UNIT 2 – CONFLICTS BETWEEN MICROBES AND HOST



UNIT TWO – CONFLICTS BETWEEN MICROBES AND HOSTUnit Two – Outline of TopicsI. Entry, Exit, and TransmissionA. OverviewB. Specifics of entry, exit, & transmission1. Skin2. Respiratory Tract - nose, trachea, bronchi, lungs3. Gastrointestinal – Stomach + Intestines4. Urogenital - Urinary + Genital5. Oropharynx – mouth; throatII. Microbial strategies to avoid host nonspecific defenses A. Avoiding destruction by complementB. Avoiding interferonC. Avoiding destruction by phagocytesIII. Microbial Spread and ReplicationA. Surface Infections = Local InfectionsB. Systemic Infections1. Spread along lymphatics2. Spread through the blood3. Spread from blood to internal tissues4. Spread from blood to brain5. Spread along nervesIV Microbial Strategies to Avoid Specific DefensesA. Prevent or delay recognition of pathogen antigensB. Antigenic variationImmunosuppressionPersistent infectionsV. Pathological Consequences of InfectionA. Pathology caused by the microbeB. Pathology caused by the immune response to the microbe1. Pathology resulting from Nonspecific immune defenses2. Pathology resulting from Specific immune defensesUNIT TWO –Terminology that will be encountered during lecture but not definedUsing a medical dictionary, define:“acutely ill”Nuchal rigidity – Chronic granulomatous disease (CGD) – Febrile – Petechiae Polyarthritis – Myalgia – Dyspnea – Diaphoresis - Erythrocyte sedimentation rate (ESR) – And what is a normal ESR for children? – Sequela – ArthralgiaAnorexiaSomnolesenceRigorIncubation period – Pyogenic - Pyrogenic – UNIT 2 – CONFLICTS BETWEEN MICROBES AND HOSTResponse to Infection – Biologic response gradientI. ENTRY, EXIT, AND TRANSMISSIONObjectives:know the first line host defenses of each of the 5 systemsexplain how microbes enter each of the 5 systemswhat is one of the most important mechanisms for establishment at each site of entry?describe how microbes exit each systemA. OVERVIEWSome microbes live on body surfaces Ex. normal skin microbiota like Staphylococcus epidermidis, diphtheroids. Also some pathogens - Vibrio cholera, Campylobacter jejuni 1. Entry into hosta. Active penetration - invasive Ex 1. S. epidermidis is not invasive but S. aureus isEx 2. Shigella invades epithelial cells of colon - Salmonella invades small intestinal epithelial cells. b. Insertion - by biting anismDiseaseInsect vectorPlasmodiummalariamosquitoRickettsia typhityphusrat fleaYersinia pestisplaguerat fleaYellow fever virusyellow fevermosquitoc. Break (bite, puncture, burn)Exs. Pasteurella multocida, rabies virus, Clostridium tetani.d. Impairment - of surface or systemic defensesEx. disorders of phagocytic cells ↑infections Attachment to target cell - aided by specific receptors After attaching:1. remain on outside of cell & multiply on the surface of the cell – Ex. Vibrio2. enter cell & multiply w/in it – Exs. Shigella, Salmonella, viruses2. Exit and Transmissiona. Exit body1) shed - secretions - resp. droplets, saliva, semen, feces2) sucked out of blood - insectsb. Successful transmission to new hostdepends on:1) number of microbes shed - the more the better2) stability in the environ. - cysts, spores, naked viruses3) number of individuals required to infect a new host - varies - Shigella 1-10, Salmonella 106The most common infections are spread via:respiratory route (Exs. colds, influenza)fecal-oral route (Ex. diarrheal diseases like Giardia) sexual transmission (Ex. gonorrhoea)needles - a new mech (Exs. HIV, Ebola, hepatitis B)B. SPECIFICS OF ENTRY, EXIT, AND TRANSMISSION1. SkinRev. of defenses of the skinSome pathogens can live on non-living layer of skin - Ex. fungi called Dermatophytes a. Entry across skin barrier1. break - wound/bite/burn2. biting insect3. hair folliclesEx. S. aureus - lipase, some strains toxin called exfoliatin - separates layers of dermisb. Exit & Transmission from skinDirect contact between infected hostsviruses: Exs. human papilloma virus (genital warts), herpes, chicken pox bacteria: Exs. pathogenic staphylococci & streptococci, Treponema pallidumdermatophytes: athletes foot, ringwormprotozoa: Leishmania 2. Respiratory Tract - nose, trachea, bronchi, lungsa. Entry to RTTransmission – person to person via respiratory droplets or fomites/fingersFate of droplet depends on the size of droplet particle:Particle diameterWhere it lands> 10 micrometersURT: nose, throat5-10 micrometersBronchioles< 5 micrometersAlveolar regionDefenses against entry1. nasal hairs (vibrissae)2. mucus (containing lysozyme, phagocytes, lactoferrin, maybe antigen specific sIgA)3. ciliary action4. cooler temperature (33°C vs 37°C)Pathogens avoid these defenses1. attach tightly - Exs. Bordetella pertussis, Neisseria meningitidis, Influenza virus, cold viruses2. take advantage of dame to muco-ciliary clearance – Streptococcus pneumoniae3. produce toxin to interfere with ciliary activity - Exs. Bordetella pertussis, Haemophilus influenzae, Pseudomonas aeruginosa, Mycoplasma pneumoniae4. inhaled directly into lungsmain defense of lungs - complement, alveolar macrophages, maybe antigen specific sIgA and IgGMycobacterium tuberculosis b. Exit & Transmission from RTCause increase in secretions inflammation vas. permeability fluid *sneezing coughingtalking easily spread because of crowding dry air impairs mucociliary action (also smoke, alcohol)from one person’s respiratory tract directly into another's3. Gastrointestinal – Stomach + Intestinesa. Entry to GITransmission – fecal-oral route (includes fecal – water/food – oral)Defenses of GI1. acid of stomach2. dense normal microbiota3. peristalsis, mucus (lysozyme, phagocytes, sIgA)4. proteolytic enz, bile5. gut associated lymphoid tissue (GALT)Pathogens avoid these defenses1. motility - Exs. V. cholera, Salmonella, some E. coli2. mucinase - Ex. V. cholera3. attachment a. via specific receptors Exs. V. cholerae, rotavirus; Shigella vs. Salmonellab. mechanical Exs. Giardia lamblia trophozoites, hookworms4. survive in presence of acid, proteolytic enzymes, bile Exs. Streptococcus faecalis, Salmonella b. Exit and Transmission from GIfecesExs. cysts (Giardia, Cryptosporidium), naked viruses (rotavirus, poliovirus)4. Urogenital - Urinary + Genitala. Entry to bladder and/or urethraTransmission – via self-inoculationUrine in the bladder is normally sterile Defenses of bladder and lower UT1. voiding urine2. phagocytes3. sIgAInvaded from the exterior- via the urethra = ascending infectionPathogens avoid these defenses1. specialized attachment mechs - fimbriae - Exs. E. coli Neisseria gonorrhoeae, Chlamydia trachomatisSpread from urethra bladder - is difficult in males - urethra is 20 cm long UTI in females are common - 14X greater - 20% get symptomatic UTI - urethra is very short - 5cmDefenses of female reproductive organs1. downward flow of mucus (lysozyme, phagocytes)2. ciliated epithelial cells3. normal microbiota – esp. lactobacilli, 108/ml in adult female - pH 5 b. Exit and Transmission from Urogenitaltransmission via contaminated urine NOT commonExceptions - leptospira, Lassa virus (rodent urine) *direct mucosal contact - STIenhances transmission:discharge - gonorrhea, chlamydiasores -syphilis, herpes simplex5. Oropharynx - mouth; throata. Entry to oropharynxTransmission via ingestion, hand-mouth, mouth-mouthDefenses of oropharynx1. cleansing mechs - flushing action of saliva2. lysozyme 3. phagocytes4. sIgA5. normal microbiotaPathogens avoid defenses1. Attachment - fimbriaeb. Exit and Transmission from oropharynx1. Saliva - Ex. streptococcisome infection of salivary glands - Exs. EBV (mono) mumps, herpesSUMMARIZE COMMON THEMES:What aids in establishment at a site of entry? What factors encourage transmission of microbes to new hosts?II. MICROBIAL STRATEGIES TO AVOID HOST NONSPECIFIC DEFENSESComplement, interferon, phagocytosisObjectives:1. Understand that successful