微生物學(xué)第16講 Flavivirus

Flavivirus

病原微生物PathogenBiologyFlaviviridaePestivirusesFlavivirusesHepaciviridaeHepatitisCvirusBVD,Hogcholera,BorderdiseaseYellowfeverJapaneseencephalitisSt.LouisencephalitisDengueWestNilevirus(arthropods,biologicalvectors)22023/3/28TogavirusesandFlavivirusesTogavirusesHumanPathogensAlphavirusArbovirusesRubivirusRubellavirusArterivirusNoneFlavivirusesArbovirusesHepaciviridaeHCVPestivirusNone32023/3/28allFlavivirusesshareacommonantigenEnvelopeglycoproteinHemagglutinin65differenttypesofflavivirusone-thirdhumanpathogensseveralantigenicsubgroupsmitebornetickborneFlaviviruses:Classification42023/3/28ReplicationincytoplasmvirionsassembledingolgiandSmoothERTransportedbyvesiclestoplasmamembraneVirusRNAactsasmRNAcapped,nopolyAtailmRNA->proteinmRNA->antisenseRNAAntisenseRNA->senseRNAFlaviviruses52023/3/28EncephalitisSt.louisencelphalitis,Japaneseencephalitis,Powassan,tickborneencephalitisFebrileillnesswithrashDenguevirusHemorrhagicfeverKyasanurForestvirusHemorrhagicfeverwithhepatitisYellowfevervirusFlaviviruses:Clinicalmanifestations62023/3/28ArthropodVectorsAedesAegyti（伊蚊）AssortedTicks（虱、蜱）CulexMosquito（庫蚊）PhlebotmineSandfly（吸血白蛉）72023/3/28Transmissionhuman-arthropod-humananimal-arthropod-humanmix82023/3/28Human-Arthropod-HumanDengueReservoirmaybeineithermanorarthropodvectorInthelattertransovarialtransmissionmaytakeplace92023/3/28Animal-Arthropod-HumanJapaneseencephalitisThereservoirisinananimal,ThevirusismaintainedinnatureinatransmissioncycleinvolvingthearthropodvectorandanimalManbecomesinfectedincidentally102023/3/28JapaneseEncephalitisBackground1870s:Japan“Summerencephalitis”epidemics1924:GreatepidemicinJapan6,125humancases;3,797deaths1934:Reproducethediseaseinmonkey1935:FirstisolatedBrainfromafatalhumanencephalitiscase1938:IsolatedfromCulextritaeniorhynchus122023/3/28Background1940-1978DiseasespreadwithepidemicsinChina,Korea,andIndia1983:ImmunizationinSouthKoreaStartedasearlyasage3Endemicareasstartedearlier1983-1987:VaccineavailableinU.S.oninvestigationalbasis132023/3/28Pathogen---JEVandFlavivirusesJEVisoneof66flavivirusesbelongstotheJapaneseencephalitisserocomplex,whichiscomposedofseveralflavivirusesAlfuy,Koutango,Kokobera,Kunjin,MurrayValleyencephalitis,Japaneseencephalitis,Stratford,Usutu,WestNile,andSt.Louisencephalitis.Usutuvirus,anAfricanmosquito-borneflavivirus,emergedin2002andsincethenhasappearedinmanyEuropeancountries,presentingevenfurthersurveillanceandtransmissionchallenges.VazquezA,etal.EuroSurveill.2011;16:Non-segmented,singlestranded,positivesenseRNAvirusesrelatedtohepacivirusesandGBvirusesSpherical,40-60nmindiameterLipidenvelopecoveredwithsurfaceprojections,especiallyE,pre-MandMproteins142023/3/28WestNileKunjinJapaneseencephalitisMurrayValleyencephalitisSt.Louisencephalitisdengue-1dengue-3dengue-2dengue-4yellowfeverCentralEuropeanencephalitisFarEasternencephalitisPowassanDakarbatJapaneseencephalitisdenguenonetick-borneencephalitisnoneXIVXIIXVIIIVIIImosquito-bornetick-bornenovectorvirusserocomplexcladeclusterFlavivirusgenus.Thedendrogramontheleftshowstherelationshipsofselectedflavivirusesbasedonarecentphylogeneticanalysis.Theserologicandphylogeneticclassificationsofthesevirusesareindicatedtotheright.FieldsVirology,4thEdition.Philadelphia,Lippincott-Williams&Wilkins.2001,p995152023/3/28Flaviviruses(some),mosquito-borneJapaneseencephalitisS.Asia,Japan,Korea,China,India,Philippines,etc.VaccineMurrayValleyencephalitisAustralia,NewGuineaNoneWestNileVirusencephalitisAfrica,MiddleEast,southernFrance,FormerSovietUnion,India,Indonesia,USScreeningbloodandbloodproductsforthevirusSt.LouisencephalitisNorthandSouthAmericaNone162023/3/28JEVGenotypicVariantsJEVTypeIChina,India,Japan,Nepal,SriLanka,Taiwan,andVietnamTypeIICambodiaandN.ThailandTypeIIIIndonesia,Malaysia,andS.ThailandVaccinetargetTypeIVIndonesianandMalaysianregions172023/3/28GeographicdistributionofmedicallyimportantflavivirusestransmissionA,Regionswithyellowfeverviraltransmission.B,RegionswithJapaneseencephalitisvirustransmission.

