942", "ISBN" : "1932-6203 (Electronic) 1932-6203 (Linking)", "ISSN" : "1932-6203", "PMID" : "22412957", "abstract" : "INTRODUCTION: Accurate analyses of microbiota composition of low-density communities (10(3)-10(4) bacteria/sample) can be challenging. Background DNA from chemicals and consumables, extraction biases as well as differences in PCR efficiency can significantly interfere with microbiota assessment. This study was aiming to establish protocols for accurate microbiota analysis at low microbial density.\\n\\nMETHODS: To examine possible effects of bacterial density on microbiota analyses we compared microbiota profiles of serial diluted saliva and low (nares, nasopharynx) and high-density (oropharynx) upper airway communities in four healthy individuals. DNA was extracted with four different extraction methods (Epicentre Masterpure, Qiagen DNeasy, Mobio Powersoil and a phenol bead-beating protocol combined with Agowa-Mag-mini). Bacterial DNA recovery was analysed by 16S qPCR and microbiota profiles through GS-FLX-Titanium-Sequencing of 16S rRNA gene amplicons spanning the V5-V7 regions.\\n\\nRESULTS: Lower template concentrations significantly impacted microbiota profiling results. With higher dilutions, low abundant species were overrepresented. In samples of <10(5) bacteria per ml, e.g. DNA <1 pg/\u00b5l, microbiota profiling deviated from the original sample and other dilutions showing a significant increase in the taxa Proteobacteria and decrease in Bacteroidetes. In similar low density samples, DNA extraction method determined if DNA levels were below or above 1 pg/\u00b5l and, together with lysis preferences per method, had profound impact on microbiota analyses in both relative abundance as well as representation of species.\\n\\nCONCLUSION: This study aimed to interpret microbiota analyses of low-density communities. Bacterial density seemed to interfere with microbiota analyses at < than 10(6) bacteria per ml or DNA <1 pg/\u00b5l. We therefore recommend this threshold for working with low density materials. This study underlines that bias reduction is crucial for adequate profiling of especially low-density bacterial communities.", "author" : [ { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roeselers", "given" : "Guus", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Xinhui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caspers", "given" : "Martien P M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trzci\u0144ski", "given" : "Krzysztof", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2012" ] ] }, "page" : "e32942", "title" : "Deep sequencing analyses of low density microbial communities: working at the boundary of accurate microbiota detection.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵⁵", "plainTextFormattedCitation" : "155", "previouslyFormattedCitation" : "¹⁵⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }155. The development of standard operating procedures including the careful use of appropriate negative controls at different stages of the sampling and laboratory workflow can help identify and exclude sequences from contaminating resourcesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.ebiom.2016.05.031", "ISSN" : "23523964", "abstract" : "Birth by Caesarian section is associated with short- and long-term respiratory morbidity. We hypothesized that mode of delivery affects the development of the respiratory microbiota, thereby altering its capacity to provide colonization resistance and consecutive pathobiont overgrowth and infections. Therefore, we longitudinally studied the impact of mode of delivery on the nasopharyngeal microbiota development from birth until six months of age in a healthy, unselected birth cohort of 102 children (n=761 samples). Here, we show that the respiratory microbiota develops within one day from a variable mixed bacterial community towards a Streptococcus viridans-predominated profile, regardless of mode of delivery. Within the first week, rapid niche differentiation had occurred; initially with in most infants Staphylococcus aureus predominance, followed by differentiation towards Corynebacterium pseudodiphtericum/propinquum, Dolosigranulum pigrum, Moraxella catarrhalis/nonliquefaciens, Streptococcus pneumoniae, and/or Haemophilus influenzae dominated communities. Infants born by Caesarian section showed a delay in overall development of respiratory microbiota profiles with specifically reduced colonization with health-associated commensals like Corynebacterium and Dolosigranulum, thereby possibly influencing respiratory health later in life.", "author" : [ { "dropping-particle" : "", "family" : "Bosch", "given" : "Astrid A.T.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Levin", "given" : "Evgeni", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Houten", "given" : "Marlies A.", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hasrat", "given" : "Raiza", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalkman", "given" : "Gino", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Biesbroek", "given" : "Giske", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steenhuijsen Piters", "given" : "Wouter A.A.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groot", "given" : "Pieter-Kees C.M.", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pernet", "given" : "Paula", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keijser", "given" : "Bart J.F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanders", "given" : "Elisabeth A.M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bogaert", "given" : "Debby", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "EBioMedicine", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "7" ] ] }, "page" : "336-345", "title" : "Development of Upper Respiratory Tract Microbiota in Infancy is Affected by Mode of Delivery", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1038/nmicrobiol.2016.113", "ISSN" : "2058-5276", "author" : [ { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singer", "given" : "Benjamin H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Newstead", "given" : "Michael W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Falkowski", "given" : "Nicole R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Standiford", "given" : "Theodore J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Microbiology", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016", "7", "18" ] ] }, "page" : "16113", "publisher" : "Nature Publishing Group", "title" : "Enrichment of the lung microbiome with gut bacteria in sepsis and the acute respiratory distress syndrome", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^20,156", "plainTextFormattedCitation" : "20,156", "previouslyFormattedCitation" : "^20,156" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20,156. Box 2 | Specific host-microbiota interactions contributing to toleranceThe respiratory microbiota has been hypothesized to control mucosal immunity in early life and contribute to immune tolerance. For example, members of the Bacteroidetes phylum, such as Prevotella spp., reduce lung inflammation, neutrophil recruitment and production of TLR2-mediated pro-inflammatory cytokines compared to H. influenzae in a mouse modelADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/imm.12376", "ISSN" : "1365-2567", "PMID" : "25179236", "abstract" : "Recent studies of healthy human airways have revealed colonization by a distinct commensal bacterial microbiota containing Gram-negative Prevotella spp. However, the immunological properties of these bacteria in the respiratory system remain unknown. Here we compare the innate respiratory immune response to three Gram-negative commensal Prevotella strains (Prevotella melaninogenica, Prevotella nanceiensis and Prevotella salivae) and three Gram-negative pathogenic Proteobacteria known to colonize lungs of patients with chronic obstructive pulmonary disease (COPD) and asthma (Haemophilus influenzae B, non-typeable Haemophilus influenzae and Moraxella catarrhalis). The commensal Prevotella spp. and pathogenic Proteobacteria were found to exhibit intrinsic differences in innate inflammatory capacities on murine lung cells in vitro. In vivo in mice, non-typeable H. influenzae induced severe Toll-like receptor 2 (TLR2)-independent COPD-like inflammation characterized by predominant airway neutrophilia, expression of a neutrophilic cytokine/chemokine profile in lung tissue, and lung immunopathology. In comparison, P. nanceiensis induced a diminished neutrophilic airway inflammation and no detectable lung pathology. Interestingly, the inflammatory airway response to the Gram-negative bacteria P. nanceiensis was completely TLR2-dependent. These findings demonstrate weak inflammatory properties of Gram-negative airway commensal Prevotella spp. that may make colonization by these bacteria tolerable by the respiratory immune system.", "author" : [ { "dropping-particle" : "", "family" : "Larsen", "given" : "Jeppe M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Musavian", "given" : "Hanieh S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Butt", "given" : "Tariq M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ingvorsen", "given" : "Camilla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thysen", "given" : "Anna H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brix", "given" : "Susanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Immunology", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "2" ] ] }, "page" : "333-42", "title" : "Chronic obstructive pulmonary disease and asthma-associated Proteobacteria, but not commensal Prevotella spp., promote Toll-like receptor 2-independent lung inflammation and pathology.", "type" : "article-journal", "volume" : "144" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁵⁷", "plainTextFormattedCitation" : "157", "previouslyFormattedCitation" : "¹⁵⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }157, which could be related to the number of acyl side chains on their respective lipopolysaccharide (LPS) moleculesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1286-4579", "PMID" : "14554246", "abstract" : "Cells of the mucosal lining are the first to encounter invading bacteria during infection, and as such, they have developed numerous ways of detecting microbial intruders. Recently, we showed that epithelial cells recognize lipopolysaccharide (LPS) through the CD14-Toll-like receptor (TLR)-4 complex. Here, we identify the substructures of LPS that are recognized by the TLR4 receptor complex. In contrast to lipid A, the O-antigen does not mediate an inflammatory response; rather it interferes with the lipid A recognition. An Escherichia coli strain genetically modified to express penta-acylated lipid A not only showed reduced immunogenicity, but was also found to inhibit pro-inflammatory signalling induced by wild-type E. coli (hexa-acylated lipid A) as well as LPS from other bacteria of the Enterobacteriaceae family. Furthermore, penta-acylated LPS from Pseudomonas aeruginosa acted as an antagonist to hexa-acylated E. coli LPS, as did E. coli, as shown by its inhibitory effect on IL-8 production in stimulated cells. Hypo-acylated lipid A, such as that of P. aeruginosa, is found in several species within the gut microflora as well as in several bacteria causing chronic infections. Thus, our results suggest that the composition of the microflora may be important in modulating pro-inflammatory signalling in epithelial cells under normal as well as pathologic conditions.", "author" : [ { "dropping-particle" : "", "family" : "B\u00e4ckhed", "given" : "Fredrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Normark", "given" : "Staffan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schweda", "given" : "Elke K H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oscarson", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richter-Dahlfors", "given" : "Agneta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbes and infection", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2003", "10" ] ] }, "page" : "1057-63", "title" : "Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0019-9567", "PMID" : "14638766", "abstract" : "E. coli lipopolysaccharide (LPS) induces cytokine and adhesion molecule expression via the toll-like receptor 4 (TLR4) signaling complex in human endothelial cells. In the present study, we investigated the mechanism by which Porphyromonas gingivalis LPS antagonizes E. coli LPS-dependent activation of human endothelial cells. P. gingivalis LPS at 1 micro g/ml inhibited both E. coli LPS (10 ng/ml) and Mycobacterium tuberculosis heat shock protein (HSP) 60.1 (10 micro g/ml) stimulation of E-selectin mRNA expression in human umbilical vein endothelial cells (HUVEC) without inhibiting interleukin-1 beta (IL-1beta) stimulation. P. gingivalis LPS (1 micro g/ml) also blocked both E. coli LPS-dependent and M. tuberculosis HSP60.1-dependent but not IL-1beta-dependent activation of NF-kappaB in human microvascular endothelial (HMEC-1) cells, consistent with antagonism occurring upstream from the TLR/IL-1 receptor adaptor protein, MyD88. Surprisingly, P. gingivalis LPS weakly but significantly activated NF-kappaB in HMEC-1 cells in the absence of E. coli LPS, and the P. gingivalis LPS-dependent agonism was blocked by transient expression of a dominant negative murine TLR4. Pretreatment of HUVECs with P. gingivalis LPS did not influence the ability