病原微生物肝炎病毒

Lecture05/06 Lecture05/06 YoujunCenterforInfection&Immunity,ZhejiangUniversitySchoolofHepatitis:InflammationHepatitis:Inflammationoftheliver,destructionofhepatocytesAcuteInfection-Icteric黃疸的ChronicInfection-Mayprogressto:Hepaticfibrosis,Liverfailure,Increasedriskofhepatocellular?Focusonthe–Details?Focusonthe–Detailsofhepaticdiseaseandtreatmentwillbedemonstratedinother?Understandsimilaritiesand––Viralstructure,biologyModesof–––HepatitisAHepatitisAVirus“Epidemic“Infectioushepatitis”BiologicalPicornavirusclassifiedasBiologicalPicornavirusclassifiedasEnterovirus72in1980s,laterclassified27nmnaked(non-envelopedicosahedralcapsid(二十面體Extremelystable???ImmatureMatureBiologicalPicornavirusclassifiedBiologicalPicornavirusclassifiedasEnterovirus72in1980s,laterclassified27nmnaked(non-enveloped)icosahedralPositive-sense,single-strandedRNAgenome,7500???3B-VPg/primerBiologicalPicornavirusclassifiedasEnterovirusBiologicalPicornavirusclassifiedasEnterovirus72in1980s,laterclassified27nmnaked(non-enveloped)icosahedralcapsidPositive-sense,single-strandedRNAgenomeResistance:Strongerthanenterovirus,resistantto????acid(pH1.0for2h),60℃for1hwaterandsaltwateroneserotypeand7surviveformonthsin?TransmissionofTransmissionofFecal-Oral?Contaminatedwaterorfood(shellfish,greenonions)Riskfactors:Poorsanitationandhygiene,overcrowding,PathogenesisofPathogenesisof?Entersbloodstreamthroughgastrointestinalepithelium?ReplicatesinhepatocytesandKupffercells?Releasedbyexocytosis,notcelllysis?Goesintobile,intestine,excretedin?Sheddingofvirusfor10dayspriortoanyAcuteHepatitisAAcuteHepatitisA?MaybemildtoasymptomaticinchildrenAbruptonsetofdiseaseinadults“Self-limited”-controlledbyimmuneLowoverallmortalityfromfulminant(爆發(fā)性hepaptitisHigherriskwithsimultaneousliverdiseasesuchascirrhosisduetoalcoholorchronicHepatitisBorDiagnosisofClinicalDiagnosisofClinicalDetectionofanti-HAVspecificIgMtiterinacuteinfection,positivefor4-6monthsIgGtiterpresentforResearch-Virusfecesbyelectronmicroscopy(nocellcultureavailable)RNAPreventionofAvoidancePreventionofAvoidanceofquestionablefoodandwaterinendemicPassivePolyclonalanti-HAVantibodiesthatpersistfor6monthsOnlyeffectivefor2weekspriortoexposureExpensive,painful,IMinjectionsiteActiveLiveattenuatedHAVHepatitisEHepatitisEvirusUsedtobecalled“Enteric”oror“Water-Non-ANonBIdentifiedinIndiainBiologicalNon-envelopedBiologicalNon-envelopedSingleStrand(+)RNA7.2-7.6kbBiologicalBiologicalHepaticdamageHepaticdamagebyhostimmuneresponseNochroniccarrierstateAcuteinfectionclinicalsyndromeverysimilartoHAV,excepthigherratesinpregnancyMortality1-2%,higherthanHAV10~20%inpregnantMechanismDiagnosedbyHEV-RNA;anti-HEVAb,IgGandIgM?????Fecal-Oraltransmission,especiallyfromfecally-contaminatedwaterPerson-to-personHighestincidenceinAsia,Africa,MiddleEastandCentralAmericaHighincidenceamongpregnantwomenwith10-20%NoNovaccine(PhaseIIIclinicaltrialinLittleknownaboutpre-orpost-exposureefficacyofimmuneNoefficacyofimmunoglobulinobtainedfromwesternHepatitisBvirusHepatitisBvirus?BaruchBlumberg,1963:“Australianantigen–1968:Auwasaviralantigen=HBsAg(surfaceantigen)HAADane,1970:Discovered42nm'Daneparticles‘HBcAg(coreantigen).1973:HBeAgdiscovered(endogenousantigen=atruncatedversionofHBcAg).1983:membersof?????BiologicalBiologicaltubularDaneparticle(completetubularDaneparticle(completevirion)sphericalElectronmicroscopyofhepatitisBvirus-positiveserumrevealsmorphologicallydistinctformsofHepatitisHepatitisBvirus.Daneparticleandincompleteparticlesthatfoundinpatient'sDane??Dane??complete42nmpartlydoublestrandedDNAvirus,the+strandnotDNAisalsofoundinthesolubleformsinvirus-positiveseralipidbilayerHBsAg,preS1,?Daneparticle-??surface(coat)“aDaneparticle-??surface(coat)“a”antigenicdeterminant?4phenotypesadw