BCellsandAntibodyPlayCriticalRolesintheImmediateDe想J0022-538X/03/$08.00OURNALOFVIROLOGY0,Feb.DOI:2021,p.2578–2586Vol.77,No.4Copyright2021,AmericanSociety10.1128/JVI.77.4.2578–2586.2021forMicrobiology.AllRightsReserved.BCellsDisseminatedandAntibodyInfectionPlayCriticalbyWestRolesNileintheEncephalitisImmediateVirusDefenseofMichaelS.Diamond,*BimmiShrestha,AnanthaMarri,DarbyMahan,andMichaelEngleDepartmentsWashingtonofMedicine,UniversityMolecularSchoolMicrobiology,ofMedicine,andSt.PathologyLouis,MissouriandImmunology,Received12September2021/Accepted20November2021immunocompromisedWestNilevirus(WNV)limitsorelderly.causessevereInthiscentralstudy,nervousweaddressedsystemthe(CNS)mechanisminfectionbyprimarilywhichtheinhumanswhoareaextraneuronallylow-passagedisseminationWNVofisolateWNVfrominfectionthebyrecentinfectingepidemicwild-typeinNewandYorkimmunodecientstate.inbredC57BL/6Jimmunemicesystemwithspreadintothespinalinthecorddrainingandthelymphbrainnodesandspleenduringtherst4daysWild-typeofinfection.miceSubsequently,replicatedvirusvirusinfectionBcellsandantibody(MTmice)developedatvirtuallyincreasedthesameCNStime.viralCongenicburdensmiceandthatwerewerevulnerablegeneticallydecientasantibodyearlyasat4lowdaysdosesafterofvirus.Notably,a500-folddifferenceinserumviralloadwasdetectedinMTtolethalmicewild-typeweredetectedininfection,wild-typeamice.pointPassiveintheinfectiontransferofwhenheat-inactivatedlowlevelsofserumneutralizingfrominfectedimmunoglobulinandimmuneMplayacriticalmiceearlyprotectedroleinMTthemicedefenseagainstagainstmorbiditydisseminatedandmortality.infectionWebyconcludeWNV.thatantibodiesandBcellsWestNilevirus(WNV),asingle-strandedpositive-polarityantibodies(MAbs)limitstheencephalitiscausedbysomea-RNAvirus,istheetiologicagentofWestNileencephalitis.viviruses(SaintLouisencephalitis[32,38],Japaneseenceph-WNVismaintainedinanaturalcyclebetweenmosquitoesandalitis[25],andyellowfever[7,40,41]viruses)andnonavivi-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,nospecictherapyorvaccinehasantibodiesmaylimitviralinfectionthroughdifferentmecha-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,...