of E. coli LPS to stimulate E-selectin mRNA expression. Taken together, these data provide the first evidence that P. gingivalis LPS-dependent antagonism of E. coli LPS in human endothelial cells likely involves the ability of P. gingivalis LPS to directly compete with E. coli LPS at the TLR4 signaling complex.", "author" : [ { "dropping-particle" : "", "family" : "Coats", "given" : "Stephen R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reife", "given" : "Robert A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bainbridge", "given" : "Brian W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pham", "given" : "T Thu-Thao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Darveau", "given" : "Richard P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Infection and immunity", "id" : "ITEM-2", "issue" : "12", "issued" : { "date-parts" : [ [ "2003", "12" ] ] }, "page" : "6799-807", "title" : "Porphyromonas gingivalis lipopolysaccharide antagonizes Escherichia coli lipopolysaccharide at toll-like receptor 4 in human endothelial cells.", "type" : "article-journal", "volume" : "71" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1128/IAI.00939-07", "ISBN" : "1098-5522 (Electronic)\\r0019-9567 (Linking)", "ISSN" : "00199567", "PMID" : "18086818", "author" : [ { "dropping-particle" : "", "family" : "Munford", "given" : "Robert S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Infection and Immunity", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2008", "2" ] ] }, "page" : "454-465", "title" : "Sensing gram-negative bacterial lipopolysaccharides: A human disease determinant?", "type" : "article", "volume" : "76" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^158\u2013160", "plainTextFormattedCitation" : "158\u2013160", "previouslyFormattedCitation" : "^158\u2013160" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }158–160. Furthermore, in vitro activation of epithelial TLR and NOD-like receptors induced the release of antimicrobial peptides, such as beta-defensin-2ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.molimm.2007.02.007", "ISSN" : "01615890", "PMID" : "17403538", "abstract" : "Epithelial cells may form the first barrier of defense against bacteria in human tissues. We recently revealed that oral epithelial cells generated anti-bacterial factors, such as peptidoglycan recognition proteins (PGRPs) and beta-defensin 2, but not proinflammatory cytokines, such as interleukin-8 (IL-8), upon stimulation with bacterial cell-surface components. In this study, we found clear expressions of Toll-like receptor (TLR)2, TLR3, TLR4, TLR7, NOD1 and NOD2 in oral, tongue, salivary gland, pharyngeal, esophageal, intestinal, cervical, breast, lung, and kidney epithelial cells. However, tongue, salivary gland, pharyngeal, esophageal, intestinal, cervical, breast, lung, and kidney epithelial cells, as well as oral epithelial cells, did not secrete IL-6, IL-8 or monocyte chemoattractant protein-1 in response to chemically synthesized TLR and NOD agonists mimicking microbial components: TLR2 agonistic lipopeptide (Pam3CSSNA), TLR3 agonistic Poly I:C, TLR4 agonistic lipid A (LA-15-PP), TLR7 agonistic single stranded RNA (ssPoly U), NOD1 agonistic iE-DAP (gamma-D-glumtamyl-meso-diaminopimelic acid), and NOD2 agonistic muramyldipeptide (MDP). Although PGRPs on oral epithelial cells were significantly up-regulated upon stimulation with these synthetic components, PGRPs on pharyngeal epithelial cells were only slightly up-regulated, and PGRPs on esophageal, intestinal and cervical epithelial cells were not up-regulated upon stimulation with the components. In contrast, stimulation with synthetic TLRs and NODs ligands induced beta-defensin 2 generation in all epithelial cells examined. These findings indicate that TLR and NOD in various epithelial cells are functional receptors that induce anti-bacterial responses in general without being accompanied by inflammatory responses.", "author" : [ { "dropping-particle" : "", "family" : "Uehara", "given" : "Akiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fujimoto", "given" : "Yukari", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fukase", "given" : "Koichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Takada", "given" : "Haruhiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular Immunology", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2007", "5" ] ] }, "page" : "3100-3111", "title" : "Various human epithelial cells express functional Toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹³⁸", "plainTextFormattedCitation" : "138", "previouslyFormattedCitation" : "¹³⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }138, which could potentially influence the URT microbiota compositionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ni.1825", "ISBN" : "1529-2916 (Electronic)\\r1529-2908 (Linking)", "ISSN" : "1529-2908", "PMID" : "19855381", "abstract" : "Antimicrobial peptides are important effectors of innate immunity throughout the plant and animal kingdoms. In the mammalian small intestine, Paneth cell alpha-defensins are antimicrobial peptides that contribute to host defense against enteric pathogens. To determine if alpha-defensins also govern intestinal microbial ecology, we analyzed the intestinal microbiota of mice expressing a human alpha-defensin gene (DEFA5) and in mice lacking an enzyme required for the processing of mouse alpha-defensins. In these complementary models, we detected significant alpha-defensin-dependent changes in microbiota composition, but not in total bacterial numbers. Furthermore, DEFA5-expressing mice had striking losses of segmented filamentous bacteria and fewer interleukin 17 (IL-17)-producing lamina propria T cells. Our data ascribe a new homeostatic role to alpha-defensins in regulating the makeup of the commensal microbiota.", "author" : [ { "dropping-particle" : "", "family" : "Salzman", "given" : "Nita H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hung", "given" : "Kuiechun", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haribhai", "given" : "Dipica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chu", "given" : "Hiutung", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Karlsson-Sj\u00f6berg", "given" : "Jenny", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Amir", "given" : "Elad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Teggatz", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barman", "given" : "Melissa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hayward", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eastwood", "given" : "Daniel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stoel", "given" : "Maaike", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Yanjiao", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sodergren", "given" : "Erica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weinstock", "given" : "George M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bevins", "given" : "Charles L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williams", "given" : "Calvin B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bos", "given" : "Nicolaas A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature immunology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2010", "1" ] ] }, "page" : "76-83", "title" : "Enteric defensins are essential regulators of intestinal microbial ecology.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁶¹", "plainTextFormattedCitation" : "161", "previouslyFormattedCitation" : "¹⁶¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }161. The production of these antimicrobial peptides is stimulated by Th17-cellsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4049/jimmunol.173.5.3482", "ISSN" : "0022-1767", "PMID" : "15322213", "abstract" : "Using microarray gene expression analysis, we first observed a profound elevation of human beta-defensin-2 (hBD-2) message in IL-17-treated primary human airway epithelial cells. Further comparison of this stimulation with a panel of cytokines (IL-1alpha, 1beta, 2-13, and 15-18; IFN-gamma; GM-CSF; and TNF-alpha) demonstrated that IL-17 was the most potent cytokine to induce hBD-2 message (>75-fold). IL-17-induced stimulation of hBD-2 was time and dose dependent, and this stimulation also occurred at the protein level. Further studies demonstrated that hBD-2 stimulation was attenuated by IL-17R-specific Ab, but not by IL-1R antagonist or the neutralizing anti-IL-6 Ab. This suggests an IL-17R-mediated signaling pathway rather than an IL-17-induced IL-1alphabeta and/or IL-6 autocrine/paracrine loop. hBD-2 stimulation was sensitive to the inhibition of the JAK pathway, and to the inhibitors that affect NF-kappaB translocation and the DNA-binding activity of its p65 NF-kappaB subunit. Transient transfection of airway epithelial cells with an hBD-2 promoter-luciferase reporter gene expression construct demonstrated that IL-17 stimulated promoter-reporter gene activity, suggesting a transcriptional mechanism for hBD-2 induction. These results support an IL-17R-mediated signaling pathway involving JAK and NF-kappaB in the transcriptional stimulation of hBD-2 gene expression in airway epithelium. Because IL-17 has been identified in a number of airway diseases, especially diseases related to microbial infection, these findings provide a new insight into how IL-17 may play an important link between innate and adaptive immunity, thereby combating infection locally within the airway epithelium.", "author" : [ { "dropping-particle" : "", "family" : "Kao", "given" : "C.-Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chen", "given" : "Yin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thai", "given" : "Philip", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wachi", "given" : "Shinichiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huang", "given" : "Fei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kim", "given" : "Christy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harper", "given" : "Richart W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wu", "given" : "Reen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal of Immunology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2004", "9", "1" ] ] }, "page" : "3482-3491", "publisher" : "American Association of Immunologists", "title" : "IL-17 Markedly Up-Regulates -Defensin-2 Expression in Human Airway Epithelium via JAK and NF- B Signaling Pathways", "type" : "article-journal", "volume" : "173" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁶²", "plainTextFormattedCitation" : "162", "previouslyFormattedCitation" : "¹⁶²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }162, which in turn was shown to be induced by specific microbial speciesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2015.08.058", "ISSN" : "00928674", "PMID" : "26411289", "abstract" : "Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.", "author" : [ { "dropping-particle" : "", "family" : "Atarashi", "given" : "Koji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tanoue", "given" : "Takeshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ando", "given" : "Minoru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kamada", "given" : "Nobuhiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nagano", "given" : "Yuji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Narushima", "given" : "Seiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suda", "given" : "Wataru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Imaoka", "given" : "Akemi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Setoyama", "given" : "Hiromi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nagamori", "given" : "Takashi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ishikawa", "given" : "Eiji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shima", "given" : "Tatsuichiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hara", "given" : "Taeko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kado", "given" : "Shoichi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jinnohara", "given" : "Toshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ohno", "given" : "Hiroshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kondo", "given" : "Takashi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Toyooka", "given" : "Kiminori", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watanabe", "given" : "Eiichiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yokoyama", "given" : "Shin-Ichiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tokoro", "given" : "Shunji", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mori", "given" : "Hiroshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Noguchi", "given" : "Yurika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morita", "given" : "Hidetoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ivanov", "given" : "Ivaylo I.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sugiyama", "given" : "Tsuyoshi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nu\u00f1ez", "given" : "Gabriel", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Camp", "given" : "J. 