英文版-Indiana-University-Purdue-University-Fort-Wayne微生物学授课讲义-lecture-06课件

PhagocytosisandtheInteractions

ofVariousPhagocytesBIOL533Lecture6MedicalMicrobiologyBIOL5331PhagocytosisandtheInteractiLeukocyteChemotaxinsTypesofchemotaxinsC5aattractsneutrophilsandmonocytesMadebybacteriaPeptideclippedoffN-terminus(beginningwithN-formylmethionine)duringpeptidematurationafterproteinsynthesisMadebybacteriaandnucleatedbloodcellsLeucotrienes—lipidproductsofcellmembranemetabolismBIOL5332LeukocyteChemotaxinsTypesofLeukocyteChemotaxinsFunctionofchemotaxinsEnhanceanddirectmotilityofphagocyticcellsToalimitedextent,oxidativemetabolismofphagocyticcellsBIOL5333LeukocyteChemotaxinsFunctionOpsonizationandOpsoninsGeneralaspectsSubstancesthatenhanceabilityofphagocytestoingestmicrobesDefendagainstpresenceofcapsulesandothermicrobialmechanismsthatinterferewithphagocytosisBIOL5334OpsonizationandOpsoninsGenerOpsonizationandOpsoninsTypesofopsoninsAntibodiesC3bcomponentofcomplementBindscovalentlytobacterialsurfaceandisrecognizedbyreceptorsonneutrophils,monocytes,andmacrophageBacteriabecomeboundtosurfaceofphagocytefacilitatingtheiruptakeBIOL5335OpsonizationandOpsoninsTypesOpsonizationandOpsoninsTypesofopsonins,continuedMechanismWhitebloodcellreceptorsforC3bAtleast3—CR1,CR2,CR3(complementreceptor)ChildrendeficientinCR3veryvulnerabletobacterialinfectionsBIOL5336OpsonizationandOpsoninsTypesPhagocytes—TypesofCellsNeutrophils—celloriginActivelymotilecellsproducedinbonemarrowDifferentiatefromstemcellsoveraboutatwo-weekperiodProductionofgranulesduringthistimeAzurophilProducespecificgranuleslaterBIOL5337Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsNeutrophils—cellorigin,continuedUponmaturation(innumbersof1010perday),theymoveintoperipheralbloodandcirculateforabout6.5hoursNextmoveintocapillarybedandmarginateBIOL5338Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsNeutrophils—cellorigin,continuedMarginationcausedbystickinessduetointerleukin-1Summonedbychemotaxis,theymovethroughendothelialcelljunctions(diapdesis)intoextravasculartissuespacesBIOL5339Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsNeutrophilsaremostactiveingutGuthasenormousmicrobialpopulationlyingjustonecelllayerawayfromaseptictissueFloragenerateslargeamountsofchemotaxinsthatrecruitmostofbody’savailableleukocytesBIOL53310Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsAsaresult,submucosaofgutisinaconstantstateofinflammationKeepmicrobialfloradownSynthesisofneutrophilsinhibitedbychemicalsorradiationInfectionsingutregionBIOL53311Phagocytes—TypesofCellsAsaPhagocytes—TypesofCellsMonocytesandmacrophageComparedtoneutrophilsArriveatdamagedtissuelaterininfectionDaysafterneutrophilshavebeenactiveinfightingintrudersEventuallysettleintissuesandbecomeresidentmacrophageBIOL53312Phagocytes—TypesofCellsMonocPhagocytes—TypesofCellsMonocytesandmacrophageShareprogenitorcelltype,butkineticsofmaturation&appearanceareverydifferentMonocytescontinuecelldifferentiationafterleavingbonemarrowMonocytesandmacrophageinvolvedinbothconstititiveandinduciblemechanismsInteractwithTcellsandplayimportantroleincell-mediatedimmunityBIOL53313Phagocytes—TypesofCellsMonocPhagocytes—TypesofCellsTissue(resident)macrophageExistthroughoutbodyDifferentnamesandfunctionsindifferenttissuesKupffercells—liverAlveolarmacrophage—lungsOsteoclasts—boneMicroglia—brainBIOL53314Phagocytes—TypesofCellsTissuPhagocytes—TypesofCellsMonocyteandmacrophagefunctionsPhagocytizeinvadingmicrobesContributegreatlytoinflammatoryresponseReleasesIL-1—enhancesstickingofneutrophiltocapillaryendotheliaTNF—activatesnewlyarrivedneutrophilsBIOL53315Phagocytes—TypesofCellsMonocMechanismofPhagocyteKillingNeutrophilsGeneralstepsAttachtomicrobesIngestmicrobesKillmicrobesGranules—consideredasenlargedlysosomescontaininghydrolyticenzymesBIOL53316MechanismofPhagocyteKillingMechanismofPhagocyteKillingNeutrophilgranuletypesAzurophil(primarygranule)ContainsLysozymeElastaseAchymotryptic-likeproteaseMyeloperoxidaseSeveralantibacterialcationicproteinsBIOL53317MechanismofPhagocyteKillingMechanismofPhagocyteKillingNeutrophilgranuletypesSpecific(secondarygranule)ContainsCytochromeLysozymeLactoferin(iron-bindingprotein)VitaminB12bindingproteinCollagenaseBIOL53318MechanismofPhagocyteKillingMechanismofPhagocyteKillingTheneutrophilmembraneContainsreceptorsforchemotaxinandopsoninsAfterbindingchemotaxins,receptorsareinternalizedandreplacedwithnewonesBIOL53319MechanismofPhagocyteKillingMechanismofPhagocyteKillingEffectivenessofchemotaxis:veryeffectiveNeutrophilsareverymotileMovebyrearrangingcytoplasmicmicrofilamentsandmicrotubulesActinandmyosininmicrofilamentsareaffectedbyproteingelsolinPortionsthatfaceupstreaminchemotacticgradientformstructurecalledlamellipodiumCytoplasmisdenselypackedwithmicrofilamentsPortionsfacedownstreamformknob-likeuropodBIOL53320MechanismofPhagocyteKillingMechanismofPhagocyteKillingProcessofphagocytosisGeneralaspectsDiffersfrompinocytosisinthatparticles,notliquids,takenupBIOL53321MechanismofPhagocyteKillingMechanismofPhagocyteKillingProcessofphagocytosis,continuedReceptorsonphagocytesurfaceprogressivelyattachtoligandsonbacterialsurfaceStimulatesmechanismsofkillingOxidativemetabolismleadingtoproductionofhydrogenperoxideandcompoundslethaltomicrobes(oxygen-dependentkilling)Dischargeoftoxiccompoundsfromgranulesintophagosome(oxygen-independentkilling)BIOL53322MechanismofPhagocyteKillingMechanismofPhagocyteKillingProcessofphagocytosis,continuedFormphagosome—pouch-likestructurethatinvaginates,displacingthenucleusandgranulestowarduropodFormphagolysosome—membraneofgranulesandphagosomefuse,releasingtoxicsubstancesFormsseparatepinched-offorganelleBacteriacoatedwithantibacterialproteinsBIOL53323MechanismofPhagocyteKillingOxygen-DependentKillingFusionofspecificgranuleswithphagosomemembrane(derivedfromplasmamembrane)bringstogether:NADPHoxidase(oxidizesNADPH;foundinneutrophilplasmamembrane)Uniquecytb(granulemembrane)AquinoneBIOL53324Oxygen-DependentKillingFusionOxygen-DependentKillingReactionO2O2— (reducesoxygentosuperoxideradical)2O2—

+H2OH2O2

