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MicrobialInterferencewith

HostDefensesBIOL533Lecture8MedicalMicrobiologyBIOL5331MicrobialInterferencewith

HOverallStrategiesDefenseagainstcomplementSubversionofphagocytosisSubversionofimmuneresponsesBIOL5332OverallStrategiesDefenseagaiGeneralAspectsPathogenfindsitselfinhostileterritoryHostfightsbackandusually—butnotalways—winsHost’sdefensesareinterrelatedandsoareorganism’scountermeasuresBIOL5333GeneralAspectsPathogenfindsGeneralAspectsGivenorganismsometimeshasnumerousdifferentvirulencefactorsDoesnothavetoharmtissuetobecalledvirulencefactor,althoughmanydoHavetodeterminepreciseroleofeachfactorifalargenumberareinvolvedNotalwayssureinvitrosituationissameasindiseasestateBIOL5334GeneralAspectsGivenorganismDefenseAgainstComplementOverallstrategiesInhibitcomplementactivationMaskactivatingsubstancesCapsuleIgAantibodiesCoveruptargetofcomplementmembraneattackcomplexBIOL5335DefenseAgainstComplementOverDefenseAgainstComplementOverallstrategies,continuedAppropriateinhibitortoactivationtosurfaceInactivatecomplementchemotaxinC5aBIOL5336DefenseAgainstComplementOverPreventComplementActivationMaskingsurfacecomponentsthatactivatebythealternativepathwayCapsulesMureinofS.aureusgoodactivator,butiscoveredbycapsuleCapsulesrichinsialicacidofGroupBstreptococciandstrainsofE.coliBIOL5337PreventComplementActivationMPreventComplementActivationIgAantibodiesMeningococcigetcoatedwithIgAantibodyDoesnotactivatecomplementPreventsotherAbthatcanactivatefromreachingsurfaceofcellBIOL5338PreventComplementActivationIPreventComplementActivationCostofhavingcapsule—antigenicElicitsactivationbyprimarypathwayDefendbetteragainstimmediatedefensesthanlateronesBIOL5339PreventComplementActivationCPreventComplementActivationCoveruptargetofmembraneattackcomplex(outermembrane)Gram—,suchasSalmonellaorE.coli