pathogens have evolved strategies to avoid nonspecific defenses 2. Explain how these pathogen avoidance strategies work.3. Understand the significance in particular of anti-phagocytic strategies.A. AVOIDING DESTRUCTION RESULTING FROM ACTIVATION OF COMPLEMENTSeveral exs. of strategies to prevent formation of MAC1. capsules prevent activation of alternate pathwayEx. S. pneumoniae, Klebsiella2. coating w/ IgA prevents activation of classical complementEx. Campylobacter3. prevent stabilization of C3 convertase and resulting cascadeEx. Pathogenic streptococci & Campylobacter4. degrade C3b & C5b before cell bindingEx. N. meningitidis, Y. pestis5. bud off membrane bound C3b & C5b so MAC doesn’t form6. long chains of polysaccharides prevent MAC formation Ex. strains of SalmonellaB. AVOIDING INHIBITION BY INTERFERONpoor inducers of interferons – hepatitis Bblock action of interferons – hepatitis B, HIV, EBVC. AVOIDING DESTRUCTION BY PHAGOCYTES – very important pathogen strategies!!1. Inhibit chemotaxis or mobilization of phagocytesa. toxins that suppress chemotaxisEx. Streptococcus, Clostridium perfringens2. prevent/delay contact with phagocyte a. capsulesEx. esp. pathogenic streptococci, Haemophilus influenzae, Klebsiella pneumoniae, many othersb. fimbriaeEx. pathogenic neisseriac. M proteinEx. S. pyogenesd. FcREx. Staphylococcus aureus Protein A & S. pyogenes Protein G, herpes group viruses induce FcR on surface of infected cell3. Escape from phagosome into cytoplasmEx. Shigella, Listeria monocytogenes, Mycobacterium leprae, Trypanosoma cruzi4. Prevent fusion of lysosome with phagocytic vacuoleEx. M. tuberculosis, Salmonella typhimurium, Toxoplasma gondii5. Resist killing and digestion in phagolysosomeEx. L. monocytogenes, Yersinia pestis, S. typhimurium, reoviruses are actually stimulated to uncoat by lysosomal enz. 6. Resist oxygen-dependent killingEx. M. tuberculosis prevents respiratory burst, M. leprae scavenges ROIEx. catalase – staphylococci, L. monocytogenes7. Kill the phagocyteEx. hemolysins of pathogenic streptococci and staphylococci, L. monocytogenesEx. Lethal factor of Bacillus anthracisCONCEPT CHECK 5Neisseria meningitidis (one causative agent of bacterial meningitis) is carried, apparently harmlessly, in the respiratory tracts of approximately 20% of the population (estimates vary). 1) Explain how, in general, respiratory tract pathogens are acquired, 2) List the defenses (defenses against entry and then nonspecific interior defenses) of the respiratory tract that would be relevant to bacterial infections, and 3) Discuss the strategies that specifically N. meningitidis has evolved that allows it to avoid the nonspecific defenses of the upper RT.III. REPLICATION AND SPREAD OF MICROBES IN THE HOSTObjectives:Know some of the general differences between local infections and systemic infectionsUnderstand the various mechanisms by which microbes can spread from the site of entry to other systems in the bodyThere are 2 basic categories of infections - surface infections and systemic infections. A. SURFACE INFECTIONS = Local InfectionsMany microbes multiply at the site of entry and don't invade deeper into tissue or spread to other systems in the body.Surface or local infections spread easily on mucosal surfaces (intestinal, respiratory).Surface infections often result in large scale production and movement of body fluids.This large scale movement of fluid can spread an infection very quickly (large areas of the body surface can be involved within a few days).General Characteristics of Surface Infections: Short incubation times - less than 1 week. Microbes are replicate very rapidlyNonspecific defenses are key to control - the early nonspecific defense mechanisms; complement activation, interferon, phagocytosis, and NK cells are key to controlling the infection - no time to wait for specific defenses to activate.Ex. Common cold, Gastroenteritis, GonorrheaB. SYSTEMIC