+O2 (superoxidedismutase)BIOL53325Oxygen-DependentKillingReactiOxygen-DependentKillingPatientslackingcytochromecomponentsChildrenhavingchronicgranulomatousdisease(CGD)FailuretosynthesizesuperoxideradicalandthereforehydrogenperoxideDuetodecreasedamountofcytochromebGeneforlargersubunitismissing(90K,20K)BIOL53326Oxygen-DependentKillingPatienOxygen-DependentKillingChildrenhavingchronicCGD,cont’d.Neutrophilscanphagocytizenormally,butdonotefficientlyoxidizeNADPHandkillviaoxidativepathwayUsuallydon’tsurviveintoadulthoodBIOL53327Oxygen-DependentKillingChildrOxygen-DependentKillingHowdoesoxidativeprocesskill?InteractionwithmyeloperoxidasesuppliedbyfusionwithazurophilCombineschlorideionsandhydrogenperoxidetoformhypochlorousions(analogoustobleach)Bacterialackingcatalaseproducehydrogenperoxide(pneumococci);basicallycommitsuicidePneumococciarenotdangeroustoCGDpatientsBIOL53328Oxygen-DependentKillingHowdoOxygen-IndependentKillingProcessTriggeredbybindingopsonizedbacteriatotheplasmamembraneofneutrophilsSpecificgranulesfusefirstDeliverseveralbacteriodicalproteins,includinglysozymeandlactoferinBIOL53329Oxygen-IndependentKillingProcOxygen-IndependentKillingAzurophilgranulesdischargeantimicrobialcationicproteinsSomeareamphipathicandresembleothercationicsurfaceproteinssuchaspolymyxinBBIOL53330Oxygen-IndependentKillingAzurOxygen-IndependentKillingAzurophilgranules,continuedDisruptoutermembraneofGram—andkillbycausingleakageofvitalcomponentsEachoftheproteinshasuniqueantimicrobialspectrum,buttendtoaffectGram—morethanGram+

ProteinsmayaccountforsurvivalofsomeCGDchildrenBIOL53331Oxygen-IndependentKillingAzurOxygen-IndependentKillingEfficiencyBacterialkillingunderhighlyanaerobicconditionsofdeepabscessesPatientslackinggenesCodingforcationicproteinsNonefound,maybelethalBIOL53332Oxygen-IndependentKillingEffiOxygen-IndependentKillingChediak-Higashisyndrome (geneticdisease)PrematurefusionofneutrophilgranuleswhilecellsinbonemarrowWhenmaturecellsphagocytize,granulesarealreadyspent,substantiallyreducingkillingpowerBIOL53333Oxygen-IndependentKillingChedComparisonofBacterialSensitivityGram—rodsingutkilledbyoxygen-independentGram+bacteriaonskinandupperrespiratoryepitheliaareresistanttooxygen-independentandkilledbyoxygen-dependentBIOL53334ComparisonofBacterialSensitMechanismofPhagocyteKillingEosinophilsMuchlikeneutrophils,butindicativeofparasiticinfectionBIOL53335MechanismofPhagocyteKillingKillingbyMonocytesandMacrophageGeneralaspectsTendtotakecareofwhatisleftafterbattlewithneutrophilsMechanismsofchemotaxis,phagocytosis,andkillingresemblemechanismsofneutrophilsNotstudiedinsamedetailBIOL53336KillingbyMonocytesandMacroKillingbyMonocytesandMacrophageDifferencesContinuetodifferentiateafterleavingbonemarrowandareactivatedCalled“angrymacrophage”PhagocytizemorevigorouslyTakeupmoreoxygenSecretelargequantityofhydrolyticenzymesIngeneral,betterpreparedtokillBIOL53337KillingbyMonocytesandMacroKillingbyMonocytesandMacrophageActivatedbyElicitedbysubstancesmadeinresponsetopresenceofbacteria(C3b)orviruses(interferon)EndotoxinofGram—Tetrapeptidederivedfromimmunoglobulins(tuftsin)BIOL53338KillingbyMonocytesandMacroKillingbyMonocytesandMacrophageMicrobial(bacterial,fungi,protozoa)growthwithinSomecangrowuntilactivated,thenkilledParticipationinimmuneresponseHelpridbodyofnotonlymicrobialinvaders,butalsotumorandforeigncellsBIOL53339KillingbyMonocytesandMacroKillingbyMonocytesandMacrophageImmuneresponseprocessStimulatedevelopmentofTlymphocytesRespondtosignalsfromotherlymphocytesthatstimulatedifferentiationandactivationofmacrophageBIOL53340KillingbyMonocytesandMacroPhagocytoticKillingMacrophages/neutrophils/mastcellsstimulatedbyTNFinterferonProducereactivenitrogenintermediatesNitricoxideNitrite(NO2—)Nitrate(NO3—)BIOL53341PhagocytoticKillingMacrophagePhagocytoticKillingReleasedfromcellsorcontainedwithinvacuolesMacrophagesproduceNOfromargininewhenstimulatedbycytokinesNOcanblockcellularrespirationbycomplexingironinelectrontransportproteinsBIOL53342PhagocytoticKillingReleasedfMacrophageKillingHerpessimplexToxoplasmagondiiLeishmaniamajorCryptococcusneoformansSchistosomamansoniBIOL53343MacrophageKillingHerpessimplLecture6Questions?Comments?Assignments...BIOL53344Lecture6Questions?BIOL53344PhagocytosisandtheInteractions

ofVariousPhagocytesBIOL533Lecture6MedicalMicrobiologyBIOL53345PhagocytosisandtheInteractiLeukocyteChemotaxinsTypesofchemotaxinsC5aattractsneutrophilsandmonocytesMadebybacteriaPeptideclippedoffN-terminus(beginningwithN-formylmethionine)duringpeptidematurationafterproteinsynthesisMadebybacteriaandnucleatedbloodcellsLeucotrienes—lipidproductsofcellmembranemetabolismBIOL53346LeukocyteChemotaxinsTypesofLeukocyteChemotaxinsFunctionofchemotaxinsEnhanceanddirectmotilityofphagocyticcellsToalimitedextent,oxidativemetabolismofphagocyticcellsBIOL53347LeukocyteChemotaxinsFunctionOpsonizationandOpsoninsGeneralaspectsSubstancesthatenhanceabilityofphagocytestoingestmicrobesDefendagainstpresenceofcapsulesandothermicrobialmechanismsthatinterferewithphagocytosisBIOL53348OpsonizationandOpsoninsGenerOpsonizationandOpsoninsTypesofopsoninsAntibodiesC3bcomponentofcomplementBindscovalentlytobacterialsurfaceandisrecognizedbyreceptorsonneutrophils,monocytes,andmacrophageBacteriabecomeboundtosurfaceofphagocytefacilitatingtheiruptakeBIOL53349OpsonizationandOpsoninsTypesOpsonizationandOpsoninsTypesofopsonins,continuedMechanismWhitebloodcellreceptorsforC3bAtleast3—CR1,CR2,CR3(complementreceptor)ChildrendeficientinCR3veryvulnerabletobacterialinfectionsBIOL53350OpsonizationandOpsoninsTypesPhagocytes—TypesofCellsNeutrophils—celloriginActivelymotilecellsproducedinbonemarrowDifferentiatefromstemcellsoveraboutatwo-weekperiodProductionofgranulesduringthistimeAzurophilProducespecificgranuleslaterBIOL53351Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsNeutrophils—cellorigin,continuedUponmaturation(innumbersof1010perday),theymoveintoperipheralbloodandcirculateforabout6.5hoursNextmoveintocapillarybedandmarginateBIOL53352Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsNeutrophils—cellorigin,continuedMarginationcausedbystickinessduetointerleukin-1Summonedbychemotaxis,theymovethroughendothelialcelljunctions(diapdesis)intoextravasculartissuespacesBIOL53353Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsNeutrophilsaremostactiveingutGuthasenormousmicrobialpopulationlyingjustonecelllayerawayfromaseptictissueFloragenerateslargeamountsofchemotaxinsthatrecruitmostofbody’savailableleukocytesBIOL53354Phagocytes—TypesofCellsNeutrPhagocytes—TypesofCellsAsaresult,submucosaofgutisinaconstantstateofinflammationKeepmicrobialfloradownSynthesisofneutrophilsinhibitedbychemicalsorradiationInfectionsingutregionBIOL53355Phagocytes—TypesofCellsAsaPhagocytes—TypesofCellsMonocytesandmacrophageComparedtoneutrophilsArriveatdamagedtissuelaterininfectionDaysafterneutrophilshavebeenactiveinfightingintrudersEventuallysettleintissuesandbecomeresidentmacrophageBIOL53356Phagocytes—TypesofCellsMonocPhagocytes—TypesofCellsMonocytesandmacrophageShareprogenitorcelltype,butkineticsofmaturation&appearanceareverydifferentMonocytescontinuecelldifferentiationafterleavingbonemarrowMonocytesandmacrophageinvolvedinbothconstititiveandinduciblemechanismsInteractwithTcellsandplayimportantroleincell-mediatedimmunityBIOL53357Phagocytes—TypesofCellsMonocPhagocytes—TypesofCellsTissue(resident)macrophageExistthroughoutbodyDifferentnamesandfunctionsindifferenttissuesKupffercells—liverAlveolarmacrophage—lungsOsteoclasts—boneMicroglia—brainBIOL53358Phagocytes—TypesofCellsTissuPhagocytes—TypesofCellsMonocyteandmacrophagefunctionsPhagocytizeinvadingmicrobesContributegreatlytoinflammatoryresponseReleasesIL-1—enhancesstickingofneutrophiltocapillaryendotheliaTNF—activatesnewlyarrivedneutrophilsBIOL53359Phagocytes—TypesofCellsMonocMechanismofPhagocyteKillingNeutrophilsGeneralstepsAttachtomicrobesIngestmicrobesKillmicrobesGranules—consideredasenlargedlysosomescontaininghydrolyticenzymesBIOL53360MechanismofPhagocyteKillingMechanismofPhagocyteKillingNeutrophilgranuletypesAzurophil(primarygranule)ContainsLysozymeElastaseAchymotryptic-likeproteaseMyeloperoxidaseSeveralantibacterialcationicproteinsBIOL53361MechanismofPhagocyteKillingMechanismofPhagocyteKillingNeutrophilgranuletypesSpecific(secondarygranule)ContainsCytochromeLysozymeLactoferin(iron-bindingprotein)VitaminB12bindingproteinCollagenaseBIOL53362MechanismofPhagocyteKillingMechanismofPhagocyteKillingTheneutrophilmembraneContainsreceptorsforchemotaxinandopsoninsAfterbindingchemotaxins,receptorsareinternalizedandreplacedwithnewonesBIOL53363MechanismofPhagocyteKillingMechanismofPhagocyteKillingEffectivenessofchemotaxis:veryeffectiveNeutrophilsareverymotileMovebyrearrangingcytoplasmicmicrofilamentsandmicrotubulesActinandmyosininmicrofilamentsareaffectedbyproteingelsolinPortionsthatfaceupstreaminchemotacticgradientformstructurecalledlamellipodiumCytoplasmisdenselypackedwithmicrofilamentsPortionsfacedownstreamformknob-likeuropodBIOL53364MechanismofPhagocyteKillingMechanismofPhagocyteKillingProcessofphagocytosisGeneralaspectsDiffersfrompinocytosisinthatparticles,notliquids,takenupBIOL53365MechanismofPhagocyteKillingMechanismofPhagocyteKillingProcessofphagocytosis,continuedReceptorsonphagocytesurfaceprogressivelyattachtoligandsonbacterialsurfaceStimulatesmechanismsofkillingOxidativemetabolismleadingtoproductionofhydrogenperoxideandcompoundslethaltomicrobes(oxygen-dependentkilling)Dischargeoftoxiccompoundsfromgranulesintophagosome(oxygen-independentkilling)BIOL53366MechanismofPhagocyteKillingMechanismofPhagocyteKillingProcessofphagocytosis,continuedFormphagosome—pouch-likestructurethatinvaginates,displacingthenucleusandgranulestowarduropodFormphagolysosome—membraneofgranulesandphagosomefuse,releasingtoxicsubstancesFormsseparatepinched-offorganelleBacteriacoatedwithantibacterialproteinsBIOL53367MechanismofPhagocyteKillingOxygen-DependentKillingFusionofspecificgranuleswithphagosomemembrane(derivedfromplasmamembrane)bringstogether:NADPHoxidase(oxidizesNADPH;foundinneutrophilplasmamembrane)Uniquecytb(granulemembrane)AquinoneBIOL53368Oxygen-DependentKillingFusionOxygen-DependentKillingReactionO2O2— (reducesoxygentosuperoxideradical)2O2—

+H2OH2O2

+O2 (superoxidedismutase)BIOL53369Oxygen-DependentKillingReactiOxygen-DependentKillingPatientslackingcytochromecomponentsChildrenhavingchronicgranulomatousdisease(CGD)FailuretosynthesizesuperoxideradicalandthereforehydrogenperoxideDuetodecreasedamountofcytochromebGeneforlargersubunitismissing(90K,20K)BIOL53370Oxygen-DependentKillingPatienOxygen-DependentKillingChildrenhavingchronicCGD,cont’d.Neutrophilscanphagocytizenormally,butdonotefficientlyoxidizeNADPHandkillviaoxidativepathwayUsuallydon’tsurviveintoadulthoodBIOL53371Oxygen-DependentKillingChildrOxygen-DependentKillingHowdoesoxidativeprocesskill?InteractionwithmyeloperoxidasesuppliedbyfusionwithazurophilCombineschlorideionsandhydrogenperoxidetoformhypochlorousions(analogoustobleach)Bacterialackingcatalaseproducehydrogenperoxide(pneumococci);basicallycommitsuicidePneumococciarenotdangeroustoCGDpatientsBIOL53372Oxygen-DependentKillingHowdoOxygen-IndependentKillingProcessTriggeredbybindingopsonizedbacteriatotheplasmamembraneofneutrophilsSpecificgranulesfusefirstDeliverseveralbacteriodicalproteins,includinglysozymeandlactoferinBIOL53373Oxygen-IndependentKillingProcOxygen-IndependentKillingAzurophilgranulesdischargeantimicrobialcationicproteinsSomeareamphipathicandresembleothercationicsurfaceproteinssuchaspolymyxinBBIOL53374Oxygen-IndependentKillingAzurOxygen-IndependentKillingAzurophilgranules,continuedDisruptoutermembraneofGram—andkillbycausingleakageofvitalcomponentsEachoftheproteinshasuniqueantimicrobialspectrum,buttendtoaffectGram—morethanGram+

ProteinsmayaccountforsurvivalofsomeCGDchildrenBIOL53375Oxygen-IndependentKillingAzurOxygen-IndependentKillingEfficiencyBacterialkillingunderhighlyanaerobicconditionsofdeepabscessesPatientslackinggenesCodingforcationicproteinsNonefound,maybelethalBIOL53376Oxygen-IndependentKillingEffiOxygen-IndependentKillingChediak-Higashisyndrome (geneticdisease)PrematurefusionofneutrophilgranuleswhilecellsinbonemarrowWhenmaturecellsphagocytize,granulesarealreadyspent,substantiallyreducingkillingpowerBIOL53377Oxygen-IndependentKillingChedComparisonofBacterialSensitivityGram—rodsingutkilledbyoxygen-independentGram+bacteriaonskinandupperrespiratoryepitheliaareresistantt