Smoothstrainswithlong‘0’antigenpolysaccharidechaindonotallowaccessofmacwhileroughstrains(withlittleorno‘0’antigen)doCorrelateswithpathogenicityBIOL53310PreventComplementActivationCSubversionofPhagocytosisOverallstrategiesInhibitionofphagocyterecruitmentMicrobialkillingofphagocytesEscapeofingestionBIOL53311SubversionofPhagocytosisOverSubversionofPhagocytosisOverallstrategies,continuedSurvivalinsidephagocytesEscapeintothecytoplasmInhibitionoflysosomeandphagosomefusionResistancetolysosomalenzymesInhibitionofphagocyteoxidativepathwayAntibodyeffects(hostcounters)BIOL53312SubversionofPhagocytosisOverSubversionofPhagocytosisGeneralaspectsBeinginsidecellisnotnecessarilybadforanorganismPowerfulstrategyistogrowwithinnonphagocyticcellShieldedfromantibodiesanddrugsBIOL53313SubversionofPhagocytosisGeneSubversionofPhagocytosisInhibitionofphagocyterecruitmentDirectinhibitionofneutrophilmotilityandchemotaxisBordetellapertussisproducestoxinsAdenylatecyclasetoxinIncreasecyclicAMPinneutrophilsLeadstoparalysisPertussistoxinImpairsmigrationofmonocytesBIOL53314SubversionofPhagocytosisInhiSubversionofPhagocytosisMicrobialkillingofphagocytesLeukocidins(exotoxins)killneutrophilsandmacrophagesCanworkatdistanceorafteringestionTypicalproducersarehighlyinvasivebacteriaPseudomonas,staphylococci,groupAstreptococci,gasgangreneclostridiaBIOL53315SubversionofPhagocytosisMicrSubversionofPhagocytosisEscapingingestionNakedcapsuleiseffective(pneumococci)OpsonizedbacterianotaseffectiveCounteringopsonizationbycomplementcomponentsorAbAnymechanisminhibitsActivationofcomplementSynthesisoractivityofAbBIOL53316SubversionofPhagocytosisEscaSubversionofPhagocytosisEscapingingestion,continuedCounteringopsonizationwhenantibodiesarepresentStaphylococciandstreptococciMakesurfacecomponent(proteinA)BindstoIgGmoleculesbythewrongend(Fcregion)CannotactasopsoninsbecauseFcregionnotfreetobindtoFcreceptorsonphagocyticcellsNotknownifantiphagocyticdefenseisrelevanttodiseaseprocessBIOL53317SubversionofPhagocytosisEscaSubversionofPhagocytosisSurvivalinsidephagocytesEscapeintocytoplasmRickettsia(RockyMountainSpottedFever)ortrypanosomesofChagas’diseasecrossmembraneofphagosometoentercytoplasmSincelysosomesdonotsecretecontentsintocytoplasm,organismissafeHowtheyentercytoplasmisnotknownforcertainPossesssurface-boundphospholipase,whichmayweakenmembraneBIOL53318SubversionofPhagocytosisSurvSubversionofPhagocytosisSurvivalinsidephagocytes,continuedInhibitionoflysosomeandphagosomefusionExamples—bacteriathatcause:TuberculosisPsittacosisLegionnaire’sdiseaseBIOL53319SubversionofPhagocytosisSurvSubversionofPhagocytosisMechanismoftuberculosisInducedbycomplexglycolipids(sulfatides)—notcertainFacts:InhibitionmustbeduetomodificationofphagosomemembraneMicroorganismmightcontributebycompoundssecretedorpresentonthesurfaceBIOL53320SubversionofPhagocytosisMechSubversionofPhagocytosisSurvivalinsidephagocytes,continuedResistancetolysosomalenzymes—surviveinphagolysosome(pHaslowas4)Leishmania(protozoa)—resistancemaybedueto:ResistantcellsurfacesExcretionofenzymeinhibitorsBIOL53321SubversionofPhagocytosisSurvSubversionofPhagocytosisSurvivalinsidephagocytes,continuedInhibitionofphagocyte’soxidativepathwayBacillusofLegionnaire’sdiseaseInhibitshexose-monophosphateshuntandoxygenconsumptioninneutrophilsReducesrespiratoryburstforkillingmicrobesStaphylococci—producescatalasethatdegradeshydrogenperoxidenecessaryforoxidativekillingBIOL53322SubversionofPhagocytosisSurvSubversionofPhagocytosisSurvivalinsidephagocytes,continuedAntibodyeffects:hostcountersparasiteSometimeshelphostguardagainstmicrobialsurvivalmeasuresAntibodiesdonotprevententryintocells,butinhibitsubsequenteffectsRickettsiacoatedwithantibodycannotpassthroughmembraneintocytoplasmAntibodiesagainstLegionnellapreventinhibitionofphagolysosomalfusionBIOL53323SubversionofPhagocytosisSurvSubversionofImmuneResponseImmunosuppression:generalaspectsHostbecomessusceptibletootherinfectionsandsurvivalprobabilityislessenedBIOL53324SubversionofImmuneResponseISubversionofImmuneResponseAIDS—infectsT4inducer-helperlymphocytesDepletionofcellsleadstocollapseofimmunesystemReductionincirculatinglymphocytesImpaireddelayedhypersensitivityDefectiveresponsesofTcellstoAgReductioninT-cellnumberscytotoxicfortumorcellsandvirusinfectedcellsBIOL53325SubversionofImmuneResponseASubversionofImmuneResponseBcellfunctionisalsoimpairedReducedproductionofspecificIgIncreasedchaoticproductionofnonspecificIgBIOL53326SubversionofImmuneResponseBSubversionofImmuneResponseOtherimmunosuppressiveviruses:MeaslesTuberculosismorecommonafterwidespreadmeaslesoutbreaksInfectedTcellsinvitrodonotdieLosecertainfunctions,includingabilitytomountdelayedhypersensitivityresponseBIOL53327SubversionofImmuneResponseOSubversionofImmuneResponseInfectedBcellsinvitroStopsynthesizingandreleasingIgPrimaryeffectonBcellsNotsecondarytoactionofvirusonTcellsormacrophageBIOL53328SubversionofImmuneResponseISubversionofImmuneResponseOtherimmunosuppressiveviruses:HepatitisBandinfluenzaImpairfunctionoflymphoidcellswithoutcausingmajorstructuraldamageImmunesuppressionasaresultofinhibitionofsynthesisoflymphokinesLeishmanias(protozoa) BIOL53329SubversionofImmuneResponseOSubversionofImmuneResponseLeishmanias(protozoa)—whengrowninmacrophageSuppresssecretionofinterleukin-1ImportantforinitiatingseriesofinflammatoryandimmunologicalreactionsimportantfortheeradicationoftheorganismAlsoexplainsTcellunresponsivenessSuppressescapacityofmacrophagetomakeclassIandclassIIproductsofmajorhistocompatibilitylocus(MHC)Potentialformarkedsuppressionofcell-mediatedimmunityBIOL53330SubversionofImmuneResponseLSubversionofImmuneResponseFinalthoughtsInfectionoflymphocytesisnotimmuno-suppressiveinnatureLargenumberoforganismsinfectlymphoreticulartissues,butdonotcauseglobaldisturbancestohostimmunityBacteriathatcausetyphoidfeverorbrucellosisliveinlymphnodesforlongperiodoftimeDonotinducenoticeableimmunesuppressionBIOL53331SubversionofImmuneResponseFSubversionofImmuneResponseFrequentchangingofantigeniccoats(antigenicvariation)Examplesofbacteria,viruses,andprotozoaTrypanosomes(protozoa)GonococciBorrelia(recurrentfever)InfluenzavirusesBIOL53332SubversionofImmuneResponseFSubversionofImmuneResponseTrypanosomabrucei (causativeagentofsleepingsickness)InfectsbloodofinterstitialfluidsofanimalsandmanExposedtocirculatingAbBIOL53333SubversionofImmuneResponseTSubversionofImmuneResponseTrypanosomabrucei