,adr,ayw,??innercoreproteinasingle??secretedproteinGenetic(-)3200Genetic(-)3200(+)50-90%of(-LEADINGDNADR1:directrepeat(+)5’-TTCACCTCTGCDR2:directrepeat(-)Geneticstructure(L-?Geneticstructure(L-?Pregion:DNAGeneticstructure(L-?Geneticstructure(L-?Xregion:0.8kbtrans-activationGeneticstructure(L-4openreadingframesSGeneticstructure(L-4openreadingframesSregion:capsidproteinSgene:preS1gene:CregionCgene:preCgene+Cgene:HBeAgPregion:DNApolymerase?????Xregion:(trans-activationPreS1,PrePreS1,Preabsorption,L-DNA→dsDNA(L-)→3.5kb,2.4kb,2.1kb,0.7-3.5kbmRNAastemplateforDNAreplication(pre-4.mRNA→3.5kbmRNA→innercapsidproteins,DNApolymerase2.4kbmRNA,2.1kbmRNA→outercapsidproteins0.8kbmRNA→HBxAgpackagingofpre-genomeandinnercaspid&mRNA(pre-genome)→DNA(-)DNA(-)→DNA(+)RNase7.virionpackagingandHBVDNApolymerase:HBVDNApolymerase:noproof-readingPreS/SPrec/C“a”eiptopemutation(ntinSgeneencodefor145aa,126aaeminus(A-Gat1896ntinPreCgeneesupression(1762/1764ntmuationinpromoterofIsolationandIsolationand?Animal--?Cellculture:notInvitroResistanttoResistanttolowtemperature,dry,UV,70%ethylether,chloroform,Dis-infectedby100℃10min,pH2.4SensitivetoTransmissionTransmissionConcentrationofHepatitisBVirusinVariousBodyFluidsConcentrationofHepatitisBVirusinVariousBodyFluidswoundBreast-??Estimated300??Estimated300millionHBVcarriersworldwideHighprevalenceareas10-20%China,southeastAsia,sub-SaharanAfricaIntermediateprevalenceareas2-5%Mediterranean,MiddleEast,Japan,CentralandS.Lowprevalenceareas0.1-N.America,Europe,Australia,New??NaturalNaturalHistoryofChronicHBVAcuteHBVAcuteHBV???LongerincubationperiodpriortosymptomsInsidiousonsetofsymptomsratherthanabruptOnly25%ofinfectedpeoplewillmanifestthefullclinicalsyndromeofhepatitisImmunecomplexdiseaserelatedtoSeeninRash,arthritis,fever,necrotizingvasculitis(polyarteritisnodosum),glomerulonephritis?ChronicHBVChronicHBV?Occursin5-10%ofacute90%of20-50%ofearly5%ofUsuallyaftermildorasymptomaticinfectionSourceofongoingtransmission10%maydevelopcirrhosisorliverfailure,mostlyduetochronicactivehepatitis???HBVinfectionHBVinfectionininfantsandyoungchildrenImmatureMildsymptoms,chronicinfectionBalancebetweenBalancebetweenvirusclearanceandliverinjuryBalanceBalancebetweenvirusclearanceandliverinjuryVirionsreleasedVirionsreleasedbyexocytosis,notTypeIITypeIII–TypeIVImmuneImmuneCTLCTLmediatedanti-virusimmuneresponsesvs.liverinjuryAntigen/AntibodysurfaceAntigen/Antibodysurface(coat)4phenotypesadw,adr,ayw,innercoreasinglesecreted&anti-&anti-–majorsignofHBV–acute–chronicinfectionor–Hepatocellularcanceranti-–neutralizationPreS1,&anti-PreS1,&anti-PreS1,–virusreplication–newlyanti-PreS1,anti-–1stappearanceantibodyafter–neutralizingantibody,clearanceof–donotroutinelycheckedforclinicaldiagnosispurpose&anti-&anti-–notdetectableintheanti-HBc,virusacuteacuteepisodeduringchronictransientanti-HBc,–donotprotectchroniclastforalong&anti-&anti-–earlystageafteranti-–thesignofbetter–variation:endingcodoninpre-LaboratoryLaboratoryLaboratoryLaboratoryAcuteinfectionbyclinical–MinorityofinfectionsdiagnosedbyAcuteandchronicinfectionbypatternsofHBVDNAassay(DNAhybridorNoculturesperformedinclinicalAcuteHepatitisAcuteHepatitisBVirusInfectionwithTypicalSerologicProgressiontoProgressiontoChronicHepatitisBVirusTypicalSerologicInterpretationofInterpretationofSerologicMarkersofPreventionandPreventionandInterferon-forHBeAg+vsInterferon-forHBeAg+vscarrierswithchronicactivehepatitis.Responserateis30to40%.?