C,CountrieswithWestNilevirustransmission.D,Countrieswithtick-borneencephalitistransmission182023/3/28Strauss,VirusesandHumanDisease.SanDiego,AcademicPress,2002AllflaviviruseswouldappearsimilartoDengue192023/3/28EpidemiologyOnlydistributesinAsiaPrimarilyadiseaseofruralAsiaVectormosquitoesproliferateincloseassociationwithbirdsandpigsBirdsandpigsarethemajoramplifyinghostsManyothermammalsandreptilesinfectedaswell,longtermviremiadocumentedinbats,othersCulextritaeniorhynchustheprincipalvectorbutmanyothermosquitoesarecompetentandcantransmitC.pipiensC.quinquefasciatusSpeciesofAedes,AnophelesVirusoverwintersinmosquitoesaswellasverticaltransmissionTraditionalseasonalspread(spring/summer)heavilyimpactedbyricepaddyfloodingAsinglericepaddycanproduce30,000mosquitoesperday202023/3/28IncidenceandPrevalenceCommonestcauseofencephalitisinAsiaInhyperendemicareashalfofallcasesoccurinchildrenunder4yearsofage,nearlyallbeforeage10Nearly100%seroprevalencebyadulthoodinheavilyinfectedareasEpidemicandendemicforms20,000casesand6,000deathsannuallyagrossunderestimateMathematicalmodelingpredicts175,000annualcases,43,750fatalities,78,750withdisability212023/3/28IncidenceandPrevalenceRatioofapparenttoinapparentinfectionrangesfrom1:250insusceptibleAsiansto1:63inadultUSmarines,1:18inTorresstraitoutbreakRatioaffectedbyage,virulenceofthestrainofvirus,crossprotectiveimmunityfromotherflaviviruses(dengue)Risktotravelers1caseper50,000monthsofexposure222023/3/28EpidemiologySymptomaticJapaneseencephalitishasamale-to-femaleratioof1.5:1.SerologicevidenceofJEVinfectioninendemicruralareasisfoundinnearlyallinhabitantsbyearlyadulthood.Mostsymptomaticinfectionsinendemicareasoccurinyoungchildren(aged2-10y)andelderlypeople.Innonendemicareas,JEVinfectionhasnoagepredilection.232023/3/28EpidemiologyOccurrenceintheUnitedIntheUnitedStates,Japaneseencephalitisdevelopsmostlyamongmilitarypersonnel,expatriates,and,rarely,returningtravelers.From1978-1993,12casesoccurredintheUnitedStates.Theriskofsymptomaticinfectionamongtravelersisestimatedtobe1caseper150,000person-monthsinanendemicarea.OutbreaksarerareintheUSterritoriesofGuamandSaipan242023/3/28EpidemiologyInternationaloccurrenceJapaneseencephalitisisaseasonaldisease,mostlyoccurringfromJunetoSeptember.Globally,morethan45,000casesarereportedeachyearInChina80～90%caseallfocusonJuly,August,SeptemberSouthChina:June~JulyNorthChina:July~AugustNE:August~SeptemberShanghai:lateJuly~earlyAugust252023/3/28262023/3/28272023/3/28TransmissionVector-borneEnzooticcycleMosquitoes:CulexspeciesCulextritaeniorhychusReservoir/amplifyinghostsPigs,bats,Ardeid(wading)birdsPossiblyreptilesandamphibiansIncidentalhostsHorses,humans,others282023/3/28ModeofTransmissionPlotkin,Orenstein.Vaccines,4thed.P928292023/3/28Morbidity/MortalitySwineMortalityhighinpiglets;rareinadultsEquineMortalityrare(<5%)HumansMortality:5to40%Seriousneurologicsequelae:45to70%302023/3/28SubcutaneousinjectionRegionallymphnodesExtraneuralTissues