INFECTIONSSome microbes enter the lymph fluid or blood and then spread through the body involving more than one system.General Characteristics of Systemic Infections: Longer incubation times, greater than 1 week. (Ebola virus, 12-21 days incubation; incubation for HIV is years.)Microbes replicate more slowlySpecific defenses (activated Tc, antibodies) are key to control - because of longer incubation times, there is time for specific defenses to activate and play a role in controlling infection.EX. Measles, Typhoid fever, Tuberculosis1. What keeps surface infections from spreading deeper?a. Temperature - Ex. Rhinovirus- upper respiratory tract is 33°C, lower respiratory tract is 37°C. Rhinovirus don’t replicate well at 37?C.b. Mechanism of exiting the infected cell - Ex. Influenza virus spreads through free surface of epithelial cells but not through the basal surface.2. Why do some microbes take the risk of spread through the blood and lymph where they will encounter the full force of the immune system?Ex. Mumps virus- enters via inhalation but multiplies in salivary glands. Ex. Hepatitis A virus enters the GI via ingestion, but it replicates in the liver. How would it get from the intestines to the liver? It needs to travel through the blood. Systemic Infections often follow a stepwise invasion of different tissues of the body.1. Spread along the LymphaticsMany bacteria that spread along the lymphatic route induce significant signs of inflammation. For example, a minor skin wound followed by red streaking and tender swollen local lymph nodes are classical signs of inflamed lymphatic vessels. The bacteria secrete toxins or cause other forms of tissue damage that early on in the course of infection set off alarm bells to cause acute inflammation and alert the nonspecific interior defenses. In general, bacterial spread is accompanied by inflammation - bacterial spread is noisy.In contrast to bacteria, many viruses can invade along the lymphatics without inducing inflammation, they are silent. Viruses cause little tissue damage early in the course of infection so inflammatory responses are absent or delayed. EBV- (infectious mono) - may be present for weeks before any inflammatory responses are activated. And some viruses can infect cells for long periods of time before they damage them.2. Spread through the BloodA microbial infection might be arrested at any point during lymphatic spread. But microbes that can evade phagocytosis or multiply within the lymph nodes will ultimately reach the blood stream, because movement from one system into the other is easy (see part (a) of picture below).Small numbers of bacteria can enter the blood without causing damage. Transient bacteremias, bacteria in the blood, are common.What happens to microbes moving through the blood is related to:1. whether they are free in the plasma where they are exposed to phagocytes and antibodies, or 2. whether they are intracellular in circulating cells, like erythrocytes, monocytes, lymphocytes, where they can escape immune detection – this is a more successful strategy. Exs: EBV and Listeria are intracellular in monocytes or lymphocytes, malaria in erythrocytes, Salmonella and Leishmania in macrophages.Microbes may leave the circulation and enter other body sites as the blood flows through these tissues/organs.3. Spread from Blood to Internal TissuesSometimes free bacteria that enter the blood have the opportunity to colonize internal sites that are less well protected before being eliminated by phagocytes.Ex. (add notes)4. Spread from Blood into BrainThere is a barrier between the blood and the cerebral spinal fluid and between the blood and brain that is impervious to most microbes (this barrier is called the Blood-Brain Barrier (BBBlefttopBut there are some microbes that can cross the blood-brain barrier and gain access to the CSF or brain. Often these microbes induce inflammation that