––α-interferon2bα-interferon2a(newer,claimstobemoreefficaciousand?Lamivudine拉米夫定anucleosideanaloguereversetranscriptaseWelltolerated,mostpatientswillrespondfavorably.However,tendencytorelapseoncessationoftreatment.Anotherproblemistherapidemergenceofdrugresistance.Adefovir阿德福韋lesslikelytodevelopresistancethanLamivudineandmaybeusedtotreatLamivudineresistanceHBV.HowevermoreexpensiveandtoxicEntecavir恩替卡韋mostpowerfulantiviralknown,similartoSuccessfulresponsetotreatmentwillresultinthedisappearanceofHBsAg,HBV-DNA,andseroconversiontoHBeAg.???Vaccination–highlyeffectiverecombinantvaccinesarenowavailable.VaccinecanbegiventothosewhoareatincreasedriskofVaccination–highlyeffectiverecombinantvaccinesarenowavailable.VaccinecanbegiventothosewhoareatincreasedriskofHBVinfectionsuchashealthcareworkers.ItisalsogivenroutinelytoneonatesasuniversalvaccinationinmanyHepatitisBImmunoglobulin–HBIGmaybeusedtoprotectpersonswhoareexposedtohepatitisB.Itis efficaciouswithin48hoursoftheincident.Itmayalsobegiventoneonateswhoareatincreasedriskofcontractinghepatitisi.e.whosemothersareHBsAgandHBeAg???Othermeasures-screeningofblooddonors,bloodandbodyfluidHepatitisBcanbeHepatitisBcanbeIfyouhaveneverhadhepatitisB,youcanget3shots...123...andgetlonglastingBabyShotsforHepatitisBifthemotherBabyShotsforHepatitisBifthemotherhasHepatitis1-2months+H-6monthsHepatitisDHepatitisDvirusHepatitis??“DeltaHepatitis??“DeltaDefectivevirussimilartoplantSmallsingle-strandedcircularRNASingleHDVLipidenvelopefromHBV,HBsAgneededforDependsonHBVforlifeCo-infectionwithacuteSuperinfectioninchronicReplicatesveryefficientlyin??GeneHepatitisGeneHepatitisdeltaagent.ThreeRNAforms.AdaptedfromWagnerandHewitt.:BasicVirology.BlackwellPublishing?InjecteddrugLessefficientsexualtransmissionthanUpto5%ofchronicHBVcarriersmayalsocarryHDVVariesgreatlybyregionEndemicinMediterranean地中海Rareinthe??PathogenesisPathogenesisofViralreplicationcauseshepatocytecellAdditivetoHBV-inducedhostinflammatoryAntibodiestoHDVAgnotlikelytobeClinicalConsequencesClinicalConsequencesofIncreasesriskoffulminanthepatitisgreatlyuponco-infectionEstimated2-20%fulminantIncreasesriskofcirrhosisinchronicinfectionwithHBVMorerapidMorelikelyDetectionDetectionofHDVantigenorClinicalAcutefulminantHepatitisCHepatitisCvirus“Non-ANon-BIdentifiedin1989bymolecularBiological Biological Relatedtoflaviviruses黃病毒）andpestivirus(瘟病毒)?????40-60nmparticle,sphericalanenvelopedvirionGenome:(+)ssRNASixgenotypes,regionalGreatheterogeneity,manyNoNoPreventionofPreventionoffurtherexposurerisksinHBVchronicinfectionBiologicalBiologicalHCVbindstoeithertheCD81antigenorlowdensitylipoprotein(LDL)receptorhepatocytesviaitsE2ThereisalsosomeevidencethatitmaybindtoBiologicalHighlyBiologicalHighlyvariedgenomeofHCVGenotypes&subtypesFig1PhylogenetictreeofHCVNS5Bsequences.Nucleotidesequencesforpositions7975–8196(numberedfromthepolyprotein AUGinitiationcodon)ofNS5BwereanalyzedusingtheprogramPhylipasdescribedpreviously(76).Majorbranchesarelabeledwiththetypenumber,andminorbrancheswithlettersindicatingthesubtypeThevariant“10a”canbeconsideredasasubtypeoftype3,andthevariants“7a”,“7b”,“8a,”andsoforthassubtypesoftype6(2,3).BiologicalHighlyBiologicalHighlyvariedgenomeofHCVQuasispecies&strainsInjectedInjecteddrugBloodtransfusions(raresincescreeninginNosocomial(醫(yī)院的EfficiencyofsexualtransmissionisrelativelyPerinatal圍產(chǎn)期riskNotfullyNotfullyProlongedcell-associatedLikelylowlevelchroniccell-mediatedhostimmuneProgressiontohepaticfibrosisandcirrhosisMoreseverediseaseprogressionHIVco-?????Acute?Acute????VastmajorityareFewcasesofsymptomaticacutehepatitisVeryrareornon-existentfulminantcasesVeryhighrateofchronicAcuteAcuteHCVRNAinserum,liverHCVAbChronicHCVAbpositive(notHCVRNAinserum,liverViruscannotbeNoNovaccineavailableNoimmuneglobulinBehavioralinterventionstoreduceTreatment:RecombinantIFN-αaloneorwith????ViralHepatitis-TypeofABCDEbodybodybodyViralHepatitis-TypeofABCDEbodybodybodyRouteofimmunizationrisk riskbehaviorSelfcontrolquestions-partSelfcontrolquestions-partEachofthefollowingstatementsconcerninghepatitisC