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Here we show that specific pathogen-free mice are more sensitive to influenza-mediated death than mice living in a natural environment. Priming with Toll-like receptor 2-ligand(+) Staphylococcus aureus, which commonly colonizes the upper respiratory mucosa, significantly attenuates influenza-mediated lung immune injury. Toll-like receptor 2 deficiency or alveolar macrophage depletion abolishes this protection. S. aureus priming recruits peripheral CCR2(+)CD11b(+) monocytes into the alveoli that polarize to M2 alveolar macrophages in an environment created by Toll-like receptor 2 signalling. M2 alveolar macrophages inhibit influenza-mediated lethal inflammation via anti-inflammatory cytokines and inhibitory ligands. Our results suggest a previously undescribed mechanism by which the airway microbiota may protect against influenza-mediated lethal inflammation.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Jian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Fengqi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sun", "given" : "Rui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gao", "given" : "Xiang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wei", "given" : "Haiming", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Lan-Juan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tian", "given" : "Zhigang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature Communications", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "7", "3" ] ] }, "page" : "2106", "publisher" : "Nature Publishing Group", "title" : "Bacterial colonization dampens influenza-mediated acute lung injury via induction of M2 alveolar macrophages", "type" : "article-journal", "volume" : "4" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁶⁴", "plainTextFormattedCitation" : "164", "previouslyFormattedCitation" : "¹⁶⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }164. Intranasal administration of Lactobacillus plantarum led to TLR-2 and NOD-2 receptor-mediated protection against lethal pneumovirus infection in the lungs of miceADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.antiviral.2016.06.002", "ISSN" : "18729096", "PMID" : "27312104", "abstract" : "Pattern recognition receptors (PRRs) engage microbial components in the lung, although their role in providing primary host defense against respiratory virus infection is not fully understood. We have previously shown that Gram-positive Lactobacillus plantarum (Lp) administered to the respiratory tract promotes full and sustained protection in response to an otherwise lethal mouse pneumovirus (PVM) infection, a robust example of heterologous immunity. While Lp engages PRRs TLR2 and NOD2 in ex vivo signaling assays, we found that Lp-mediated protection was unimpaired in single gene-deleted TLR2-/- and NOD2-/- mice. Here we demonstrate substantial loss of Lp-mediated protection in a double gene-deleted NOD2-/-TLR2-/- strain. Furthermore, we demonstrate protection against PVM infection by administration of the bi-functional NOD2-TLR2 agonist, CL-429. The bi-functional NOD2-TLR2 ligand CL-429 not only suppresses virus-induced inflammation, it is significantly more effective at preventing lethal infection than equivalent amounts of mono-molecular TLR2 and NOD2 agonists. Interestingly, and in contrast to biochemical NOD2 and/or TLR2 agonists, Lp remained capable of eliciting primary proinflammatory responses from NOD2-/-TLR2-/- mice in vivo and from alveolar macrophages challenged ex vivo. Taken together, we conclude that coordinate engagement of NOD2 and TLR2 constitutes a key step in the genesis of Lp-mediated protection from a lethal respiratory virus infection, and represents a critical target for modulation of virus-induced inflammatory pathology.", "author" : [ { "dropping-particle" : "", "family" : "Rice", "given" : "Tyler A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brenner", "given" : "Todd A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Percopo", "given" : "Caroline M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ma", "given" : "Michelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Keicher", "given" : "Jesse D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Domachowske", "given" : "Joseph B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rosenberg", "given" : "Helene F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Antiviral Research", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016", "8" ] ] }, "page" : "131-140", "title" : "Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection", "type" : "article-journal", "volume" : "132" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁶⁵", "plainTextFormattedCitation" : "165", "previouslyFormattedCitation" : "¹⁶⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }165. Also, gut microbiota-induced priming of innate immune cells at the intestinal mucosa has been shown to affect respiratory health, for example through NOD-1 receptor-mediated activation of the neutrophils required for S. pneumoniae clearance in the URTADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm.2087", "ISSN" : "1546-170X", "PMID" : "20081863", "abstract" : "Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system. A broader role for the microbiota as a major modulator of systemic immunity has been proposed; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow-derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain-containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide). We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1(-/-) mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.", "author" : [ { "dropping-particle" : "", "family" : "Clarke", "given" : "Thomas B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davis", "given" : "Kimberly M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lysenko", "given" : "Elena S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhou", "given" : "Alice Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yu", "given" : "Yimin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiser", "given" : "Jeffrey N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature medicine", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2010", "2", "17" ] ] }, "page" : "228-31", "title" : "Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1371/journal.ppat.0030118", "ISBN" : "1553-7374 (Electronic)", "ISSN" : "15537366", "PMID" : "17722978", "abstract" : "Airway infection by the Gram-positive pathogen Streptococcus pneumoniae (Sp) leads to recruitment of neutrophils but limited bacterial killing by these cells. Co-colonization by Sp and a Gram-negative species, Haemophilus influenzae (Hi), provides sufficient stimulus to induce neutrophil and complement-mediated clearance of Sp from the mucosal surface in a murine model. Products from Hi, but not Sp, also promote killing of Sp by ex vivo neutrophil-enriched peritoneal exudate cells. Here we identify the stimulus from Hi as its peptidoglycan. Enhancement of opsonophagocytic killing was facilitated by signaling through nucleotide-binding oligomerization domain-1 (Nod1), which is involved in recognition of gamma-D-glutamyl-meso-diaminopimelic acid (meso-DAP) contained in cell walls of Hi but not Sp. Neutrophils from mice treated with Hi or compounds containing meso-DAP, including synthetic peptidoglycan fragments, showed increased Sp killing in a Nod1-dependent manner. Moreover, Nod1(-/-) mice showed reduced Hi-induced clearance of Sp during co-colonization. These observations offer insight into mechanisms of microbial competition and demonstrate the importance of Nod1 in neutrophil-mediated clearance of bacteria in vivo.", "author" : [ { "dropping-particle" : "", "family" : "Lysenko", "given" : "Elena S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clarke", "given" : "Thomas B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shchepetov", "given" : "Mikhail", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ratner", "given" : "Adam J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roper", "given" : "David I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowson", "given" : "Christopher G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Weiser", "given" : "Jeffrey N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS Pathogens", "id" : "ITEM-2", "issue" : "8", "issued" : { "date-parts" : [ [ "2007", "8", "24" ] ] }, "page" : "1073-1081", "title" : "Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^72,166", "plainTextFormattedCitation" : "72,166", "previouslyFormattedCitation" : "^72,166" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }72,166. Furthermore, in germ-free mice, inoculation with microbiota has shown to be essential for DC recruitment to the lungsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201010-1574OC", "ISSN" : "1073-449X", "abstract" : "Rationale: The incidence of allergic disorders is increasing in developed countries and has been associated with reduced exposure to microbes and alterations in the commensal bacterial flora.Objectives: To ascertain the relevance of commensal bacteria on the development of an allergic response, we used a model of allergic airway inflammation in germ-free (GF) mice that lack any exposure to pathogenic or nonpathogenic microorganisms.Methods: Allergic airway inflammation was induced in GF, specific pathogen\u2013free (SPF), or recolonized mice by sensitization and challenge with ovalbumin. The resulting cellular infiltrate and cytokine production were measured.Measurements and Main Results: Our results show that the total number of infiltrating lymphocytes and eosinophils were elevated in the airways of allergic GF mice compared with control SPF mice, and that this increase could be reversed by recolonization of GF mice with the complex commensal flora of SPF mice. 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This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. 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Cross-talk between DCs and T-cells induces IgA-release at the mucosal interface, which prevents pathogens from interacting with the epithelium and selects for a heterogeneous gut microbiota composition, which facilitated the expansion of regulatory T cells (Treg cells) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.immuni.2014.05.016", "ISSN" : "10747613", "PMID" : "25017466", "abstract" : "Foxp3(+) T cells play a critical role for the maintenance of immune tolerance. Here we show that in mice, Foxp3(+) T cells contributed to diversification of gut microbiota, particularly of species belonging to Firmicutes. The control of indigenous bacteria by Foxp3(+) T cells involved regulatory functions both outside and inside germinal centers (GCs), consisting of suppression of inflammation and regulation of immunoglobulin A (IgA) selection in Peyer's patches, respectively. 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Correspondingly, a positive correlation between the relative abundance of members of the phylum Proteobacteria and both alveolar and systemic inflammation was described for patients with acute respiratory distress syndrome (ARDS)175.Box 3 | An early ‘window of opportunity’Evidence is mounting that early environmental and microbiota-derived cues are paramount in the development of lymphoid tissue in neonates, and ultimately shape the host immune system long term. 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Similarly, exposure of neonatal mice to LPS led to the formation of bronchus-associated lymphoid tissue (BALT), which was not observed when mice were only exposed later in lifeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/ni.2053", "ISBN" : "1529-2916 (Electronic)\\r1529-2908 (Linking)", "ISSN" : "1529-2916", "PMID" : "21666689", "abstract" : "Ectopic or tertiary lymphoid tissues, such as inducible bronchus-associated lymphoid tissue (iBALT), form in nonlymphoid organs after local infection or inflammation. However, the initial events that promote this process remain unknown. Here we show that iBALT formed in mouse lungs as a consequence of pulmonary inflammation during the neonatal period. Although we found CD4(+)CD3(-) lymphoid tissue-inducer cells (LTi cells) in neonatal lungs, particularly after inflammation, iBALT was formed in mice that lacked LTi cells. 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Furthermore, it was demonstrated that neonatal, but not adult, bacterial colonization, attracts activated Treg-cells to the skin and is necessary to induce immune tolerance to skin commensalsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.immuni.2015.10.016", "ISSN" : "10974180", "PMID" : "26588783", "abstract" : "The skin is a site of constant dialog between the immune system and commensal bacteria. However, the molecular mechanisms that allow us to tolerate the presence of skin commensals without eliciting destructive inflammation are unknown. Using a model system to study the antigen-specific response to S. epidermidis, we demonstrated that skin colonization during a defined period of neonatal life was required for establishing immune tolerance to commensal microbes. This crucial window was characterized by an abrupt influx of highly activated regulatory T (Treg) cells into neonatal skin. Selective inhibition of this Treg cell wave completely abrogated tolerance. Thus, the host-commensal relationship in the skin relied on a unique Treg cell population that mediated tolerance to bacterial antigens during a defined developmental window. 