,continuedCoveredwiththickproteincoat(variablesurfaceglycoprotein)UndergoesantigenicshiftsduringinfectionHaveseveralhundredgenesthatencodedifferentantigens,butexpressonlyoneatatimeBIOL53334SubversionofImmuneResponseTSubversionofImmuneResponseTrypanosomabrucei

,continuedWhenantibodiesagainstonetypearemade:NumberofparasitesinblooddropsSoonreplacedbynewantigenictypeCanbemanysuccessivewavesofantigenicchangesinasinglehostProtectiveimmunitydoesnotfunctionwellBIOL53335SubversionofImmuneResponseTSubversionofImmuneResponseGonococcusanditsadhesinPeriodicchangeinPilin(proteinfimbriae;attachtocells)MajoroutermembraneproteinsBIOL53336SubversionofImmuneResponseGSubversionofImmuneResponseAntigenicvariationamonginfluenzaviruses—majorobstacletoeffectivevaccine(yearafteryear)DefinitionsAntigenicdrift—minorchangesthatoccurevery2to3yearsAntigenicshift—majorchangesthatoccuraboutevery10yearsBIOL53337SubversionofImmuneResponseASubversionofImmuneResponseAntigenicvariation,continuedMechanisminvolvestwoproteinsHemagglutinin-bindstocellreceptorsNeuraminidase-changesreceptorsBIOL53338SubversionofImmuneResponseASubversionofImmuneResponseProteolysisofantibodiesMakeextracellularproteasesthatinactivatesecretoryIgAantibody(majorAbtypeonhumanmucosalsurfaces;subclassesIandII)CleaveonlysubclassIathingeregiontoleavecompletebyinactivepeptidefragmentsExamples:

Gonococci,meningococci,Haemophilusinfluenzae,andsomepathogenicdentalstreptococciBIOL53339SubversionofImmuneResponsePSubversionofImmuneResponseProteolysisofantibodies,continuedSpecificityofIgA1proteasesfromdifferentbacteriaHighlyspecificforsubclassIBiochemicalandgeneticdifferencesthatsuggestpropertyevolvedindependentlyPresenceinfluidsandtissuesActiveformininfectedtissuesandfluidsBIOL53340SubversionofImmuneResponsePSubversionofImmuneResponseProteolysisofantibodies,continuedPossiblerelationshiptopathogenicity;suggested,notprovenNonpathogeicrelativeslacktheseproteasesFabulation(cleavagewithFabfragmentattached)AgunavailableforbindingwithintactantibodymoleculesMayservetoprotectsomeorganismsagainstAbBIOL53341SubversionofImmuneResponsePSubversionofImmuneResponseOtherviralsurvivalstrategies: generalaspectsChronicinfection—evadehostdefenseslongerBIOL53342SubversionofImmuneResponseOSubversionofImmuneResponseHerpesinfectionDonotusuallyenterextracellularfluid,butpassamongcellsthroughcytoplasmicbridgesCanalsobelatent(residewithinnervecellsbutdonotmultiply)Inthesecircumstances,notaffectbyantibodies,cell-mediatedimmunity,orinterferonSurviveforlongperiodsoftime,thenlaterreactivate(perhapswhendefensesarelower)BIOL53343SubversionofImmuneResponseHLecture8Questions?Comments?Assignments...BIOL53344Lecture8Questions?BIOL53344MicrobialInterferencewith

HostDefensesBIOL533Lecture8MedicalMicrobiologyBIOL53345MicrobialInterferencewith

HOverallStrategiesDefenseagainstcomplementSubversionofphagocytosisSubversionofimmuneresponsesBIOL53346OverallStrategiesDefenseagaiGeneralAspectsPathogenfindsitselfinhostileterritoryHostfightsbackandusually—butnotalways—winsHost’sdefensesareinterrelatedandsoareorganism’scountermeasuresBIOL53347GeneralAspectsPathogenfindsGeneralAspectsGivenorganismsometimeshasnumerousdifferentvirulencefactorsDoesnothavetoharmtissuetobecalledvirulencefactor,althoughmanydoHavetodeterminepreciseroleofeachfactorifalargenumberareinvolvedNotalwayssureinvitrosituationissameasindiseasestateBIOL53348GeneralAspectsGivenorganismDefenseAgainstComplementOverallstrategiesInhibitcomplementactivationMaskactivatingsubstancesCapsuleIgAantibodiesCoveruptargetofcomplementmembraneattackcomplexBIOL53349DefenseAgainstComplementOverDefenseAgainstComplementOverallstrategies,continuedAppropriateinhibitortoactivationtosurfaceInactivatecomplementchemotaxinC5aBIOL53350DefenseAgainstComplementOverPreventComplementActivationMaskingsurfacecomponentsthatactivatebythealternativepathwayCapsulesMureinofS.aureusgoodactivator,butiscoveredbycapsuleCapsulesrichinsialicacidofGroupBstreptococciandstrainsofE.coliBIOL53351PreventComplementActivationMPreventComplementActivationIgAantibodiesMeningococcigetcoatedwithIgAantibodyDoesnotactivatecomplementPreventsotherAbthatcanactivatefromreachingsurfaceofcellBIOL53352PreventComplementActivationIPreventComplementActivationCostofhavingcapsule—antigenicElicitsactivationbyprimarypathwayDefendbetteragainstimmediatedefensesthanlateronesBIOL53353PreventComplementActivationCPreventComplementActivationCoveruptargetofmembraneattackcomplex(outermembrane)Gram—,suchasSalmonellaorE.coli

