病毒基本性状课件

医学微生物学病毒的基本性状

GeneralPropertiesofViruses

重要性？！Itis“timetoclosethebook”ontheproblemofinfectiousdiseases.1969USSurgeonGeneralThefutureofinfectiousdiseaseswillbeverydull.1972FrankMacfarlaneBurnet(1960NoblePrizeinPhysiologyorMedicine)SpanishinfluenzaHIV&EmergenceInfectiousDiseasesExamplesofrecentemergingdiseasesSource:NATURE;Vol430;July2004;/nature病毒的危害

所致疾病约占传染病的80%传染性强、流行广泛，很少有效药物有些所致疾病严重，病死率高或有后遗症持续性感染与肿瘤和自身免疫病有关威胁健康的新病原体不断出现学习病毒学，要注意防治和控制ABriefHistoryofVirology~1400BCFirstwrittenrecordofvirusinfectionsinheiroglyphicsfoundinMemphis,Eygpt100BC–ChinaProtectionfromsmallpoxusingvariolationpractice1796-Vaccination

EdwardJennervaccinatedaboywithcowpox-infectedmaterial1880–GermTheoryRobertKoch&LouisPasteurPasteuridentifiedrabiestobecausebyanagenthetermed“virus”fromtheLatinfor‘poison’.1892beginningofvirologyDmitriIwanowskishowedthatceramicfilteredextractsfromdiseasedplantscouldtransmitdiseasetootherplants.1898MartinusBeijerinickworkonTMVFreidrichLoeffler&PaulFroschworkonfoot-and-mouthdiseaseincattle1909Landsteiner&PopperPoliomyelitis(YellowFever)wasthefirsthumandiseasetoberecognizedasaviraldisease1950-2003DiscoveriesofEbola,WestNile,HIV,SARS1935WendellStanleydiscoveredvirusweremadeofnucleicacidandprotein.ABriefHistoryofVirology~1400BCFirstwrittenrecordofvirusinfectionsinheiroglyphicsfoundinMemphis,Eygpt100BC–ChinaProtectionfromsmallpoxusingvariolationpractice1796-Vaccination

EdwardJennervaccinatedaboywithcowpox-infectedmaterial1880–GermTheoryRobertKoch&LouisPasteurPasteuridentifiedrabiestobecausebyanagenthetermed“virus”fromtheLatinfor‘poison’.1892beginningofvirologyDmitriIwanowskishowedthatceramicfilteredextractsfromdiseasedplantscouldtransmitdiseasetootherplants.1898MartinusBeijerinickworkonTMVFreidrichLoeffler&PaulFroschworkonfoot-and-mouthdiseaseincattle1909Landsteiner&PopperPoliomyelitis(YellowFever)wasthefirsthumandiseasetoberecognizedasaviraldisease1950-2003DiscoveriesofEbola,WestNile,HIV,SARS1935WendellStanleydiscoveredvirusweremadeofnucleicacidandprotein.1400BC，埃及孟非思壁画中长老患小儿麻痹症ABriefHistoryofVirology~1400BCFirstwrittenrecordofvirusinfectionsinheiroglyphicsfoundinMemphis,Eygpt100BC–ChinaProtectionfromsmallpoxusingvariolationpractice1796-Vaccination

EdwardJennervaccinatedaboywithcowpox-infectedmaterial1880–GermTheoryRobertKoch&LouisPasteurPasteuridentifiedrabiestobecausebyanagenthetermed“virus”fromtheLatinfor‘poison’.1892beginningofvirologyDmitriIwanowskishowedthatceramicfilteredextractsfromdiseasedplantscouldtransmitdiseasetootherplants.1898MartinusBeijerinickworkonTMVFreidrichLoeffler&PaulFroschworkonfoot-and-mouthdiseaseincattle1909Landsteiner&PopperPoliomyelitis(YellowFever)wasthefirsthumandiseasetoberecognizedasaviraldisease1950-2003DiscoveriesofEbola,WestNile,HIV,SARS1935WendellStanleydiscoveredvirusweremadeofnucleicacidandprotein.10Smallpox(天花/牛痘疫苗)EdwardJenner(1796)developedasmallpoxvaccineusingmildercowpoxvirusesDeadlyvirusesaresaidtobevirulentSmallpoxhasbeeneradicatedintheworldtodaycopyrightcmassengaleABriefHistoryofVirology~1400BCFirstwrittenrecordofvirusinfectionsinheiroglyphicsfoundinMemphis,Eygpt100BC–ChinaProtectionfromsmallpoxusingvariolationpractice1796-Vaccination