makes the BBB more permeable. Infections of the CNS are especially dangerous as the BBB also keeps out most host immune cells and drugs. – Exs. Neisseria meningitidis, Haemophilus influenzae- cause increased permeability of BBB and cross over into the brain.5. Spread along NervesSome microbes can spread along nerve networks. There are few if any host defenses to control, especially viral, spread once the nerves are infected.Exsherpes simplex is never eliminatedvaricella-zoster is never eliminated Rabies is never eliminated and is 100% fatalCovered in more detail in Unit 3, Diseases of the NS.CONCEPT CHECK 6Neisseria meningitidis enters the host via the nasopharynx, but invasive strains cause the disease bacterial meningitis when they infect the meninges of the brain. Discuss how N. meningitidis moves step-wise through the body from the nasopharynx to the meninges of the brain.IV MICROBIAL STRATEGIES TO AVOID SPECIFIC DEFENSESObjectives:1. Understand the significance of pathogen avoidance strategies in relation to replication and spread, pathology, and transmission.2. Explain the potential consequences to the host of microbial mimicry.3. Discuss the significance of antigenic variation.4. Explain, in detail, the 3 mechanisms that produce antigenic variationPATHOGEN PREVENTS OR DELAYS RECOGNITION OF ITS ANTIGENS1.Pathogen colonizes “privileged” sitesexternal sites – skin & intestinal lumeninternal sites - CNS, joints, testis, and placentapathogen-created sites – cysts – Ex. Echinococcusintegrate in to cell’s DNA – Ex. retrovirusesPathogen is intracellulardoes not display antigens on cell surface – Ex. herpesputs proteins on an internal membranes – Ex. coronavirusprevents MHC + antigen traffic to cell surface – ex. adenovirusPathogen’s antigens are very similar to host antigens = mimicry – immune response may be weak or absent – Ex. scrapie (PrPS is similar to PrPC)Does NOT always prevent immune detection and pathological consequences.Example – Association between Streptococcus pyogenes and rheumatic heart disease (take good notes here)Pathogen covers surface with host molecules (camouflage)antibody molecules absorbed via FcR – bacteria and virusesfibrin – coagulase-positive staphylococcihost blood group glycoproteins + MHC molecules + antibodies – parasitic worms5. Pathogen induces a lack of responsiveness to its antigensinfection of the fetus – Ex. CMV, rubellaproduce large quantities of antigen or antigen-antibody complexes and desensitize immune response– Ex. fungal and protozoan infectionsexploit gaps in immune responseB. ANTIGENIC VARIATION - change surface Ag presented to host immune Occurs in the antigens that are recognized by the immune responseMore common in long-lived hostsMore common in infections that have short incubation times and pathogen is transmitted before a secondary response would come to full force.Antigenic variation may occur in a given individual during an infection. Ex - Trypanosoma, Neisseria, Influenza virusAntigenic variation may occur as the pathogen circulates through the community of hostsEx – Poliovirus, Influenza virus3 main mechanisms that produce antigenic variation:1. mutation2. recombination3. gene switching mutation – single base substitutions subtle changes in surface antigens = antigenic drift.Exs. rhinovirus, enterovirus, poliovirus, HIV**Ex. Influenza virus –hemagglutinin and neuraminidase surface proteinsHemagglutininNeuraminidaseentry into cellRNA genome – 8 segmentsSingle base mutations in RNA produce slight changes in H that gradually accumulate year to year = antigenic driftSeasonal flu epidemics2. recombination of genes major changes in surface proteins = antigenic shift.