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INFECTIONS VIVASGeneral Principals2009-2What are the normal barriers to infection by ingested pathogens in the gastrointestinal tract?Acid gastric secretionsViscous mucosal layerLytic pancreatic enzymesDefensins (mucosal antimicrobial peptides)Bile detergentsSecreted IgA antibodiesCompetition for nutrients with commensal bacteriaClearance by defaecationThese barriers are lost with loss of gastric acidity, disruption of normal flora (antibiotics), loss of pancreatic function, diminished bowel motility.Describe the barriers to infection that exist within the respiratory tractMucociliary blanket within upper airways for trapping large microbesCoughing (clears microbes from trachea)Ciliary action within trachea and large airways (moves them up to be swallowed)Alveolar macrophages or neutrophils attack and destroy microbesSecreted IgADefensinsWhat processes can disrupt the normal protective mucociliary action?Smoking, cystic fibrosis (viscous secretions), aspiration of stomach contents, trauma of intubation, viral infection, bacterial infection.Additional:Skin defencesKeratinised outer layerFatty AcidsLow pHCan be breached directly, or by damage (e.g. burns, trauma, IV lines)Urogenital tract defensesFrequent bladder flushingCatabolism of glycogen by normal lactobacilli (in vagina) – lowers pH reducing fungal growthBarriers lost with atonia, flow obstruction, reflux, antibiotics kill lactobacilli (-> candidal infection)Viral Infections2011-1, 2007-1Describe the pathogenesis of measles Paramyxovirus (single stranded RNA) Respiratory droplet spread Multiplies in upper respiratory tract epithelial cells Spreads to lymphoid tissue where it replicates in mononuclear cellsHaematogenous spreadPreventable by vaccination as only single strainEpidemics amongst un-vaccinated individuals What type of immune responses occur in measles?T cell mediated immunity controls infection and causes rash (hypersensitivity to infected cutaneous cells)Antibody mediated protects against re-infectionEpidemics in unvaccinated hostsDescribe some of the systemic features of measles virus infectionRash–blotchy, red/brown. Skin hypersensitivity reaction Oral mucosal ulceration – Koplik’s spots (pathomonic)CroupInterstitial pneumoniaConjunctivitis and Keratitis, with scarring and visual lossEncephalitis; - plus SSPE, measles inclusion-body encephalitisDiarrhoea with protein losing enteropathyImmunosuppressionSecondary bacterial infectionWhat are the cell-surface receptors for the measles virus 2007-1CD 46 (complement regulatory protein): inactivates C3 convertases; present on all nucleated cells; binds viral haemagglutinin proteinSLAM (Signalling Lymphocytic Activation Molecule): involved in T cell activation; only present on cells of the immune system; binds viral haemagglutinin protein2007-1Please give some examples of clinical Herpes Simplex Infection?Cold sores and Gingivostomatitis (HSV-1)Genital herpes (HSV-2)Keratitis (epithelial & stromal) – HSV-1 major infectious cause of corneal blindnessEncephalitis - HSV-1 major cause of fatal encephalitis in USDisseminated visceral herpes (esp in compromised cellular immunity e.g. HIV) - esophagitis, bronchopneumonia, hepatitis, Kaposi varicelliform eruption, eczema herpeticum)After primary herpes simplex infection, how does reactivation occur?Viral nucleocapsids travel from the skin/ oropharynx/genitalia to the nucleus in the sensory neuron.During latent period, only viral mRNA is produced, no viral proteins are made to escape immune recognitionReactivation from latency occurs by avoiding immune recognition, inhibiting the MHC class I recognition pathway, and elude humoral immune defences by producing receptors for the Fc domain of immunoglobulin and inhibitors of complementAntidromically along sensory nerve2006-1, 2005-2Describe the illness caused by acute varicella infectionTransmitted in epidemic fashion by aerosols -> respiratory infection -> haemtogenous spreadRash occurs 2 weeks after exposureRash begins centrally and spread centrifugally in wavesInitially macular with rapid progression to a vesicle “like a dewdrop on a rose petal”After a few days the vesicle ruptures and crusts – most heal with no scarring unless bacterial superinfection (disruption of the basal epidermal layer)Involves skin, mucous membranes