EdwardJennervaccinatedaboywithcowpox-infectedmaterial1880–GermTheoryRobertKoch&LouisPasteurPasteuridentifiedrabiestobecausebyanagenthetermed“virus”fromtheLatinfor‘poison’.1892beginningofvirologyDmitriIwanowskishowedthatceramicfilteredextractsfromdiseasedplantscouldtransmitdiseasetootherplants.1898MartinusBeijerinickworkonTMVFreidrichLoeffler&PaulFroschworkonfoot-and-mouthdiseaseincattle1909Landsteiner&PopperPoliomyelitis(YellowFever)wasthefirsthumandiseasetoberecognizedasaviraldisease1950-2003DiscoveriesofEbola,WestNile,HIV,SARS1935WendellStanleydiscoveredvirusweremadeofnucleicacidandprotein.ABriefHistoryofVirology~1400BCFirstwrittenrecordofvirusinfectionsinheiroglyphicsfoundinMemphis,Eygpt100BC–ChinaProtectionfromsmallpoxusingvariolationpractice1796-Vaccination

EdwardJennervaccinatedaboywithcowpox-infectedmaterial1880–GermTheoryRobertKoch&LouisPasteurPasteuridentifiedrabiestobecausebyanagenthetermed“virus”fromtheLatinfor‘poison’.1892beginningofvirologyDmitriIwanowskishowedthatceramicfilteredextractsfromdiseasedplantscouldtransmitdiseasetootherplants.1898MartinusBeijerinickworkonTMVFreidrichLoeffler&PaulFroschworkonfoot-and-mouthdiseaseincattle1909Landsteiner&PopperPoliomyelitis(YellowFever)wasthefirsthumandiseasetoberecognizedasaviraldisease1950-2003DiscoveriesofEbola,WestNile,HIV,SARS1935WendellStanleydiscoveredvirusweremadeofnucleicacidandprotein.病毒（virus）非细胞型的微生物特点体积微小结构简单只含一种类型核酸严格的细胞内寄生对抗生素不敏感，对干扰素敏感增殖方式：复制第一节病毒形态学病毒体(Virion)具有一定形态结构和感染性的完整病毒颗粒病毒的大小纳米（nm）Points:

Virus(1895)

Nano-unit“Incells” 依赖于细胞Virus

病毒真核原核病毒蛋白其他：朊病毒Prions病毒的形态螺旋对称型二十面体对称型复合对称型TobaccoMosaicVirusTobaccoMosaicVirus(TMV)isanexampleofaviruswithahelicalstructure.ProteinsubunitswraparoundthespiralingRNAstrand.ThisimagetakenusinganElectronMicroscopeHelicalCapsidsHelicalcapsidsarerod-likestructureswiththeRNAinthecenterofthehelix.Ahelixismadebystackingrepeatingunitsinaspiral.RNAproteincoatAdenovirusIntroduction–Structure–Replication–Virology–Medicine-ReviewAdenovirusescausediseaseslikepink-eyeorthecommoncoldIcosahedralsymmetry六邻体五邻体IcosahedralsymmetryBacteriophageBacteriophageisavirusthatinfectsbacteria.EnvelopedVirusesIntroduction–Structure–Replication

–Virology–Medicine-ReviewEnvelopedvirusesareviruseswhichhaveamembranecoatsurroundingtheproteincoatorcapsid.Thesevirusesarecommoninanimalviruses,butareuncommoninplantviruses.HerpesSimplexVirusAmembrane(withproteins)surroundsthecapsid(alsomadeofproteins)whichsurroundstheviralDNA.核心衣壳包膜Envelope核衣壳Nucleocapsid病毒颗粒Virion刺突刺探结构RSV（Cryo-EM）病毒的结构和组成－核心（core）成分核酸功能蛋白功能决定病毒的特性病毒复制具有感染性分类dsDNA(+)ssDNA(-)ssDNAdsRNA(+)ssRNA(-)ssRNA病毒的结构和组成－衣壳