Smoothstrainswithlong‘0’antigenpolysaccharidechaindonotallowaccessofmacwhileroughstrains(withlittleorno‘0’antigen)doCorrelateswithpathogenicityBIOL53354PreventComplementActivationCSubversionofPhagocytosisOverallstrategiesInhibitionofphagocyterecruitmentMicrobialkillingofphagocytesEscapeofingestionBIOL53355SubversionofPhagocytosisOverSubversionofPhagocytosisOverallstrategies,continuedSurvivalinsidephagocytesEscapeintothecytoplasmInhibitionoflysosomeandphagosomefusionResistancetolysosomalenzymesInhibitionofphagocyteoxidativepathwayAntibodyeffects(hostcounters)BIOL53356SubversionofPhagocytosisOverSubversionofPhagocytosisGeneralaspectsBeinginsidecellisnotnecessarilybadforanorganismPowerfulstrategyistogrowwithinnonphagocyticcellShieldedfromantibodiesanddrugsBIOL53357SubversionofPhagocytosisGeneSubversionofPhagocytosisInhibitionofphagocyterecruitmentDirectinhibitionofneutrophilmotilityandchemotaxisBordetellapertussisproducestoxinsAdenylatecyclasetoxinIncreasecyclicAMPinneutrophilsLeadstoparalysisPertussistoxinImpairsmigrationofmonocytesBIOL53358SubversionofPhagocytosisInhiSubversionofPhagocytosisMicrobialkillingofphagocytesLeukocidins(exotoxins)killneutrophilsandmacrophagesCanworkatdistanceorafteringestionTypicalproducersarehighlyinvasivebacteriaPseudomonas,staphylococci,groupAstreptococci,gasgangreneclostridiaBIOL53359SubversionofPhagocytosisMicrSubversionofPhagocytosisEscapingingestionNakedcapsuleiseffective(pneumococci)OpsonizedbacterianotaseffectiveCounteringopsonizationbycomplementcomponentsorAbAnymechanisminhibitsActivationofcomplementSynthesisoractivityofAbBIOL53360SubversionofPhagocytosisEscaSubversionofPhagocytosisEscapingingestion,continuedCounteringopsonizationwhenantibodiesarepresentStaphylococciandstreptococciMakesurfacecomponent(proteinA)BindstoIgGmoleculesbythewrongend(Fcregion)CannotactasopsoninsbecauseFcregionnotfreetobindtoFcreceptorsonphagocyticcellsNotknownifantiphagocyticdefenseisrelevanttodiseaseprocessBIOL53361SubversionofPhagocytosisEscaSubversionofPhagocytosisSurvivalinsidephagocytesEscapeintocytoplasmRickettsia(RockyMountainSpottedFever)ortrypanosomesofChagas’diseasecrossmembraneofphagosometoentercytoplasmSincelysosomesdonotsecretecontentsintocytoplasm,organismissafeHowtheyentercytoplasmisnotknownforcertainPossesssurface-boundphospholipase,whichmayweakenmembraneBIOL53362SubversionofPhagocytosisSurvSubversionofPhagocytosisSurvivalinsidephagocytes,continuedInhibitionoflysosomeandphagosomefusionExamples—bacteriathatcause:TuberculosisPsittacosisLegionnaire’sdiseaseBIOL53363SubversionofPhagocytosisSurvSubversionofPhagocytosisMechanismoftuberculosisInducedbycomplexglycolipids(sulfatides)—notcertainFacts:InhibitionmustbeduetomodificationofphagosomemembraneMicroorganismmightcontributebycompoundssecretedorpresentonthesurfaceBIOL53364SubversionofPhagocytosisMechSubversionofPhagocytosisSurvivalinsidephagocytes,continuedResistancetolysosomalenzymes—surviveinphagolysosome(pHaslowas4)Leishmania(protozoa)—resistancemaybedueto:ResistantcellsurfacesExcretionofenzymeinhibitorsBIOL53365SubversionofPhagocytosisSurvSubversionofPhagocytosisSurvivalinsidephagocytes,continuedInhibitionofphagocyte’soxidativepathwayBacillusofLegionnaire’sdiseaseInhibitshexose-monophosphateshuntandoxygenconsumptioninneutrophilsReducesrespiratoryburstforkillingmicrobesStaphylococci—producescatalasethatdegradeshydrogenperoxidenecessaryforoxidativekillingBIOL53366SubversionofPhagocytosisSurvSubversionofPhagocytosisSurvivalinsidephagocytes,continuedAntibodyeffects:hostcountersparasiteSometimeshelphostguardagainstmicrobialsurvivalmeasuresAntibodiesdonotprevententryintocells,butinhibitsubsequenteffectsRickettsiacoatedwithantibodycannotpassthroughmembraneintocytoplasmAntibodiesagainstLegionnellapreventinhibitionofphagolysosomalfusionBIOL53367SubversionofPhagocytosisSurvSubversionofImmuneResponseImmunosuppression:generalaspectsHostbecomessusceptibletootherinfectionsandsurvivalprobabilityislessenedBIOL53368SubversionofImmuneResponseISubversionofImmuneResponseAIDS—infectsT4inducer-helperlymphocytesDepletionofcellsleadstocollapseofimmunesystemReductionincirculatinglymphocytesImpaireddelayedhypersensitivityDefectiveresponsesofTcellstoAgReductioninT-cellnumberscytotoxicfortumorcellsandvirusinfectedcellsBIOL53369SubversionofImmuneResponseASubversionofImmuneResponseBcellfunctionisalsoimpairedReducedproductionofspecificIgIncreasedchaoticproductionofnonspecificIgBIOL53370SubversionofImmuneResponseBSubversionofImmuneResponseOtherimmunosuppressiveviruses:MeaslesTuberculosismorecommonafterwidespreadmeaslesoutbreaksInfectedTcellsinvitrodonotdieLosecertainfunctions,includingabilitytomountdelayedhypersensitivityresponseBIOL53371SubversionofImmuneResponseOSubversionofImmuneResponseInfectedBcellsinvitroStopsynthesizingandreleasingIgPrimaryeffectonBcellsNotsecondarytoactionofvirusonTcellsormacrophageBIOL53372SubversionofImmuneResponseISubversionofImmuneResponseOtherimmunosuppressiveviruses:HepatitisBandinfluenzaImpairfunctionoflymphoidcellswithoutcausingmajorstructuraldamageImmunesuppressionasaresultofinhibitionofsynthesisoflymphokinesLeishmanias(protozoa) BIOL53373SubversionofImmuneResponseOSubversionofImmuneResponseLeishmanias(protozoa)—whengrowninmacrophageSuppresssecretionofinterleukin-1ImportantforinitiatingseriesofinflammatoryandimmunologicalreactionsimportantfortheeradicationoftheorganismAlsoexplainsTcellunresponsivenessSuppressescapacityofmacrophagetomakeclassIandclassIIproductsofmajorhistocompatibilitylocus(MHC)Potentialformarkedsuppressionofcell-mediatedimmunityBIOL53374SubversionofImmuneResponseLSubversionofImmuneResponseFinalthoughtsInfectionoflymphocytesisnotimmuno-suppressiveinnatureLargenumberoforganismsinfectlymphoreticulartissues,butdonotcauseglobaldisturbancestohostimmunityBacteriathatcausetyphoidfeverorbrucellosisliveinlymphnodesforlongperiodoftimeDonotinducenoticeableimmunesuppressionBIOL53375SubversionofImmuneResponseFSubversionofImmuneResponseFrequentchangingofantigeniccoats(antigenicvariation)Examplesofbacteria,viruses,andprotozoaTrypanosomes(protozoa)GonococciBorrelia(recurrentfever)InfluenzavirusesBIOL53376SubversionofImmuneResponseFSubversionofImmuneResponseTrypanosomabrucei (causativeagentofsleepingsickness)InfectsbloodofinterstitialfluidsofanimalsandmanExposedtocirculatingAbBIOL53377SubversionofImmuneResponseTSubversionofImmuneResponseTrypanosomabrucei

,continuedCoveredwiththickproteincoat(variablesurfaceglycoprotein)UndergoesantigenicshiftsduringinfectionHaveseveralhundredgenesthatencodedifferentantigens,butexpressonlyoneatatimeBIOL53378SubversionofImmuneResponseTSubversionofImmuneResponseTrypanosomabrucei

,continuedWhenantibodiesagainstonetypearemade:NumberofparasitesinblooddropsSoonreplacedbynewantigenictypeCanbemanysuccessivewavesofantigenicchangesinasinglehostProtectiveimmunitydoesnotfunctionwellBIOL53379SubversionofImmuneResponseTSubversionofImmune

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