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Similarly, lung microbiota promotes the transient expression of PD-L1 (programmed cell-death ligand 1) in DCs during the first two weeks of life, which is necessary for Treg-mediated attenuation of allergic airway responsesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm.3568", "ISBN" : "1546-170X (Electronic)\\r1078-8956 (Linking)", "ISSN" : "1546-170X", "PMID" : "24813249", "abstract" : "Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. 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Furthermore, hypermethylation of the CXC-chemokine ligand 16 (Cxcl16) gene in the lungs of germ-free mice increases CXCL16 expression and the accumulation of invariant natural killer T (NKT) cells that are known for their role in inflammation and asthmaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1126/science.1219328", "ISSN" : "1095-9203", "PMID" : "22442383", "abstract" : "Exposure to microbes during early childhood is associated with protection from immune-mediated diseases such as inflammatory bowel disease (IBD) and asthma. Here, we show that in germ-free (GF) mice, invariant natural killer T (iNKT) cells accumulate in the colonic lamina propria and lung, resulting in increased morbidity in models of IBD and allergic asthma as compared with that of specific pathogen-free mice. This was associated with increased intestinal and pulmonary expression of the chemokine ligand CXCL16, which was associated with increased mucosal iNKT cells. Colonization of neonatal-but not adult-GF mice with a conventional microbiota protected the animals from mucosal iNKT accumulation and related pathology. These results indicate that age-sensitive contact with commensal microbes is critical for establishing mucosal iNKT cell tolerance to later environmental exposures.", "author" : [ { "dropping-particle" : "", "family" : "Olszak", "given" : "Torsten", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "An", "given" : "Dingding", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zeissig", "given" : "Sebastian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vera", "given" : "Miguel Pinilla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richter", "given" : "Julia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Franke", "given" : "Andre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Glickman", "given" : "Jonathan N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Siebert", "given" : "Reiner", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baron", "given" : "Rebecca M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kasper", "given" : "Dennis L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blumberg", "given" : "Richard S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Science (New York, N.Y.)", "id" : "ITEM-1", "issue" : "6080", "issued" : { "date-parts" : [ [ "2012", "4", "27" ] ] }, "page" : "489-93", "publisher" : "NIH Public Access", "title" : "Microbial exposure during early life has persistent effects on natural killer T cell function.", "type" : "article-journal", "volume" : "336" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6. Transplanting microbiota from normal mice at neonatal, but not adult age, prevented NKT cells from accumulating, which abrogated disease in these mice. Altogether, these data suggest that the presence of a respiratory microbiota within a specific developmental period is critical in shaping the adaptive immune response to commensals in adult life and orchestrating the delicate balance between host, microbiota and the environment towards a long-term equilibrium. Although this early period of development can be regarded as a susceptible window for aberrant microbial colonization that could lead to the induction of immune disorders, importantly, this same phase of development may also provide a window of opportunity to intervene.Box 4 | Viral-host interactionsPersistent viral infections naturally occur in humans and may regulate innate and adaptive immunity. In serum, there is an estimated daily turnover of >109 anellovirus particles, which is thought to induce continuous immune-surveillance and influence inhabitation by other microorganismsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2009.06.036", "ISSN" : "1097-4172", "PMID" : "19596234", "abstract" : "Viruses that cause chronic infection constitute a stable but little-recognized part of our metagenome: our virome. Ongoing immune responses hold these chronic viruses at bay while avoiding immunopathologic damage to persistently infected tissues. The immunologic imprint generated by these responses to our virome defines the normal immune system. The resulting dynamic but metastable equilibrium between the virome and the host can be dangerous, benign, or even symbiotic. These concepts require that we reformulate how we assign etiologies for diseases, especially those with a chronic inflammatory component, as well as how we design and interpret genome-wide association studies, and how we vaccinate to limit or control our virome.", "author" : [ { "dropping-particle" : "", "family" : "Virgin", "given" : "Herbert W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wherry", "given" : "E John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ahmed", "given" : "Rafi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2009", "7", "10" ] ] }, "page" : "30-50", "publisher" : "Elsevier", "title" : "Redefining chronic viral infection.", "type" : "article-journal", "volume" : "138" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷¹", "plainTextFormattedCitation" : "171", "previouslyFormattedCitation" : "¹⁷¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }171. Similarly, chronic infection with herpesviruses, which have co-evolved with mammals for millions of yearsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.virusres.2006.01.002", "ISSN" : "01681702", "abstract" : "Herpesviruses comprise an abundant, widely distributed group of large DNA viruses of humans and other vertebrates, and overall are among the most extensively studied large DNA viruses. Many herpesvirus genome sequences have been determined, and interpreted in terms of gene contents to give detailed views of both ubiquitous and lineage-specific functions. Availability of gene sequences has also enabled evaluations of evolutionary relationships. For herpesviruses of mammals, a robust phylogenetic tree has been constructed, which shows many features characteristic of synchronous development of virus and host lineages over large evolutionary timespans. It has also emerged that three distinct groupings of herpesviruses exist: the first containing viruses with mammals, birds and reptiles as natural hosts; the second containing viruses of amphibians and fish; and the third consisting of a single invertebrate herpesvirus. Within each of the first two groups, the genomes show clear evidence of descent from a common ancestor, but relationships between the three groups are extremely remote. Detailed analyses of capsid structures provide the best evidence for a common origin of the three groups. At a finer level, the structure of the capsid shell protein further suggests an element of common origin between herpesviruses and tailed DNA bacteriophages.", "author" : [ { "dropping-particle" : "", "family" : "McGeoch", "given" : "Duncan J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rixon", "given" : "Frazer J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davison", "given" : "Andrew J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Virus Research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2006" ] ] }, "page" : "90-104", "title" : "Topics in herpesvirus genomics and evolution", "type" : "article-journal", "volume" : "117" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷²", "plainTextFormattedCitation" : "172", "previouslyFormattedCitation" : "¹⁷²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }172 and can be detected in over 90% of humansADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cell.2009.06.036", "ISSN" : "1097-4172", "PMID" : "19596234", "abstract" : "Viruses that cause chronic infection constitute a stable but little-recognized part of our metagenome: our virome. Ongoing immune responses hold these chronic viruses at bay while avoiding immunopathologic damage to persistently infected tissues. The immunologic imprint generated by these responses to our virome defines the normal immune system. The resulting dynamic but metastable equilibrium between the virome and the host can be dangerous, benign, or even symbiotic. These concepts require that we reformulate how we assign etiologies for diseases, especially those with a chronic inflammatory component, as well as how we design and interpret genome-wide association studies, and how we vaccinate to limit or control our virome.", "author" : [ { "dropping-particle" : "", "family" : "Virgin", "given" : "Herbert W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wherry", "given" : "E John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ahmed", "given" : "Rafi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Cell", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2009", "7", "10" ] ] }, "page" : "30-50", "publisher" : "Elsevier", "title" : "Redefining chronic viral infection.", "type" : "article-journal", "volume" : "138" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷¹", "plainTextFormattedCitation" : "171", "previouslyFormattedCitation" : "¹⁷¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }171, protects against bacterial infections by increasing basal IFN-γ (interferon gamma) expression and facilitating the activation of macrophagesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nature05762", "ISSN" : "1476-4687", "PMID" : "17507983", "abstract" : "All humans become infected with multiple herpesviruses during childhood. After clearance of acute infection, herpesviruses enter a dormant state known as latency. Latency persists for the life of the host and is presumed to be parasitic, as it leaves the individual at risk for subsequent viral reactivation and disease. Here we show that herpesvirus latency also confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, are resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection is not antigen specific but involves prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. We speculate that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, whereas the immune evasion capabilities and lifelong persistence of herpesviruses are commonly viewed as solely pathogenic, our data suggest that latency is a symbiotic relationship with immune benefits for the host.", "author" : [ { "dropping-particle" : "", "family" : "Barton", "given" : "Erik S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "White", "given" : "Douglas W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cathelyn", "given" : "Jason S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brett-McClellan", "given" : "Kelly A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Engle", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "Michael S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Miller", "given" : "Virginia L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Virgin", "given" : "Herbert W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature", "id" : "ITEM-1", "issue" : "7142", "issued" : { "date-parts" : [ [ "2007", "5", "17" ] ] }, "page" : "326-9", "title" : "Herpesvirus latency confers symbiotic protection from bacterial infection.", "type" : "article-journal", "volume" : "447" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷³", "plainTextFormattedCitation" : "173", "previouslyFormattedCitation" : "¹⁷³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }173. Likewise, acute infection with common respiratory viruses activates innate immune pathways, which remain active after the virus has been cleared. For example, infection with Sendai virus in mice is associated with IL-13-dependent NKT cell and lung macrophage activation, and subsequent airway hyperreactivityADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm1770", "ISSN" : "1546-170X", "PMID" : "18488036", "abstract" : "To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of chronic lung disease with pathology that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after an infection with a common type of respiratory virus is cleared to only trace levels of noninfectious virus. Chronic inflammatory disease is generally thought to depend on an altered adaptive immune response. However, here we find that this type of disease arises independently of an adaptive immune response and is driven instead by interleukin-13 produced by macrophages that have been stimulated by CD1d-dependent T cell receptor-invariant natural killer T (NKT) cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a previously undescribed NKT cell-macrophage innate immune axis.", "author" : [ { "dropping-particle" : "", "family" : "Kim", "given" : "Edy Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Battaile", "given" : "John T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patel", "given" : "Anand C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "You", "given" : "Yingjian", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Agapov", "given" : "Eugene", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grayson", "given" : "Mitchell H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Benoit", "given" : "Loralyn A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Byers", "given" : "Derek