ConnectivetissueStriatedmusclePancreasAdrenalSmoothmuscleEfferentlymphaticsThoracicductPlasmaViremiaReticuloendothelialcellclearanceHumoralantibodyOlfactoryepitheliumVascularendotheliumNeuralParenchymaNeurons,Glia(?)CNSantibodylymphocytes,macrophageCellulardysfunctionCellularlysisInflammation??PathogenesisModifiedbasedonFieldsVirology,Vol1,FourthEdition.Lippincott-Williams&Wilkins,pp1057,2001BBBSubclinicalformMildformCNS–JapaneseEncephalitisLighttypeMediumtypeSeveretype312023/3/28ClinicalManifestations35,000-50,000casesannuallyLessthan1case/yearinU.S.Military,travelersMostasymptomaticormildsigns1per250JEVinfectionsresultsinsymptomaticdiseaseChildrenandelderlyHighestriskforseveredisease322023/3/28ClinicalManifestationHistoryofmosquitoexposureinanendemicareaIncubationperiodaverage:6-8days,witharangeof5-15daysProdromalperiod:severaldaysFever39-40℃HeadacheNauseaDiarrheaVomitingMyalgia332023/3/28ClinicalManifestationsIncubation6-16days.SpectrumfrommildfebrileheadachetosevereencephalitisHeadache,fever,nausea,vomiting,drowsiness.AbdominalpainanddiarrheacommoninchildrenProgressionoverseveraldaystoseverediseaseDull,mask-likefaciesMuscularrigidityCranialnervepalsiesTremulouseyeandextremitymusclemovementsGeneralizedandlocalizedparesis,incoordination,pathologicreflexesSeizuresfrequentinchildren,<10%ofadultsAssociatedPress342023/3/28ClinicalManifestationsDeathin5-40%Somedeathsafteracutefulminantcourse,othersfromcardiopulmonarycomplicationswithprolongedcomaChildrenunder10morelikelytodieorhaveresidualneurologicaldefectsPoorprognosisassociatedwithRespiratorydysfunctionBabinsky’ssignFrequentorprolongedseizuresProlongedfeverAlbuminuriaHighviralreplicationinthebrainSource:ReutersNewsAgency352023/3/28ClinicalManifestationLighttype38-39℃,alwaysconsciousnessnotwitch,noevidentmeningealirratation,recoverywithinaweekMildtype39-40℃,stateofconsciousness:lethargy/delirium/obtundation,lightcoma,seizureoccasionally,last10daysSeveretypeTmax>40℃,coma,persistentlytwitch,mighthavefailureofrespiratory,mighthavesequelaeFulminatetypeTmax>40℃

highfever,deepcoma,intractableseizure,centrallyrespiratoryfailureduringveryshortperiod,severesequelaeforsurvivals362023/3/28TypeTemperature（℃）LevelofconsciousnessseizureMeningealIrritation/PathologicalreflexRespiratoryfailureNeuropsychiatricsequelaeLight38-39arousenolightnonoMild39-40lethargy/delirium/obtundationoccasionallyobviousnonoSevere

40Studor/comafrequent/persistentobviousmightmightFulminate

40DeepcomaintractableobviousrapidoftenClinicalManifestation372023/3/28ClinicalManifestation:SevereAcuteencephalitisHeadache,highfever,stiffneck,stuporMayprogresstoparalysis,seizures,convulsions,coma,anddeathNeuropsychiatricsequelae45to70%ofsurvivorsInuteroinfectionpossibleAbortionoffetus382023/3/28PostMortemLesionsPan-encephalitisInfectedneuronsthroughoutCNSOccasionalmicroscopicnecroticfociThalamusgenerallyseverelyaffected392023/3/28Singh,AJNR2001;22:1131MagneticResonanceAbnormalitiesinSevereJEKalita,AJNR2000;21:1978SubstantianigrainvolvementBilateralasymmetricthalamichyperintensity

402023/3/28ChineseMedicalJournal1997;60:10514daysafteronset.ThalamicandbasalgangliainvolvementBasalGangliaThalamiMidbraininvolvement220dayspostonset.Hyperintenselesionsatglobuspallidusbilaterally412023/3/28MRIinFlaviviralEncephalitisSolomon,NEJM2004T2-WeightedImagesshowingThalamicenhancementandswellingin:(A)Japaneseencephalitis(B)WestNileEncephalitis(C)MurrayValleyEncephalitisJapaneseencephalitisWestNileencephalitisMurrayValleyencephalitis422023/3/28SummaryonClinicalManifestationSpecialseasonalonset,endemicareaHistoryofmosquitoexposureinanendemicareaAbsentorpartialvaccinationquickonset,headache,highfever,variableCNSsymtomsincluding:neckstiffness,stupor,disorientation,coma,tremors,occasionalconvulsions(especiallyininfants)andspastic(butrarelyflaccid)paralysis432023/3/28DiagnosisHistoryofmosquitoexposureinanendemicarea.ClinicaldiagnosisisunreliableIgMcaptureEIAthemostwidelyusedmethodCSForserumpositivein75%ofpatientswithin4daysofsymptomonset,nearly100%within7daysBothserumandCSFshouldbetestedtomaximizesensitivity442023/3/28DiagnosisLaboratoryconfirmationrequiredSuspectedcaseAntibodytiter:HI,IFA,CF,ELISAJE-specificIgMinserumorCSFDefinitivecaseVirusisolation:CSF,brain452023/3/28DiagnosisCaseDefinition-

