B Cells and Antibody Play Critical Roles in the Immediate De

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J0022-538X/03/$08.00OURNALOFVIROLOGY 0,Feb.DOI:2003,p.2578–2586

Vol.77,No.4

Copyright©2003,AmericanSociety10.1128/JVI.77.4.2578–2586.2003

forMicrobiology.AllRightsReserved.

BCellsDisseminatedandAntibodyInfectionPlayCriticalbyWestRolesNileintheEncephalitisImmediateVirus

Defenseof

MichaelS.Diamond,*BimmiShrestha,AnanthaMarri,DarbyMahan,andMichaelEngle

DepartmentsWashingtonofMedicine,UniversityMolecularSchoolMicrobiology,ofMedicine,andSt.PathologyLouis,Missouri

andImmunology,

Received12September2002/Accepted20November2002

immunocompromisedWestNilevirus(WNV)limitsorelderly.causessevereInthiscentralstudy,nervousweaddressedsystemthe(CNS)mechanisminfectionbyprimarilywhichtheinhumanswhoareaextraneuronallylow-passagedisseminationWNVofisolateWNVfrominfectionthebyrecentinfectingepidemicwild-typeinNewandYorkimmunode cientstate.inbredC57BL/6Jimmunemicesystemwithspreadintothespinalinthecorddrainingandthelymphbrainnodesandspleenduringthe rst4daysWild-typeofinfection.miceSubsequently,replicatedvirusvirusinfectionBcellsandantibody( MTmice)developedatvirtuallyincreasedthesameCNStime.viralCongenicburdensmiceandthatwerewerevulnerablegeneticallyde cientasantibodyearlyasat4lowdaysdosesafterofvirus.Notably,a 500-folddifferenceinserumviralloadwasdetectedin MTtolethalmicewild-typeweredetectedininfection,wild-typeamice.pointPassiveintheinfectiontransferofwhenheat-inactivatedlowlevelsofserumneutralizingfrominfectedimmunoglobulinandimmuneMplayacriticalmiceearlyprotectedrole inMTthemicedefenseagainstagainstmorbiditydisseminatedandmortality.infectionWebyconcludeWNV.

thatantibodiesandBcellsWestNilevirus(WNV),asingle-strandedpositive-polarityantibodies(MAbs)limitstheencephalitiscausedbysome a-RNAvirus,istheetiologicagentofWestNileencephalitis.viviruses(SaintLouisencephalitis[32,38],Japaneseenceph-WNVismaintainedinanaturalcyclebetweenmosquitoesandalitis[25],andyellowfever[7,40,41]viruses)andnon avivi-birdsbutalsoinfectshumans,horses,andotheranimals.Itisruses(Sindbis[19–21,44,48],murinehepatitis[6,33,37],andendemicinpartsofAfrica,Europe,theMiddleEast,andAsialymphocyticchoriomeningitis[43]viruses).However,formany(24),andoutbreaksintheUnitedStatesoverthepast3yearsofthesevirusesthemechanismbywhichantibodyattenuatesindicatethatithasestablisheditspresenceintheWesternCNSinfectionhasnotbeenclearlydemonstrated.TheinvitroHemisphere(28).Humansdevelopafebrileillness,withapropertiesofMAbs,includingisotype,avidity,andneutraliza-subsetofcasesprogressingtoameningitisorencephalitistion,donotnecessarilycorrelatewithprotection(2,47),assyndrome(24).Currently,nospeci ctherapyorvaccinehasantibodiesmaylimitviralinfectionthroughdifferentmecha-beenapprovedforhumanuse.

nismsatseveralstagesofpathogenesis.AntibodymaydecreaseThemolecularbasisofWNVinfectioninhumansandotherviralloadintheCNSbylimitinghematogenousspreadthroughanimalsisnotclearlyestablished.Althoughpriorrodentmod-directneutralization,complementactivation,orincreasedviralelsofWNVinfection(5,15,16,22,49,50)haveshownevi-uptakebyphagocyticcells(52).Alternatively,antibodiesmaydenceofviralreplicationinserumandthecentralnervousactdirectlyintheCNSbypreventingreplicationandspreadinsystem(CNS),manyofthemechanisticquestionsaboutpatho-neurons(47).

genesisandtheimmuneresponseremainunanswered.ForTodate,nosystematicinfectionandpathogenesisstudiesexample,aperipheralsiteofreplicationhasnotbeende nedwithWNVhavebeenperformedwithimmunode cientinbredandthemechanismofspreadtotheCNSremainsunclear.mice.Inthisstudy,weestablishedamousemodelofinfectionAdditionally,atargetcellforinfectionintheCNShasnotbeenwithC57BL/6micethatparalleledhumandisease:infectionviade nitivelyidenti ed,andwhethertissueinjuryisrelateddi-asubcutaneousrouteresultedinasubsetofmicedevelopingrectlytoviralinfectionortotheimmuneresponseremainsencephalitis.Infectiousvirusappearedinthelymphnodeandunknown.Finally,althoughsusceptibilitytosevereWNVin-spleenwithinthe rst4daysofinfectionandthenspreadfectioncorrelateswithanimpairedimmunesystem(1,24,46),concomitantlytothespinalcordandbrain.Congenicmicethatthemechanismsbywhichtheinnateandadaptiveimmuneweregeneticallyde cientinBcellsandantibody(strain MT)responseslimitdiseasehavenotbeenestablished.

werevulnerabletolethalinfectionatverylowdosesofvirusExperimentswithrelatedandunrelatedRNAviruseshaveanddevelopedhigherviralloadsinserumandtheCNS.Be-suggestedthatantibodymayhaveanimportantprotectiverolecausepassivetransferofserafrominfectedandimmunemiceagainstWNVinfection.Passiveadministrationofmonoclonal

protected MTmiceagainstmorbidityandmortalityafterinfection,weconcludethatantibodiesandBcellshaveacriticalearlyroleinthedefenseagainstdisseminatedinfectionbyWNV.

cine,*CorrespondingingtonMolecularMicrobiology,author.Mailingaddress:DepartmentsofMedi-MATERIALSANDMETHODS

St.UniversitySchoolOfMedicine,andPathology660S.andEuclidImmunology,Ave.,Wash-Cellsandviruses.BHK-21,Vero,andC6/36Aedesalbopictuscellswerecul-E-mail:Louis,diamond@borcim.wustl.edu.

MO63110.Phone:(314)362-2842.Fax:(314)Box362-9230.8051,turedaspreviouslydescribed(12,13).TheWNVstrain(3000.0259)wasisolated

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