**Ex. influenza A viruses – segments of RNA from human and animal strains recombine (also known as reassortment)Co-infecting a single host target cellHuman strainAnimal strainFrom the animal strainRecombination leads to a sudden and total change in surface protein = antigenic shiftPandemic3. gene switching - most dramatic change in antigenExs. Trypanosoma - 1000 different genes coding for surface glycoprotein - sequence of totally unrelated infections.Neisseria gonorrhoeae – genes coding for pilin and outer membrane proteins.Time IMMUNOSUPPRESSIONInfection of the immune cells blocking of immune cell function.Exs.T cells - HIV, measles virusB cells – EBVMacrophages – HIV, CMV, LeishmaniaUpset coordination of immune regulationpolyclonal activation of T or B cells production of lots of cytokines - upset the balance. Ex – staphylococciinhibit T cell proliferation. Ex - glycoproteins on the surface of the envelope of HIV.inhibit IL-2 productioninduce Tregsinterfere with local immune defenses. a. IgA protease. Ex - Neisseria, Streptococcus pneumoniae, Haemophilus influenzae (remember as Nice STriP of Ham)PERSISTENT INFECTIONS - remain in the host in a persistent state for many years, or even for the life time of the host. 1. infectious form – hepatitis B in blood2. low or partial infectivity – adenovirus in tonsils3. non-infectious form – herpes virus in dorsal root ganglionSignificance of persistence:1. can be reactivated, usually when host is immunocompromised. Ex – herpes viruses2. associated with chronic disease of organs like liver. Ex – hepatitis viruses3. associated with cancer. Exs. – hepatitis, human papilloma virusCONCEPT CHECK 7The virulence of many viruses is attributable, at least in part, to their ability to evade the body’s immune defense systems. Viruses exhibit diverse mechanisms for subverting the immune defenses. Discuss how the human immunodeficiency virus (HIV) evades the host’s specific immune defenses.DISCUSSIONDiscuss the mechanism of antigenic drift in Influenza viruses.Discuss the mechanism of antigenic shift in Influenza A viruses.V. PATHOLOGICAL CONSEQUENCES OF INFECTIONObjectives: Know the various ways that microbes can directly affect the cells/tissues of a hostContrast exotoxins and endotoxinsList the 4 modes of action of exotoxins and be able to discuss examples of eachUnderstand the physiological responses of the host to the presence of endotoxin in the bodyRecognize the physiological responses to LPS as part of a clinical presentation of a diseaseDiscuss, in detail, how microbial infections result in feverCompare and contrast two example lung infections; pneumonia and tuberculosis and the bacteria that cause them.A. PATHOLOGY CAUSED BY THE MICROBEmetabolic shutdown of infected cell – viruseslysis of infected cell – viruses, intracellular bacteria, protozoafusion of infected cells – virusesalter antigens that mark host cells, set them up as targets of body’s own defenses – virusesactivate acute inflammatory response – bacteria toxin production – bacteria2 categories of bacterial toxins – exotoxins (secreted) and endotoxins (cell-wall bound)a.Exotoxins = proteins secreted by Gram positive and Gram negative bacteria (usually extracellular bacteria)are encoded by genes located on plasmids or infecting bacteriophagesare extremely potentExotoxins (see table 17.2) may show one of 4 different modes of action:1. Aid in survival or spread – very common - many examples of enzymatic toxins (-ase)a. Hyaluronidase – hydrolyzes hyaluronic acid present in connective tissueb. Collagenase – disintegrates collagen in connective tissuec. DNase – degrades DNAd. Streptokinase – converts plasminogen plasmin – lysis of fibrin clotse. Lipases – break lipidsf. Coagulase - splits fibrinogen fibrin, creating clots2. Damage or destroy cells – very common - membrane active cytotoxins - lyse RBC (= hemolysins), phagocytes & lymphocytes (= leukocidins)a. enzymes like lecithinase, phospholipaseb. pore-forming molecules 3. Superantigens – toxins that over stimulate cytokine release by T cells.Ex. Staphylococcus aureus TSS strains. Over abundance of IL-2 nausea, vomiting, fever, rash, falling blood pressure, shock.THAPCsecreted