E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alevy", "given" : "Yael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tucker", "given" : "Jennifer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Swanson", "given" : "Suzanne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tidwell", "given" : "Rose", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tyner", "given" : "Jeffrey W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morton", "given" : "Jeffrey D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Castro", "given" : "Mario", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Polineni", "given" : "Deepika", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Patterson", "given" : "G Alexander", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwendener", "given" : "Reto A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allard", "given" : "John D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peltz", "given" : "Gary", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Holtzman", "given" : "Michael J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature medicine", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2008", "6" ] ] }, "page" : "633-40", "publisher" : "NIH Public Access", "title" : "Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.", "type" : "article-journal", "volume" : "14" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷⁴", "plainTextFormattedCitation" : "174", "previouslyFormattedCitation" : "¹⁷⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }174. Similarly, early infection with RSV leads to impaired regulatory T-cell function in mice, which increases the risk of allergic airway diseaseADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nm.2896", "ISSN" : "1546-170X", "PMID" : "22961107", "abstract" : "Immune tolerance is instituted early in life, during which time regulatory T (T(reg)) cells have an important role. Recurrent infections with respiratory syncytial virus (RSV) in early life increase the risk for asthma in adult life. Repeated infection of infant mice tolerized to ovalbumin (OVA) through their mother's milk with RSV induced allergic airway disease in response to OVA sensitization and challenge, including airway inflammation, hyper-reactivity and higher OVA-specific IgE, as compared to uninfected tolerized control mice. Virus infection induced GATA-3 expression and T helper type 2 (T(H)2) cytokine production in forkhead box P3 (FOXP3)(+) T(reg) cells and compromised the suppressive function of pulmonary T(reg) cells in a manner that was dependent on interleukin-4 receptor \u03b1 (IL-4R\u03b1) expression in the host. Thus, by promoting a T(H)2-type inflammatory response in the lung, RSV induced a T(H)2-like effector phenotype in T(reg) cells and attenuated tolerance to an unrelated antigen (allergen). Our findings highlight a mechanism by which viral infection targets a host-protective mechanism in early life and increases susceptibility to allergic disease.", "author" : [ { "dropping-particle" : "", "family" : "Krishnamoorthy", "given" : "Nandini", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khare", "given" : "Anupriya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oriss", "given" : "Timothy B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Raundhal", "given" : "Mahesh", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Morse", "given" : "Christina", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yarlagadda", "given" : "Manohar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wenzel", "given" : "Sally E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Moore", "given" : "Martin L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Peebles", "given" : "R Stokes", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ray", "given" : "Anuradha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ray", "given" : "Prabir", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature medicine", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2012", "10" ] ] }, "page" : "1525-30", "title" : "Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma.", "type" : "article-journal", "volume" : "18" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷⁵", "plainTextFormattedCitation" : "175", "previouslyFormattedCitation" : "¹⁷⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }175. These findings are further supported by data from a human infant cohort study, in whom persisting immune dysregulation was still detected one month following acute RSV infectionADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pmed.1001549", "ISBN" : "1549-1676 (Electronic)\\r1549-1277 (Linking)", "ISSN" : "1549-1676", "PMID" : "24265599", "abstract" : "BACKGROUND Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity. METHODS AND FINDINGS This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%-98%]) and specificity (98% [95% CI 88%-99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2. CONCLUSIONS Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary.", "author" : [ { "dropping-particle" : "", "family" : "Mejias", "given" : "Asuncion", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dimo", "given" : "Blerta", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suarez", "given" : "Nicolas M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garcia", "given" : "Carla", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suarez-Arrabal", "given" : "M Carmen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jartti", "given" : "Tuomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blankenship", "given" : "Derek", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jordan-Villegas", "given" : "Alejandro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ardura", "given" : "Monica I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Xu", "given" : "Zhaohui", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Banchereau", "given" : "Jacques", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chaussabel", "given" : "Damien", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ramilo", "given" : "Octavio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PLoS medicine", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2013", "11" ] ] }, "page" : "e1001549", "title" : "Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection.", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷⁶", "plainTextFormattedCitation" : "176", "previouslyFormattedCitation" : "¹⁷⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }176.Figure 1 | Physiological and microbial gradients along the respiratory tractPhysiological and microbial gradients exist along the nasal cavity, nasopharynx, oropharynx, trachea and lung. The pH gradually increases along the respiratory tractADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0307-7772", "PMID" : "10196653", "abstract" : "The nasal mucosal pH is approximately 5.5-6.5, and increases in rhinitis to 7.2-8.3. This knowledge has not led to the widespread measurement of the nasal mucosal pH as an objective clinical parameter. The purpose of this study was to assess whether repeatable measures of nasal mucosal pH could be obtained in the clinical setting. Fifty-four adults without nasal symptoms were prospectively recruited. Using a semi-disposable antimony pH catheter, the nasal mucosal pH was measured in four specific areas of the nose and each reading repeated three times. The patients' age, sex, smoking habits, nasal anatomical variation and clearest nostril at the time of measurement were also recorded. The data shows that it is possible to obtain reliable and repeatable values for the pH of the nasal mucosa (Spearman-Brown R = 0.84). Analysis shows there is no significant difference between septal and turbinate mucosal pH. Subset analysis implies that nasal mucosal pH is higher in men then women (P < 0.05). The other variables did not affect the nasal mucosal pH significantly.", "author" : [ { "dropping-particle" : "", "family" : "England", "given" : "R J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Homer", "given" : "J J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Knight", "given" : "L C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ell", "given" : "S R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical otolaryngology and allied sciences", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1999", "2" ] ] }, "page" : "67-8", "title" : "Nasal pH measurement: a reliable and repeatable parameter.", "type" : "article-journal", "volume" : "24" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0003-4894", "PMID" : "22844860", "abstract" : "OBJECTIVES We sought to ascertain the normal pH values in the aerosolized environment of the nasopharynx in healthy subjects and utilize a novel pH probe that allows measuring acidity in a nonliquid environment. METHODS Between November 2009 and February 2011, healthy volunteers without a history of reflux or eustachian tube dysfunction were enrolled in the prospective study. A total of 20 subjects had a Dx-pH Measurement System Probe (Respiratory Technology Corp) placed near the torus tubarius. The pH probe records the pH throughout the 24-hour study. A pH below 5.5 while the subject was upright or below 5.0 while the subject was supine was used as a criterion to determine a reflux event. Recording was stopped during meals. RESULTS For normal individuals with no history of reflux or eustachian tube dysfunction, the pH values obtained from the nasopharynx ranged from 6.10 to 7.92. The average pH was 7.03 (SD, 0.67). Eight subjects (40%) had at least 1 reflux event during the 24-hour pH study. CONCLUSIONS By utilizing a novel self-condensing pH probe, we were able to perform a 24-hour pH study in the nasopharynx of 20 healthy individuals. In our study, the average pH for individuals without symptomatic reflux or eustachian tube dysfunction was 7.03. Interestingly, 8 control subjects had at least 1 episode of pH below 5.5 while awake or below 5.0 while asleep, which was considered to be a reflux event in our study.", "author" : [ { "dropping-particle" : "", "family" : "Brunworth", "given" : "Joseph D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garg", "given" : "Rohit", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mahboubi", "given" : "Hossein", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Johnson", "given" : "Brandon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Djalilian", "given" : "Hamid R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Annals of otology, rhinology, and laryngology", "id" : "ITEM-2", "issue" : "7", "issued" : { "date-parts" : [ [ "2012", "7" ] ] }, "page" : "427-30", "title" : "Detecting nasopharyngeal reflux: a novel pH probe technique.", "type" : "article-journal", "volume" : "121" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1007/s11605-009-0915-6", "ISSN" : "1873-4626", "PMID" : "19421822", "abstract" : "INTRODUCTION Identifying gastroesophageal reflux disease as the cause of respiratory and laryngeal complaints is difficult and depends largely on the measurements of increased acid exposure in the upper esophagus or ideally the pharynx. The current method of measuring pharyngeal pH environment is inaccurate and problematic due to artifacts. A newly designed pharyngeal pH probe to avoid these artifacts has been introduced. The aim of this study was to use this probe to measure the pharyngeal pH environment in normal subjects and establish pH thresholds to identify abnormality. METHODS Asymptomatic volunteers were studied to define the normal pharyngeal pH environment. All subjects underwent esophagram, esophageal manometry, upper and lower esophageal pH monitoring with a dual-channel pH catheter and pharyngeal pH monitoring with the new probe. Analyses were performed at 0.5 pH intervals between pH 4 and 6.5 to identify the best discriminating pH threshold and calculate a composite pH score to identify an abnormal pH environment. RESULTS The study population consisted of 55 normal subjects. The pattern of pharyngeal pH environment was significantly different in the upright and supine periods and required different thresholds. The calculated discriminatory pH threshold was 5.5 for upright and 5.0 for supine periods. The 95th percentile values for the composite score were 9.4 for upright and 6.8 for supine. CONCLUSION A new pharyngeal pH probe which detects aerosolized and liquid acid overcomes the artifacts that occur in measuring pharyngeal pH with existing catheters. Discriminating pH thresholds were selected and normal values defined to identify patients with an abnormal pharyngeal pH environment.", "author" : [ { "dropping-particle" : "", "family" : "Ayazi", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lipham", "given" : "J C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hagen", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tang", "given" : "A L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zehetner", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leers", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Oezcelik", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Abate", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Banki", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeMeester", "given" : "S R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "DeMeester", "given" : "T R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract", "id" : "ITEM-3", "issue" : "8", "issued" : { "date-parts" : [ [ "2009", "8" ] ] }, "page" : "1422-9", "title" : "A new technique for measurement of pharyngeal pH: normal values and discriminating pH threshold.