（capsid）成分蛋白质壳粒功能保护病毒核酸参与感染过程具有抗原性

包膜

（envelope）成分蛋白质、多糖、脂类刺突spike功能维护病毒体结构完整性具有与宿主细胞膜亲和及融合的性能具有抗原性

包膜

核酸基质蛋白

糖蛋白

核衣壳核心衣壳一种类型的核酸小量非结构蛋白壳粒组成螺旋对称20面体立体对称复合对称包膜蛋白质多糖脂类病毒的结构和化学组成Theconceptofavirusasanorganismchallengesthewaywedefinelife:* Virusesdonotbreathe（呼吸）.* Virusesdonotmetabolize（代谢）.* Virusesdonotgrow（生长）.* However,theydoreproduce（增殖）.

1.Thevirallifecycle病毒吸附细胞上受体病毒侵入细胞内膜融合内吞病毒脱壳释放基因组复制转录翻译加工细胞内转运入核出核病毒组装病毒释放发芽裂解EachstepispreprogrammedandtightlyregulatedintimeandspaceAttachment&ReceptorPenetration(Fusion&Endocytosis)Virusentry转录、出核、翻译、加工逆转录入核整合复制AssemblyBuddingRelease1.1Cellsurfaceattachment吸附-acriticalmomentThekeyroleofthereceptor受体orco-receptorAims:Transfercapsidandaccessoryproteinsintothecellinareplication-competentformMinimaldamagetothecellLeavinglittleevidenceNOTeasyA“Trojanhorse”strategyReceptorsandAttachmentFactorsFirststepofinfectionMoleculesonthesurfaceCellularproteins(glycoprotein)CarbohydratesLipids(glycolipid)AttachmentfactorsvsTRUEreceptorsFromPrinciplesofVirology,Flintetal.ASMPressReceptors:

Tropism

-celltypes,tissues,andorganismsGuidingtheboundvirusesintoendocyticpathwaysTransmittingsignalstothecytoplasmServeascuesthatinduceconformationalchanges-FusionandpenetrationCellularMoleculesusedasvirusreceptors

Receptor-BindingProteins

受体结合蛋白（与细胞表面受体结合的病毒蛋白）Envelopedviruses:SpikeglycoproteinsoftenserveasreceptorbindingproteinInfluenzavirus hemagglutinin(HA) SialicacidHIV-1 gp120 CD4Herpessimplex glycoproteinD HVEA

virus1(HSV-1) Epstein-Barrvirusgp42 humanlymphocyteantigen (HLA)–DRNewcastlediseaseHNprotein beta-anomerofsialicacid

Virus Non-envelopedviruses:projectionsorindentationsinthecapsidsurface病毒纤突介导吸附：Adenoviruses，纤突内陷处为受体结合处裂缝介导吸附：Rhino,enter,poliovirusCarbohydrate/ProteinInteractionsSialicacid(唾液酸)Glycosaminoglycans(氨基葡聚糖）Glycolipids(糖酯)Heparansulfate(硫酸乙酰肝素):herpesviruses;adenoassociatedviruses;denguevirusInmostcases,carbohydratesserveasattachmentfactorsthatdonottriggerconformationalchangesNotUncommonForVirusestoUse2ReceptorsHumanimmunodeficiencyvirus–1(CD4andCCR5orCXCR4)Onereceptorfordockingandoneforendocytosisgp120bindstoCD4undergoesaconformationalchangeallowsthevirustoassociatewithitsco-receptors(CXCR4orCCR5)Theinteractionbetweengp120andCXCR4orCCR5triggersthefusionwithgp41fusiondomainReceptorsandAttachmentFactors结合与变构CCR5变构引起结合共受体再度引发gp41变构gp41激发的膜融合脱壳，进入细胞1.2Penetration&UncoatingAdenovirusInfluenzavirusHIVVirusescanpenetratedirectlyattheplasmamembrane,orviaendosomesornuclearmembrane倾入脱壳：使病毒基因组核酸从衣壳或包膜中释放出来PenetrationEnvelopedviruses:

occursbymembranefusioncatalyzedbyfusionproteinsintheviralenvelope(膜融合)Fusionactivityistriggeredbycues信号intheformofreceptorbindingorlowpHIrreversibleconformationalchanges(不可逆的结构改变)Nonenvelopedviruses:

penetrateeitherbylysingamembraneorbycreatingaporelikestructureinamembrane(裂膜)AlsoinvolvescooperativechangesinvirusparticlestriggeredbyreceptorbindingorlowpHThevirusesbecomemorehydrophobic(疏水化)andinteractwithmembranesdirectly51F,G,SHN,P,LM,M2RSV52?Endosomes内体

areusedbycellsfornutrientandgrowthfactoruptakeThevirus“hijacks”thecellularpathwayOnekeyfeatureofendosomesistheirprogressive

acidification

-duethetheactionofthevacuolarH+/vATPaseGenerally,

pH6.2-6.5issufficientforfusionTheloweredpHcausesconformationalchangesinthespikeglycoprotein,andtheexposureofafusionpeptide

Thisisthe“trigger”neededforvirusentryEndocytosis(Endosomes&virusentry)内吞FromCellBiology,PollardandEarnshaw,SaundersMicrotubulesandIntracellularTransport•Tofacilitatetransportvirusesoftenbindtothecytoskeletonandusemicrotubule-mediatedmotorproteins

马达蛋白fortransport,i.e.dynein动力蛋白VSV/Rabies,influenzaAdenovirusHerpesvirusFromSodeik,TrendsMicrobiol8:465SignalingDuringVirusEntryAtwo-waydialogue(双通路)Thevirustakesadvantageofthecell’sownsignaltransductionsystemstotransmitsignalstothecellUsuallygeneratedatthecellsurfacethroughthevirusbindingtoreceptorsthatarethemselvessignalingmoleculesormodulatorse.g.,growthfactorreceptors,chemokinereceptors,integrins整合素,andgangliosides神经节苷脂1.3NuclearImport入核Nucleus:excellent“service”functionsforvirusreplication进入细胞核复制病毒的基因组ConfocalmicroscopyWhyreplicateinthenucleus?Whatarethe“benefits?”

DNAviruses

-needcellularDNApolymeraseand/oraccessoryproteins(egtopoisomerase)AllDNAvirusesreplicateinthenucleus,exceptionofPoxviruses痘

(无法在去核细胞中复制)AlmostallRNAviruses

replicateinthecytoplasm,andmostwillreplicateinacytoplast,exceptionofRetroviruses

逆转录

andinfluenzavirus流感Whatarethe“problems”withnuclearreplication?NucleusisdifficulttoenterandexitThenucleusofaeukaryoticcellissurroundedbyadoublelipidbilayer-thenuclearenvelope核膜Nuclearlocalizationsignal(NLS)核定位信号Thenuclearenvelopeisstuddedwithtransportchannels-thenuclearpores核孔FromFlintetalPrinciplesofVirologyASMPressExample：AdenovirusContainsNLSsonitscapsids,bindsmicrotubulesBut,Thefunctionalsizelimitofthenuclearporeis26nmThevirusisthereforetransportedasfarasthepore.Itdockstothenuclearporeandthenundergoesfinaldisassembly,andtheDNAis“injected”intothenucleus-withDNAbindingproteinsattachedSpecificimportins(输入蛋白)helpdisassemblethecapsidExample：InfluenzavirusThenucleoprotein(NP)containsNLSsandthevRNPs(螺旋状核糖核蛋白复合体)aresmallenoughtotranslocateacrossthenuclearporeThekeytoinfluenzanuclearimportisthepH-dependentdissociationofthematrixprotein(M1)fromthevRNPs.ThisreliesoftheM2ionchannel离子通道inthevirusenvelope,thetargetofamantadineFromWhittakerExp.Rev.Mol.Med.8February,http://www-ermm.c