by pathogenOther exs. avian influenza in humans, SARS4. Interfere with cell metabolism –very common (diphtheria, cholera, anthrax, etc) - share a common structural arrangement.2 subunit types – A & BA subunit is responsible for toxicityB subunit binds to specific receptors4732020121920Example 1 - DiphtheriaAction of diphtheria toxin – prevents protein synthesis & so cell dies. Enough cells die, organ systems fail cardiovascular collapse.Example 2 - Tetanus Tetanus produces an enzyme called tetanospasmin – can get to the brain by 2 routes:1. toxin blood brain = sudden death2. toxin along nerve trunks peripheral nerves spinal column brain = slower deathAction of tetanospasmin - blocks neurotransmitter release of inhibitory neurons – excitatory transmitter is continuously stimulating rigid, spastic paralysisExample 3 – Cholera - will be discussed in Unit 3 (Gastrointestinal)B. PATHOLOGY CAUSED BY THE IMMUNE RESPONSE TO THE MICROBE1. Pathology resulting from Nonspecific immune defensesa. Physical impairment of function of organ systemEx. S. pneumoniae infection of lungs induces acute inflammation (take good notes here)b. Response to endotoxin = lipopolysaccharide (LPS)not secreted, but released when bacterium dies toxic only in high doses, mg/kg body weightLPS triggers a series of physiological responses (Fig. 17.4) in the body that are due to:1. mast cell degranulation secondary to IgE large amts of C3a & C5a2. clotting of blood (via Hageman factor)3. release of cytokines (esp. TNF, IL1, ?-IFN)Physiological responses to endotoxin are numerous, can be mild to very severe and fatal:1. macrophages release cytokines that stimulate prod. of prostaglandins fever, weakness, aches2. ↓in circulating neutrophils as they aggregate & stick to vessel walls where they release their toxic granules causing damage to endothelial cells. 3. clotting of blood in peripheral vasculature = disseminated intravascular coagulation (DIC) – rare - internal hemorrhaging (meningococcemia, Ebola, Dengue)4. Bradykinin - vasodilation, ↑ vascular permeability5. hypotension (severe drop in blood volume) vascular collapse - called endotoxic shock = septic shock 6. Multiple Organ System Failure (MOSF) a. lungs - acute respiratory distress syndrome (ARDS) b. kidneys - kidney failurec. brain - mental deliriumd. liver - liver failurec. Response to some cytokines = FeverFever is a pathological consequence of cytokine production (IL-1 and TNF)fever = pyrexia -OralNormalFeverWhat part of the brain regulates body temperature? Mechanisms that result in fever1. Stimulating an increase in body temperature – how body “knows” that temperature should be increased – happens at the chemical/cellular levelExogenous signals (signal originating from outside the body)Microbial pyrogens include (best known): Gram negative LPS = endotoxin teichoic acid - GPunits of peptidoglycan - GN and GPTSST1 produced by S. aureus erythrogenic toxin prod by Group A strep (S. pyogenes)others yet unknownEndogenous signals (signals originating from inside the body, produced locally or systemically) = cytokines (TNF, IL-1)DrawingActually raising body temperature – happens at a physiological levelHeat conservation mechanisms:behavioral changespiloerection - traps an air layer, retains body heat rather than letting it escapevasoconstriction - blood is diverted away from body surface where it normally would be cooled to the body’s interior where it is warmed up.Heat generation mechanisms:shivering – rhythmic contraction of muscles generates heatResolution of fever – cooling mechanisms activated so body temperature returns to normal:behavioral changesvasodilation - increases flow of blood to the body surface where it is cooled sweating - evaporation from the surfaceSymptoms that accompany this cytokine production (in addition to fever):back paingeneralized myalgiaarthralgiaanorexiasomnolencechillsWhat are the potential benefits to the host