and neuronesMilder illness in children vs adults and the immunocompromisedWhat are the complications of acute vaicella infectionSecondary bacterial skin infectionEncephalitis/cerebellitisInterstitial pneumonitisTransverse myelitisNecrotising visceral lesions (esp. in the immunosuppressed)Describe the relationship between varicella infection and subsequent zoster eruptionVZV evades immune defences and infects neurons in and round the dorsal root gngliaAble to remain latent for yearsUsually a single episode of recurrence in the form of zosterReactivation often in the elderly or otherwise immuno-compromisedInfection of sensory nerve to keratinocytes (dermatomal vesicular eruptions)Often very painful due to radiculoneuritis, especially if trigeminalIf the geniculate nucleus is involved may cause facial paralysis (Ramsay Hunt Syndrome)Additional:Cytomegalovirus (CMV)Causes marked cellular enlargementInfections are usually asymptomatic, but can manifest as a mononucleosis-like syndrome (e.g. fever, lymphocytosis, lymphadenopathy, hepatosplenomegaly)Infects dendritic cells, and can be latent in leukocytesIn the immunocompromised can cause colitis, pneumonitis, hepatitis, chorioretinitis, meningoencephalitisMost common opportunistic viral pathogen in AIDSIn 5% of congenitally infected infants and cause cytomegalic inclusion disease (CID) similar to erythroblastosis fetalis (IUGR, haemolytic anaemia, jaundice, encephalitis)Epstein-Barr VirusCauses infectious mononucleosisBy saliva, blood or venerealInfects B cells – most latently, by some lytic and release more vironsCD8+ T cells (CTLs) kill infected B cells – the prolifereaion of these T cells -> lymphadeopthy and splenomegalyOther symptoms: fever, fatigue, sore throat, lymphocytosis, hepatitis and rashRoll in B cell lymphoma and Burkitt lymphomaBacterial Infections2009-2What are streptococci?Gram-positive cocci growing in pairs or chains.Facultative or obligate anaerobes.Cause variety of suppurative infections and immunologically mediated post-streptococcal syndromesName some of the different types of streptococci and give examples of diseases they causeAlpha haemolyticS. pneumonia: pneumonia, meningitisS viridans: endocarditisβ HaemolyticGroup A.?(Pyogenes)pharyngitis,?scarlet fever,?erysipelas, impetigoRheumatic fever,?Toxic Shock Syndrome,?GlomerulonephritisGroup B.? (Agalactiae)neonatal sepsis and meningitis,?chorioamnionitisStrept. mutans: dental cariesWhat factors in streptococci contribute to their virulence?Capsules: pyogenes, pneumoniaeM Protein: prevents phagocytosis?Complement C5a peptidasePneumolysin: lyses target cells (S pneumoniae) activates complementPyrogenic exotoxin- rash and feverHigh MW glucans: ?plaque formation,?aggregation of plateletsSucrose => lactic acid (S. mutans, plaque and tooth decay)2009-1What are the two clinically significant NeisseriaN. meningitidisN. gonorrhoeaeDescribe the pathogenesis of a N. meningitidis infectionRespiratory spreadCommon coloniser of the oropharynx (10% of the population at any one time)Colonisation lasts for monthsImmune response leads to protection against that strainInvasive disease crosses respiratory epithelium to enter bloodCapsule of Neisseria reduces opsonisation & protects against destruction by complement proteins Outbreaks in young people living in crowded quarters who encounter new strainsWhat are the microbiological features of NeisseriaAerobicGram –ve diplococciCoffee bean shapedRequire chocolate blood agar13 serotypes of N. meningitides2011-1, 2005-1What is secondary tuberculosis?Pattern of disease that arises in a previously sensitised hostHow may infection occur in secondary tuberculosis?May follow shortly after primary infection, but more commonly years laterReactivation of latent organisms – typically in areas of low disease prevalenceReinfection - typical in regions of high prevalenceDescribe the pathological features in the lung of secondary infection with TBLocale - apical UL in secondaryArea of inflammation / granuloma / multinucleate giant cellsCentral caseous necrosisCavitationHealing with fibrosis and calcificationComplications include: tissue destruction, erosion of blood vessels, miliary spread, pleural effusion, empyema, fibrous pleuritis2008-2, 2003-2Describe the pathogenesis of TB in a previously unexposed immunocompetent personInfection by