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1378/chest.74.4.426", "ISSN" : "0012-3692", "author" : [ { "dropping-particle" : "", "family" : "West", "given" : "J B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "CHEST", "id" : "ITEM-4", "issue" : "4", "issued" : { "date-parts" : [ [ "1978", "10", "1" ] ] }, "page" : "426", "publisher" : "American College of Chest Physicians", "title" : "Regional differences in the lung.", "type" : "article-journal", "volume" : "74" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^177\u2013180", "plainTextFormattedCitation" : "177\u2013180", "previouslyFormattedCitation" : "^177\u2013180" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }177–180, whereas most of the increase in relative humidity (RH) and temperature (Temp) occurs in the nasal cavityADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3205/cto000072", "ISSN" : "1865-1011", "PMID" : "22073112", "abstract" : "Heating and humidification of the respiratory air are the main functions of the nasal airways in addition to cleansing and olfaction. Optimal nasal air conditioning is mandatory for an ideal pulmonary gas exchange in order to avoid desiccation and adhesion of the alveolar capillary bed. The complex three-dimensional anatomical structure of the nose makes it impossible to perform detailed in vivo studies on intranasal heating and humidification within the entire nasal airways applying various technical set-ups. The main problem of in vivo temperature and humidity measurements is a poor spatial and time resolution. Therefore, in vivo measurements are feasible only to a restricted extent, solely providing single temperature values as the complete nose is not entirely accessible. Therefore, data on the overall performance of the nose are only based on one single measurement within each nasal segment. In vivo measurements within the entire nose are not feasible. These serious technical issues concerning in vivo measurements led to a large number of numerical simulation projects in the last few years providing novel information about the complex functions of the nasal airways. In general, numerical simulations merely calculate predictions in a computational model, e.g. a realistic nose model, depending on the setting of the boundary conditions. Therefore, numerical simulations achieve only approximations of a possible real situation. The aim of this review is the synopsis of the technical expertise on the field of in vivo nasal air conditioning, the novel information of numerical simulations and the current state of knowledge on the influence of nasal and sinus surgery on nasal air conditioning.", "author" : [ { "dropping-particle" : "", "family" : "Keck", "given" : "Tilman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lindemann", "given" : "J\u00f6rg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "GMS current topics in otorhinolaryngology, head and neck surgery", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "Doc08", "title" : "Numerical simulation and nasal air-conditioning.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "8750-7587", "PMID" : "3693240", "abstract" : "We developed and tested a method, based on conduction heat transfer analysis, to infer airway mucosal temperatures from airstream temperature-time profiles during breath-hold maneuvers. The method assumes that radial conduction of heat from the mucosal wall to inspired air dominates heat exchange during a breath-hold maneuver and uses a simplified conservation of energy analysis to extrapolate wall temperatures from air temperature vs. time profiles. Validation studies were performed by simultaneously measuring air and wall temperatures by use of a retractable basket probe in the upper airways of human volunteers and intrathoracic airways of paralyzed intubated dogs during breath holding. In both protocols, a good correlation was demonstrated between directly measured wall temperatures and those calculated from adjacent airstream temperature vs. time profiles during a breath hold. We then calculated intrathoracic bronchial wall temperatures from breath-hold airstream temperature-time profiles recorded in normal human subjects after cold air hyperpnea at 30 and 80 l/min. The calculations show airway wall temperatures in the upper intrathoracic airways that are below core body temperature during hyperpnea of frigid air and upper thoracic airways that are cooler than more peripheral airways. The data suggest that the magnitude of local intrathoracic heat/water flux is not represented by heat/water loss measurements at the airway opening. Both the magnitude and locus of heat transport during cold gas hyperventilation vary with changes in inspired gas temperature and minute ventilation; both may be important determinants of airway responses.", "author" : [ { "dropping-particle" : "", "family" : "Ingenito", "given" : "E P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Solway", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McFadden", "given" : "E R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichurko", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowman", "given" : "H F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Michaels", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drazen", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of applied physiology (Bethesda, Md. : 1985)", "id" : "ITEM-2", "issue" : "5", "issued" : { "date-parts" : [ [ "1987", "11" ] ] }, "page" : "2075-83", "title" : "Indirect assessment of mucosal surface temperatures in the airways: theory and tests.", "type" : "article-journal", "volume" : "63" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "8750-7587", "PMID" : "3980358", "abstract" : "To characterize the intrathoracic thermal events that occur during breathing in humans, we developed a flexible probe (OD 1.4 mm) containing multiple thermistors evenly spaced over 30.2 cm, that could be inserted into the tracheobronchial tree with a fiberoptic bronchoscope. With this device we simultaneously recorded the airstream temperature at six points from the trachea to beyond the subsegmental bronchi in six normal subjects while they breathed ambient and frigid air at multiple levels of ventilation (VE). During quiet breathing of room air the average temperature ranged from 32.0 +/- 0.05 degrees C in the upper trachea to 35.5 +/- 0.3 degrees C in the subsegmental bronchi. As ventilation was increased, the temperature along the airways progressively decreased, and at a VE of 100+ 1/min the temperature at the above two sites fell to 29.2 +/- 0.5 and 33.9 +/- 0.8 degrees C, respectively. Interval points were intermediate between these extremes. With cold air, the changes were considerably more profound. During quiet breathing, local temperatures approximated those recorded in the maximum VE room-air trial, and at maximum VE, the temperatures in the proximal and distal airways were 20.5 +/- 0.6 and 31.6 +/- 1.2 degrees C, respectively. During expiration, the temperature along the airways progressively decreased as the air flowed from the periphery of the lung to the mouth: the more the cooling during inspiration, the lower the temperature during expiration. These data demonstrate that in the course of conditioning inspired air the intrathoracic and intrapulmonic airways undergo profound thermal changes that extend well into the periphery of the lung.", "author" : [ { "dropping-particle" : "", "family" : "McFadden", "given" : "E. R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pichurko", "given" : "B. M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bowman", "given" : "H. F.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ingenito", "given" : "E.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Burns", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dowling", "given" : "N.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Solway", "given" : "J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of applied physiology (Bethesda, Md. : 1985)", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "1985", "2" ] ] }, "page" : "564-70", "title" : "Thermal mapping of the airways in humans.", "type" : "article-journal", "volume" : "58" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^181\u2013183", "plainTextFormattedCitation" : "181\u2013183", "previouslyFormattedCitation" : "^181\u2013183" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }181–183. Furthermore, the partial pressure of oxygen (pO2) and carbon dioxide (pCO2) have opposite gradientsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1378/chest.74.4.426", "ISSN" : "0012-3692", "author" : [ { "dropping-particle" : "", "family" : "West", "given" : "J B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "CHEST", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "1978", "10", "1" ] ] }, "page" : "426", "publisher" : "American College of Chest Physicians", "title" : "Regional differences in the lung.", "type" : "article-journal", "volume" : "74" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸⁰", "plainTextFormattedCitation" : "180", "previouslyFormattedCitation" : "¹⁸⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }180, which are determined by environmental air conditions and gas exchange at the surface of the lungADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.3205/cto000072", "ISSN" : "1865-1011", "PMID" : "22073112", "abstract" : "Heating and humidification of the respiratory air are the main functions of the nasal airways in addition to cleansing and olfaction. Optimal nasal air conditioning is mandatory for an ideal pulmonary gas exchange in order to avoid desiccation and adhesion of the alveolar capillary bed. The complex three-dimensional anatomical structure of the nose makes it impossible to perform detailed in vivo studies on intranasal heating and humidification within the entire nasal airways applying various technical set-ups. The main problem of in vivo temperature and humidity measurements is a poor spatial and time resolution. Therefore, in vivo measurements are feasible only to a restricted extent, solely providing single temperature values as the complete nose is not entirely accessible. Therefore, data on the overall performance of the nose are only based on one single measurement within each nasal segment. In vivo measurements within the entire nose are not feasible. These serious technical issues concerning in vivo measurements led to a large number of numerical simulation projects in the last few years providing novel information about the complex functions of the nasal airways. In general, numerical simulations merely calculate predictions in a computational model, e.g. a realistic nose model, depending on the setting of the boundary conditions. Therefore, numerical simulations achieve only approximations of a possible real situation. The aim of this review is the synopsis of the technical expertise on the field of in vivo nasal air conditioning, the novel information of numerical simulations and the current state of knowledge on the influence of nasal and sinus surgery on nasal air conditioning.", "author" : [ { "dropping-particle" : "", "family" : "Keck", "given" : "Tilman", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lindemann", "given" : "J\u00f6rg", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "GMS current topics in otorhinolaryngology, head and neck surgery", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "Doc08", "title" : "Numerical simulation and nasal air-conditioning.", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISBN" : "0300-0729 (Print)", "ISSN" : "03000729", "PMID" : "8919216", "abstract" : "Sixty acoustic rhinographs from subjects of three different ethnic groups (Caucasian [Europeans], Negro, and Oriental) were examined at baseline and after decongestion. The main parameters analysed were minimal cross-sectional area (MCA), the distance at which this occurred (D), nasal volume at 0-4 cm (Vol), mean cross-sectional area at 0-6 cm (MA), and the cross-sectional area at 10 points in the nose (0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, and 6 cm) analysed as a series (A). Values from left and right were combined and mean values used. Analysis was carried out using multiple linear regression and grouped linear regression with analysis of covariance and, for A, multifactorial analysis of variance. For MCA, race was the main determining factor with Orientals and Caucasians significantly lower than Negroes: p<0.0001 (corrected means and 95% confidence intervals [c.i.]: Orientals: 0.63 cm2, 0.55-0.71 cm2; Caucasians: 0.69 cm2, 0.62-0.77 cm2; Negroes: 0.87 cm2, 0.79-0.95 cm2). Height alone correlated with D in the decongested state (p<0.0001); race as well as height in non-decongested noses (p = 0.018). There were significant racial differences in Vol in both decongested (p = 0.014), and non decongested noses (p<0.0001). In the non-decongested state MA was significantly different in all racial groups: p<0.0001 (corrected means and c.i.: Orientals: 3.89 cm2, 3.47-4.31 cm2; Caucasians: 4.67 cm2, 4.27-5.09 cm2; Negroes: 5.13 cm2, 4.72-5.53 cm2). In the decongested state there was a significant difference between Negroes and the other two groups (p = 0.015), and Orientals and Caucasians were a homogenous population. We conclude that race has a significant effect on acoustic rhinometry measurements and this needs to be taken into account.", "author" : [ { "dropping-particle" : "", "family" : "Morgan", "given" : "N J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "MacGregor", "given" : "F B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Birchall", "given" : "M A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lund", "given" : "V J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sittampalam", "given" : "Y", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rhinology", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "1995", "12" ] ] }, "page" : "224-228", "title" : "Racial differences in nasal fossa dimensions determined by acoustic rhinometry", "type" : "article-journal", "volume" : "33" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1111/j.1365-2869.2008.00647.x", "ISSN" : "1365-2869", "PMID" : "18422508", "abstract" : "This study compared shape, size and length of the pharyngeal airway in individuals with and without obstructive sleep apnoea (OSA) using a novel endoscopic imaging technique, anatomical optical coherence tomography (aOCT). The study population comprised a preliminary study group of 20 OSA patients and a subsequent controlled study group of 10 OSA patients and 10 body mass index (BMI)-, gender- and age-matched control subjects without OSA. All subjects were scanned using aOCT while awake, supine and breathing quietly. Measurements of airway cross-sectional area (CSA) and anteroposterior (A-P) and lateral diameters were obtained from the hypo-, oro- and velopharyngeal regions. A-P : lateral diameter ratios were calculated to provide an index of regional airway shape. In all subjects, pharyngeal CSA was lowest in the velopharynx. Patients with OSA had a smaller velopharyngeal CSA than controls (maximum CSA 91 +/- 40 versus 153 +/- 84 mm(2); P < 0.05) but comparable oro- (318 +/- 80 versus 279 +/- 129 mm(2); P = 0.48) and hypopharyngeal CSA (250 +/- 105 versus 303 +/- 112 mm(2); P = 0.36). In each pharyngeal region, the long axis of the airway was oriented in the lateral diameter. Airway shape was not different between the groups. Pharyngeal airway length was similar in both groups, although the OSA group had longer uvulae than the control group (16.8 +/- 6.2 versus 11.2 +/- 5.2 mm; P < 0.05). This study has shown that individuals with OSA have a smaller velopharyngeal CSA than BMI-, gender- and age-matched control volunteers, but comparable shape: a laterally oriented ellipse. These findings suggest that it is an abnormality in size rather than shape that is the more important anatomical predictor of OSA.", "author" : [ { "dropping-particle" : "", "family" : "Walsh", "given" : "Jennifer H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leigh", "given" : "Matthew S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paduch", "given" : "Alexandre", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maddison", "given" : "Kathleen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Philippe", "given" : "Danielle L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Armstrong", "given" : "Julian J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sampson", "given" : "David D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hillman", "given" : "David R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eastwood", "given" : "Peter R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of sleep research", "id" : "ITEM-3", "issue" : "2", "issued" : { "date-parts" : [ [ "2008", "6" ] ] }, "page" : "230-8", "publisher" : "Blackwell Publishing Ltd", "title" : "Evaluation of pharyngeal shape and size using anatomical optical coherence tomography in individuals with and without obstructive sleep apnoea.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^181,184,185", "plainTextFormattedCitation" : "181,184,185", "previouslyFormattedCitation" : "^181,184,185" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }181,184,185. Inhalation results in deposition of particles from the environment into the respiratory tract; whereas inhaled particles of >10 ?m are deposited in the URT, particles <1 ?m can reach the lungs. These particles, however, include bacteria- and virus-containing particles, which are typically larger than 0.4 ?m in diameterADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0005-3678", "PMID" : "13905321", "author" : [ { "dropping-particle" : "", "family" : "Hatch", "given" : "T F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Bacteriological reviews", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1961", "9" ] ] }, "page" : "237-40", "title" : "Distribution and deposition of inhaled particles in respiratory tract.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸⁶", "plainTextFormattedCitation" : "186", "previouslyFormattedCitation" : "¹⁸⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }186. These physiological parameters determine the niche-specific selective growth conditions that ultimate shape the microbial communities along the respiratory tract. *The unit by which the bacterial density is measured varies per niche; the density of the environment is depicted as bacteria per cm3 (indoor) airADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1186/s40168-015-0144-z", "ISSN" : "2049-2618", "abstract" : "Each day people are exposed to millions of bioaerosols, including whole microorganisms, which can have both beneficial and detrimental effects. The next chapter in understanding the airborne microbiome of the built environment is characterizing the various sources of airborne microorganisms and the relative contribution of each. We have identified the following eight major categories of sources of airborne bacteria, viruses, and fungi in the built environment: humans; pets; plants; plumbing systems; heating, ventilation, and air-conditioning systems; mold; dust resuspension; and the outdoor environment. Certain species are associated with certain sources, but the full potential of source characterization and source apportionment has not yet been realized. Ideally, future studies will quantify detailed emission rates of microorganisms from each source and will identify the relative contribution of each source to the indoor air microbiome. This information could then be used to probe fundamental relationships between specific sources and human health, to design interventions to improve building health and human health, or even to provide evidence for forensic investigations.", "author" : [ { "dropping-particle" : "", "family" : "Prussin", "given" : "Aaron J.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Marr", "given" : "Linsey C.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Microbiome", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015", "12", "22" ] ] }, "page" : "78", "publisher" : "BioMed Central", "title" : "Sources of airborne microorganisms in the built environment", "type" : "article-journal", "volume" : "3" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸⁷", "plainTextFormattedCitation" : "187", "previouslyFormattedCitation" : "¹⁸⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }187, density measures for the nasal cavity and nasopharynx are shown as estimated number of bacteria per nasal swabADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷⁴", "plainTextFormattedCitation" : "74", "previouslyFormattedCitation" : "⁷⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }74, and the density of oropharynx and lung represents the estimated number of bacteria per mL oral washADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201204-0693OC", "ISSN" : "1073-449X", "abstract" : "Rationale: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers.Objectives: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing.Methods: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover.Measurements and Main Results: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tra...", "author" : [ { "dropping-particle" : "", "family" : "Charlson", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "Joshua M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Ayannah S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yadav", "given" : "Anjana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "Andrew R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "Frederic D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2012", "9", "15" ] ] }, "page" : "536-545", "publisher" : "American Thoracic Society", "title" : "Lung-enriched Organisms and Aberrant Bacterial and Fungal Respiratory Microbiota after Lung Transplant", "type" : "article-journal", "volume" : "186" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. 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The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^57,74", "plainTextFormattedCitation" : "57,74", "previouslyFormattedCitation" : "^57,74" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }57,74 or bronchoalveolar lavage (BAL)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.201204-0693OC", "ISSN" : "1073-449X", "abstract" : "Rationale: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers.Objectives: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing.Methods: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover.Measurements and Main Results: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tra...", "author" : [ { "dropping-particle" : "", "family" : "Charlson", "given" : "Emily S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diamond", "given" : "Joshua M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bittinger", "given" : "Kyle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fitzgerald", "given" : "Ayannah S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yadav", "given" : "Anjana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Haas", "given" : "Andrew R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bushman", "given" : "Frederic D.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collman", "given" : "Ronald G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American Journal of Respiratory and Critical Care Medicine", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2012", "9", "15" ] ] }, "page" : "536-545", "publisher" : "American Thoracic Society", "title" : "Lung-enriched Organisms and Aberrant Bacterial and Fungal Respiratory Microbiota after Lung Transplant", "type" : "article-journal", "volume" : "186" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1128/mBio.00037-15", "ISSN" : "2150-7511", "abstract" : "No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stomach). Oral wash, bronchoalveolar lavage (BAL) fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BAL fluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach contained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant membership with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological continuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.", "author" : [ { "dropping-particle" : "", "family" : "Bassis", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Erb-Downward", "given" : "John R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dickson", "given" : "Robert P.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Freeman", "given" : "Christine M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schmidt", "given" : "Thomas M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Young", "given" : "Vincent B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beck", "given" : "James M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Curtis", "given" : "Jeffrey L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huffnagle", "given" : "Gary B.