SuspectedcaseAcuteonsetoffever(≤7days)changeinmentalstatusWith/withoutNewonsetofseizures(excludingfebrileseizures)(Otherearlyclinicalfindings-mayincludeirritability,

somnolenceorabnormalbehaviorgreaterthanthatseenwithusualfebrileillness)CaseClassificationLaboratory-ConfirmedcaseSuspectedcasewithanyoneofthefollowingmarkers:PresenceofIgMantibodyinserumand/orCSFFourfolddifferenceinIgGantibodytiterinpairedseraVirusisolationfrombraintissueAntigendetectionbyimmunofluroscenceNucleicaciddetectionbyPCRInthesentinelsurveillancenetworkJEwillbediagnosedbyIgMCaptureELISA,andvirusisolationcanbedoneinNationalReferencelaboratory462023/3/28DiagnosisProbableCasesSuspectedcaseinclosegeographicandtemporalrelationshiptoalaboratory-confirmedcaseofJEinanoutbreakAcuteEncephalitisSyndromeduetootheragentAsuspectedcaseinwhichdiagnostictestingisperformedandanetiological

agentotherthanJEisidentifiedAcuteEncephalitisSyndromeduetounknownagentAsuspectedcaseinwhichnodiagnostictestingisperformed/noetiologicalagentwasidentified/testresultswereindeterminate472023/3/28LaboratoryWorkupCompletebloodcounts:Earlystage:WBCPMNdominantPeripheralbloodsmear-MalarialparasiteBloodglucoseCSFandBloodforserologybyIgMELISA/virusisolation,CSFispreferredsincebythetimepatientpresentswithCNSmanifestationsthelevelofviremiainbloodhasdecreasedandthereiscrossreactionwithotherflaviviruses482023/3/28DifferentialDiagnosisNoninfectiousconditions:CNSlupuserythematosusCNStumors(nonmetastatic)CerebrovasculardiseasesBacterialinfectionsPyogenicfocalbrainabscessTuberculousmeningitisMycoplasmameningitisShigellosisTyphoidfeverTuberculosisRockyMountainspottedfever492023/3/28DifferentialDiagnosisViralinfectionsArboviraldiseases(WestNilevirus,MurrayValleyencephalitis)NipahvirusinfectionCaliforniaencephalitisEnterovirusinfectionHerpessimplexDenguefever502023/3/28TreatmentNoknowntreatmentotherthanaggressivesymptommanagementManagementofJEisessentiallysymptomaticRefertheseveretohealthfacilityAirwayandBreathing,ventilationifnecessaryConvulsionCirculationTemperaturecontroliscritical,<38℃512023/3/28PrognosisOnly1per250Japaneseencephalitisvirus(JEV)infectionsresultsinsymptomaticdiseaseTwofactorsforagoodprognosishighconcentrationsofneutralizingAbsinCSFhighlevelsofJEVIgGintheCSF522023/3/28PrognosisPoorprognosticfactorsAgeyoungerthan10yearsLowGlasgowcomascaleHyponatremiaShockPresenceofimmunecomplexesinCSFPresenceofincreasedamountsofantineurofilamentantibodiesIncreasedlevelsoftumornecrosisfactorCoexistingneurocysticercosisRespiratorydysfunctionBabinsky’ssignFrequentorprolongedseizuresProlongedfeverAlbuminuriaHighviralreplicationinthebrain532023/3/28NeuropsychiatricSequelaeOccurin45-70%ofsurvivors,particularlysevereinchildrenParkinsonismSeizuresParalysisMentalretardationPsychiatricdisordersLucknow,NorthernIndia.WashingtonPost542023/3/28VaccinesforJEvirusTwovaccinesaremanufacturedanddistributedinChinaInactivatedvaccinegrowninprimaryhamsterkidneycellsLiveattenuatedvaccine(SA14-14-2)growninhamsterkidneycellsThethirdismanufacturedinJapananddistributedabroadbyarrangementwithSanofi-PasteurLicensedasJE-VAXRandistheonlyFDAapprovedvaccineforuseintheU.S.Hasbeeninwideuseworldwidesincethe1960’sThreesubcutaneousinjectionsoveramonthwithaboosterat3years91%efficacyinalargefieldtrialinThailand552023/3/28SafetyofCurrentJEVaccineSideeffects“Generallyinconsequential.”Localtendernessormildsystemicsymptomsin10-30%-Field’svirologyNoneurologiceventsinJapanesesurveillanceInfrequentallergicreacti