of experiencing fever?2. Pathology resulting from Specific immune defenses = Hypersensitivitiesa. Type I Hypersensitivity – IgE – Anaphylactic Ex. Typical allergic rxnWhat if happens on a large scale? - systemic mast cell degranulation acute fatal anaphylaxis (anaphylactic shock - constriction of smooth muscle, decrease in blood pressure, vascular collapse, pulmonary edema) Ex. worm infections, rupture of tapeworm cysts.b. Type II – IgG – Cytolytic or cytotoxicEx - malaria - complement-mediated lysis of the RBC hemolytic anemiaAlso hepatitis B, yellow feverc. Type III - IgM and IgG- stick to blood vessels or tissues, activating C & neutrophils.Ex. glomerulonephritis - inflammation of nephrons in kidney Ex. systemic lupus erythematosus d. Type IV – Delayed Type Hypersensitivity – mediated by T-cells & macrophages = Cell-mediated immunity = CMI.Ex. measlesEx. Tuberculosis - An ancient disease of humans; chronically-infected macrophages & persistently stimulated THMycobacterium tuberculosis – obligate aerobe, obligate pathogen. Gram positive that stains acid-fast due to mycolic acid. Highly resistant to killing by macrophages.TB is contracted via the respiratory route by inhalation of infectious droplets transmitted by an infected individual – can remain in the air for hours – inhaled directly into lungs by-passing muco-ciliary defenses.Primary Infection – 7 stepsM. tuberculosis are inhaled into middle region of lungsM. tb are engulfed by alveolar macrophages (resident in the lungs), but prevent phagolysosome fusion.Multiply both within macrophages (destroying them) and extracellularly.Lymphocytes and monocytes are attracted. Monocytes differentiate into macrophages that also phagocytize M. tb.Infected macrophages are carried by lymphatics to regional nodes and also to apices of lungs.First few weeks, no effective host defense against infection. Ab play no role in immune defense. M. tb are not opsonized & do not activate classical complement. **2 possible outcomes from primary infection:Control. By 3-8 wks, macs present to and activate TH. TH secrete IL-2 and TNF-? and macs are activated to kill intracellular M. tb. Macs and TH control infection. The macs and T cells and fibroblasts surround infection and a tubercle (= granuloma) forms, becomes fibrotic, encapsulated, scars. M. tb are not all killed, can remain in tubercle for decades, provide continuous boost to CMI.ORClinical disease. CMI does not control infection and progressive primary disease results– children under 5, elderly, advanced AIDS. Bacteria continue to spread in lungs, macrophage secretion of IL-1 and TNF clinical symptoms of fever, weight loss, and profuse night sweats. Lesions fill lungs, interfere with lung function death.Endogenous ReactivationUsually within 2 years of a controlled, primary infection, but can occur anytime after primary infection.M. tb are still alive in tubercles. Control and absence of signs of disease results from precarious balance between presence of M. tb and activity of macrophages and TH.Reactivation of disease results from decline in immune competence.Lesions usually seen first in apex of lungs. Tubercles necrotic caseous coalesce into larger complexes centers liquefy discharge bacteria into bronchial tree resume multiplication and spread.Clinical disease (with symptoms as described above)Mycobacterium tuberculosis has no direct or toxin-mediated means of causing damage; in tuberculosis all pathology is caused by the damage induced by the response of macrophages and T PARE AND CONTRASTProcesses that may result in pathology during viral infections versus processes that may result in pathology during infection by extracellular bacteria. (Ex. think of the two genital pathogens herpes virus versus Neisseria gonorrhoeae)Pneumonia to tuberculosisPrimary progressive tuberculosis with reactivation tuberculosis ................
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