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "mBio", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2015", "5", "1" ] ] }, "page" : "e00037-15", "publisher" : "American Society for Microbiology", "title" : "Analysis of the Upper Respiratory Tract Microbiotas as the Source of the Lung and Gastric Microbiotas in Healthy Individuals", "type" : "article-journal", "volume" : "6" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1164/rccm.201304-0775OC", "ISSN" : "1535-4970", "PMID" : "24024497", "abstract" : "RATIONALE The role of airway microbiome in corticosteroid response in asthma is unknown. OBJECTIVES To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids. METHODS 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation. MEASUREMENTS AND MAIN RESULTS Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subjects with CR and CS asthma did not differ in richness, evenness, diversity, and community composition at the phylum level, but did differ at the genus level, with distinct genus expansions in 14 subjects with CR asthma. Preincubation of asthmatic airway macrophages with Haemophilus parainfluenzae, a uniquely expanded potential pathogen found only in CR asthma airways, resulted in p38 MAPK activation, increased IL-8 (P < 0.01), mitogen-activated kinase phosphatase 1 mRNA (P < 0.01) expression, and inhibition of corticosteroid responses (P < 0.05). This was not observed after exposure to commensal bacterium Prevotella melaninogenica. Inhibition of transforming growth factor-\u03b2-associated kinase-1 (TAK1), upstream activator of MAPK, but not p38 MAPK restored cellular sensitivity to corticosteroids. CONCLUSIONS A subset of subjects with CR asthma demonstrates airway expansion of specific gram-negative bacteria, which trigger TAK1/MAPK activation and induce corticosteroid resistance. TAK1 inhibition restored cellular sensitivity to corticosteroids.", "author" : [ { "dropping-particle" : "", "family" : "Goleva", "given" : "Elena", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jackson", "given" : "Leisa P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harris", "given" : "J Kirk", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Robertson", "given" : "Charles E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sutherland", "given" : "E Rand", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hall", "given" : "Clifton F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Good", "given" : "James T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gelfand", "given" : "Erwin W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Martin", "given" : "Richard J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leung", "given" : "Donald Y M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-3", "issue" : "10", "issued" : { "date-parts" : [ [ "2013", "11", "15" ] ] }, "page" : "1193-201", "title" : "The effects of airway microbiome on corticosteroid responsiveness in asthma.", "type" : "article-journal", "volume" : "188" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^57,74,153", "plainTextFormattedCitation" : "57,74,153", "previouslyFormattedCitation" : "^57,74" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }57,74,153, respectively.Figure 2 | Host and environmental factors that influence the respiratory microbiotaDuring early life, respiratory microbial communities are highly dynamic and are driven by multiple factors, including mode of birth, feeding type, crowding conditions and antibiotic treatment. Together these host and environmental factors can shape the microbial composition towards a stable community at equilibrium, which is resistant to pathogenic overgrowth, or conversely, an unstable community develops that is predisposed to a state of infection and inflammation.Figure 3 | Host-microbiota interactions in the respiratory tractHost-microbiota interactions in the respiratory tract occur mostly at the mucosal surface. Resident microbiota primes immune cells either locally or systemically. These include epithelial cells, neutrophils, and dendritic cells (DCs), which all contribute to the clearance of pathogens. Moreover, microbial signaling is necessary for the recruitment and activation of regulatory cells such as anti-inflammatory alveolar macrophages (AMs) and regulatory T (Treg) cells. Locally, the host will respond to microbial colonization by the release of antimicrobial peptides (AMPs) and soluble immunoglobulin A (sIgA). Sensing of microbiota involves microfold (M) cells, which activate tolerogenic DCs. Additionally, alveolar DCs can directly sample luminal microorganisms. Together, these pathways will lead to regulation of inflammation and induction of tolerance, which in turn shape resident bacterial communities. It is also plausible that early bacterial colonization is key to long-term immune regulation, which is illustrated by microbiota-induced hypermethylation of chemokine (C-X-C motif) ligand 16 (CXCL16), which prevents the accumulation of inducible natural killer T (iNKT) cells, and by programmed death ligand 1 (PD-L1)-mediated induction of tolerogenic DCs. This tolerant milieu in turn contributes to the normal development and maintenance of resident bacterial communities, which are also influenced by host and environmental factors (FIG. 1). URT: upper respiratory tract; AEC: alveolar epithelial cell; LPS: lipopolysaccharide; PRR: pattern recognition receptor.GlossaryMicrobiota: Collection of microorganisms (including bacteria, archaea and single-celled eukaryotes) and viruses that inhabit a particular niche.Microbiome: All of the genetic content of a microbial community.Inhabitation: the presence or occupancy of organisms.Colonization: the act of settlement and reproduction of organisms that are subject to selective pressure.Symbiotic relationship: a close biological interaction between two different species.Nasal (olfactory) placodes: thickening of the embryonic head ectoderm that appears in the fifth embryonic week and marks the start of the formation of the nose and nasal cavity. Oropharyngeal membrane: a transient bilaminar (ectoderm and endoderm) membrane that appears in the fourth embryonic week during the development of the primitive mouth and pharynx.Lung buds: a pair of endodermal outgrowths of the foregut that develops into the larynx, trachea and lungs. Anterior nares or nostrils: Openings in the nose connecting the exterior and the nasal cavity.Acute otitis media (AOM): acute onset viral and/or bacterial infection of the middle ear. Chronic rhinosinusitis: common condition typified by prolonged inflammation of the paranasal sinuses.Quorum sensing: communication system between bacterial cells capable of triggering microbial group behavior (e.g. biofilm formation) once a certain threshold of signaling molecules is reached.NALT (nasopharynx-associated lymphoid tissue): one of the anatomical locations of mucosa-associated lymphoid tissue (MALT), which in humans consists of the lymphoid tissue of Waldeyer's pharyngeal ring, including the adenoids (the unpaired nasopharyngeal tonsil) and the paired palatine tonsils.Lamina propria: layer of loose connective tissue located directly underneath the epithelium.Biodiversity: The composite of species richness (the number of species present in an ecosystem) and evenness (the equitability of the abundance of these species).Keystone species: A sole species which is typically not highly abundant, yet is disproportionally important in maintaining the whole community’s organization and structure. Biofilm: microorganisms embedded in a self-produced matrix of extracellular polymeric substances that are adherent to each other and/or a surface.Mucosal dispersion: the separation and scattering of organisms from the mucosaMicro-aspiration: subclinical aspiration of small dropletsToll-like receptors: evolutionary conserved transmembrane proteins which have a crucial role in innate immune responses against invading pathogensT-helper 17 cell: a subset of T helper cells that are characterized as preferential producers of interleukin 17, mediate host defensive mechanisms to various infections, and are involved in the pathogenesis of multiple autoimmune disorders.Mucus: Viscous secretion produced by goblet cells and composed of a diverse array of mucin proteins.,Mucin: A class of gel-forming glycoproteins that give mucus its viscosity.Alveolar surfactant: mixture of proteins and lipids that reduce surface tension and prevent alveolar collapse, and additionally possess antimicrobial and anti-inflammatory properties. LPS (lipopolysaccharide): the main constituent of the cell wall of Gram-negative bacteria and a potent TLR-4 ligandNOD (nucleotide-binding oligomerization domain)-like proteins: Intracellular, innate pattern recognition receptor molecules that recognize molecular fragments in peptidoglycan (constituent of the bacterial cell wall).Beta-defensin-2: antimicrobial peptide produced by airway epithelial cells upon microbial stimulation. Bronchial alveolar lavage: Fluid containing bronchoalveolar cells, obtained by infusing and extracting saline during bronchoscopy.Regulatory T (Treg)-cells: subpopulation of T cells that modulate the host immune system and are pivotal in maintenance of tolerance.Acute respiratory distress syndrome (ARDS): clinical phenotype that occurs in critically ill patients and is characterized by overt lung inflammation in response to various pathologies, including trauma, sepsis and pneumonia.Key pointsThe anatomical development and maturation of the human respiratory tract is a complex, multistage process, which occurs not only in prenatal life, but also postnatally. This maturation process depends (in part) on exposure to microbial and environmental triggers and results in a highly specialized organ system that contains several distinct niches, each subjected to specific microbial, cellular and physiological gradients.The early life respiratory microbiome is dynamic and its development is affected by a myriad of host and environmental factors, including mode of birth, feeding type, antibiotic treatment and crowding conditions, such as the presence of siblings and daycare attendance.The upper respiratory tract is inhabited by specialized resident bacterial, viral and fungal assemblages, which presumably prevent potential pathogens from overgrowing and disseminating towards the lungs, thereby functioning as gatekeepers to respiratory health.The upper respiratory tract is the primary source of the lung microbiome. In health, the lung microbiome appears to largely reflect transient microorganisms, and its composition is determined by the balance between microbial immigration and elimination.Next-generation sequencing has unmasked intricate interbacterial association networks, comprising true symbiotic or antagonistic direct or indirect relationships. Alternatively, bacterial co-occurrence seems to be driven by host and environmental factors, as well as by interactions with viruses and fungi.The respiratory microbiome provides cues to the host immune system, which appear to be vital in immune training, organogenesis and maintenance of immune tolerance. Increasing evidence supports the existence of a ‘window of opportunity’ early in life, during which adequate microbiota sensing is essential for immune maturation and consecutive respiratory health.Future studies should focus on large scale, multidisciplinary holistic approaches and adequately account for host and environmental factors. Associations identified by these studies can then be corroborated in reductionist surveys, for example by exploiting in vitro or in vivo studies.AcknowledgementsWe apologize to all authors whose work could not be cited due to space limitations.This work was supported by the Netherlands Organization for Scientific Research through NWO-Vidi (grant 91715359) (DB), a Scottish Senior Clinical Fellowship award (DB), the Spaarne Gasthuis Academy Hoofddorp (WHM) and Wilhelmina Children’s Hospital intramural funds (WAASP).We thank our colleagues in Utrecht, Hoofddorp and Edinburgh for all in depth discussions we had in the past on the topic of this manuscript: without doubt these discussions have significantly contributed to the content of this peting interests statementThe authors declare no competing interests.Highlighted references3.Bogaert, D., De Groot, R. & Hermans, P. W. M. Streptococcus pneumoniae colonisation: The key to pneumococcal disease. Lancet Infect. 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In this review, Man, de Steenhuijsen Piters and Bogaert discuss the role of the respiratory microbiota in maintaining human health.Subject categoriesBiological sciences / Microbiology / Pathogens[URI /631/326/421]Biological sciences / Microbiology / Microbial communities / Microbiome[URI /631/326/2565/2134]Health sciences / Diseases / Respiratory tract diseases[URI /692/699/1785]Biological sciences / Microbiology / Microbial communities / Clinical microbiology[URI /631/326/2565/107]Biological sciences / Microbiology / Microbial communities / Symbiosis[URI /631/326/2565/547]Biological sciences / Microbiology / Bacteria / Infectious-disease epidemiology[URI /631/326/41/1470]Author biographiesWing Ho Man is a medical doctor who is in the process of completing his Ph.D. in pediatric immunology and infectious diseases under the supervision of Prof. Debby Bogaert, Prof. Elisabeth Sanders and Dr. Marlies van Houten at the Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands and the Spaarne Gasthuis Academy, Hoofddorp and Haarlem, The Netherlands. He is currently investigating the human microbiome and virome of children with lower respiratory tract infections in comparison with healthy children.Wouter de Steenhuijsen Piters is a medical doctor and Ph.D. student at the University Medical Center Utrecht, Utrecht, The Netherlands under the supervision of Prof. Debby Bogaert and Prof. Elisabeth Sanders. He studies the upper respiratory tract microbiome in association with respiratory health and disease, focusing on bio-informatic processing and data-analyses tools to answer health-related research questions. Currently, he works at the University of Edinburgh, studying healthy microbiota development in relation to environmental drivers and health consequences.Professor Debby Bogaert is a physician scientist leading a research group on pathogenesis of respiratory infections at the MRC Centre for Inflammation Research of the Edinburgh University Moreover, she works as honorary consultant in Paediatric Infectious Diseases and Immunology at the Royal Hospital for Sick Children in Edinburgh. In addition, she leads a research group at the University Medical Center Utrecht/Wilhelmina Children’s Hospital in Utrecht, the Netherlands, collaborating closely with clinical, environmental and public health scientists. She received her Ph.D. from the University of Rotterdam investigating host-pathogen interactions during S. pneumoniae colonization and infection, and worked as postdoctoral fellow at Harvard Medical School, Boston, Massachusetts, USA, where she studied pneumococcal colonization and infection in vitro and in animal models. Her current work focusses on healthy respiratory microbiome development and the microbiota perturbations associated with respiratory disease with the ultimate aim to develop measures to prevent or treat respiratory diseases. ................
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