M. tuberculosis airborne, usually person to person airborne droplet spreadM. tuberculosis enters alveolar macrophages and replicates by blocking phagosome/lysosome fusion leading to bacteraemia (person generally (95%) asymptomatic or mild flu like illness)Immunity through T cell mediated delayed type hypersensitivity reaction that also causes hypersensitivity and tissue destruction - in particular granuloma formation and caseationAbout 3 weeks later T cell activation via MHC antigens on macrophages and IL-2 leading to macrophage becoming bactericidal (thru IFN-γ)This macrophage response also causes tuberculin positivity and formation of granuloma and caseation by recruiting monocytes (“epithelioid histiocytes”)Granulomas formed usually at the lower part of upper lobe or upper part of lower lobe and the parenchymal lesion and draining lymph node is termed the Ghon complexEventual control leaves behind a tiny fibrocalcifc nodule where viable organisms may remain dormant for decades5% of primary infections are symptomatic with lobar consolidation, hilar adenopathy and pleural effusionsRarely haematogenous spread leads to TB meningitis and military TBRe- exposure or reactivation causes heightened immune reaction as well as tissue destruction2011-2, 2008-1What type of organisms are the Clostridia?Gram +ve anaerobic spore-forming bacilliName the organisms and the diseases they cause in humans?Tetanus (lockjaw) – Clostridium tetaniBotulism (paralytic food poisoning) – Clostridium botulinumGas gangrene, necrotizing cellulitis – Clostridium perfringens, C. septicumPseudomembranous colitis – Clostridium difficileHow does botulism toxin cause disease? 2011-2Normally ingestedIn the cytoplasm, the “A” fragment cleaves the protein “synactobrevin”Synactobrevin is needed for fusion of neurotransmitter vesiclesResults in flaccid paralysisWhat is the pathogenesis of gas gangrene (C. perfringens, C. septicum)? 2008-1Release enzymes – hyaluronidase; collagenaseVirulence factors – 14 toxins, multiple actionsα-toxin most importantPhospholipase C: degrades membranes; muscle; RBCRelease phospholipid derivatives: ITP; prostaglandinsThese cause derangement in cell metabolism and cell deathMarked oedema, enzymatic necrosis, fermentation gas bubbles, haemolysis and thrombosisAdditional: C. tetani produces a neurotoxin that blocks the release of GABA (inhibitory) leading to the convulsive contraction of muscleFungal Infections2008-2What is the clinical spectrum of candida infection?Benign commensalSuperficial mucosal infection: mouth, vagina, oesophagusSuperficial cutaneous? infection: intertrigo, nappy rash, balanitis, folliculitis, paronychia, onychomycosisChronic mucocutaneous (T-cell defects, endocrinopathy)Invasive (disseminated): myocardial/ abscess/endocarditis, cerebral abscess/meningitis, renal/hepatic abscess, endophthalmitis, pneumoniaWhat mechanisms enable candida to cause disease?Phenotypic switching to adapt rapidly to changes in host environmentAdhesion to host cells -? imp. determ. of virulence –via adhesins (several types)Production of enzymes (aspartyl proteases and catalases) degrade extracellular matrix proteins and may aid intracellular survival secretion of adenosine – blocks neutrophil degranulationParasitic Infections2008-2, 2003-2What micro-organisms cause malaria?Parasitic protozoa: Plasmodium falciparum, vivax, ovale, malarieTransmitted by the female Anopheles genus mosquito How does Plasmodium falciparum infection differ from other forms of malaria?All do: sporozoite→liver→merozoites formed → release & bind to RBC→ Hb hydrolysed → trophozoite→ schizont?→ merozoite/gametocyteP. falciparum: infects RBCs of any age, causing clumping/rosetting so ischemia, high cytokine production, high level parasitemia, severe anemia, HSM, splenic rupture, cerebral symptoms, renal failure, pulmonary oedema, DIC, deathOthers: infect only new or old RBCs, P vivax & ovale form latent hynpnozoites (relapses), low parasitemia, mild anemia, rarely splenic rupture, nephrotic syndromeWhat factors can make people less susceptible to malaria?Inherited alterations in RBCs: HbS trait, HbCAbsence of Duffy group Ag prevents P. vivax binding to erythrocytesRepeated exposure stimulates immune response: Ab and T lymphocytes (P falc avoids this) ................
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