想

VOL.77,2003BCELLSANDANTIBODYPROTECTAGAINSTWNVINFECTION2585

detailedexperimentsarerequiredbeforeade nitiveconclu-sioncanbereachedregardingtheprotectiveroleofnaturalantibodiesagainstWNV.

Overall,ourdatasuggesttheimportanceoftheearlyanti-bodyresponseincontainingviremiaandlimitingdisseminatedinfectionofWNVintheCNS.TheseresultsareconsistentwiththoseofearlierstudiesthatshowedthattheabsenceofBandTcells(SCIDmice)butnotthatofTcellsalone(nudemice)intheBALB/cbackgroundincreasedmortalityassociatedwithWNVinfection(22).Nonetheless,itislikelythatotheraspectsoftheinnate(e.g.,interferonandNKcells)andadaptive(Tcells)immunesystemsalsohavecriticalrolesincontrollingWNVinfection.Indeed,preliminaryexperimentsinourlabo-ratorydemonstratedthatgeneticde cienciesofgammainter-feronorCD4 orCD8 TcellscauseincreasedmortalityinC57BL/6mice(M.Engle,B.Shrestha,andM.Diamond,un-publishedobservations).

ItisintriguingthatseverehumanWNVinfection,whichisheavilybiasedtowardanelderlypopulation,occursbecauseofadysfunctionalantibodyresponseagainstWNVearlyduringinfection;manyelderlypeoplehavedecreasedantibodypro-ductionandshorteneddurationsofprotectiveimmunityfol-lowingimmunization(39,51).Pharmacologicalinterventionwithantibodies,suchasimmuneimmunoglobulinorhuman-izedMAbs,mayprovideastrategyformitigatingCNSdiseaseinpatientswithWestNileencephalitis(38;Z.Shimoni,M.J.Niven,S.Pitlick,andS.Bulvik,Letter,Emerg.Infect.Dis.7:759,2001).

ACKNOWLEDGMENTS

andWeexperimentalR.thankBeatty,L.KramerE.Harris,andK.BernardforWNVisolatesandcelllinesandS.Virginadviceand/orS.reagents.Shresta,WeT.Chambers,thankD.Leib,andS.S.Schlesinger,VirginforControlTheworkmedicalandwasforcriticalPreventionsupportedreadingofthemanuscript.

(U50/CCU720545-02),bygrantsfromtheCentersforDiseaseNIH(T32Program,GM07067).

theEdwardMallinckrodt,Jr.,Foundation,thePharmaciaandBio-theREFERENCES

1.Asnis,D.S.,R.Conetta,A.A.Teixeira,G.Waldman,andB.A.Sampson.2000.TheWestNilevirusoutbreakof1999inNewYork:theFlushingHospitalexperience.Clin.Infect.Dis.30:413–418.

2.Bachmann,M.F.,U.Kalinke,A.Althage,G.Freer,C.Burkhart,H.Roost,M.Aguet,H.Hengartner,andR.M.Zinkernagel.1997.Theroleofantibodyconcentrationandavidityinantiviralprotection.Science276:2024–2027.3.Baumgarth,N.,O.C.Herman,G.C.Jager,L.E.Brown,L.A.Herzenberg,andJ.Chen.2000.B-1andB-2cell-derivedimmunoglobulinMantibodiesarenonredundantcomponentsoftheprotectiveresponsetoin uenzavirusinfection.J.Exp.Med.192:271–280.

4.Beasley,D.W.,L.Li,M.T.Suderman,andA.D.Barrett.2002.MouseneuroinvasivephenotypeofWestNilevirusstrainsvariesdependinguponvirusgenotype.Virology296:17–23.

5.Ben-Nathan,D.,I.Huitinga,S.Lustig,N.vanRooijen,andD.Kobiler.1996.WestNilevirusneuroinvasionandencephalitisinducedbymacrophagedepletioninmice.Arch.Virol.141:459–469.

6.Bergmann,C.C.,C.Ramakrishna,M.Kornacki,andS.A.Stohlman.2001.ImpairedTcellimmunityinBcell-de cientmicefollowingviralcentralnervoussysteminfection.J.Immunol.167:1575–1583.

7.Brandriss,M.W.,J.J.Schlesinger,E.E.Walsh,andM.Briselli.1986.Lethal17Dyellowfeverencephalitisinmice.I.Passiveprotectionbymono-clonalantibodiestotheenvelopeproteinsof17Dyellowfeveranddengue2viruses.J.Gen.Virol.67:229–234.

8.Broom,A.K.,M.J.Wallace,J.S.Mackenzie,D.W.Smith,andR.A.Hall.2000.ImmunisationwithgammaglobulintoMurrayValleyencephalitisvirusandwithaninactivatedJapaneseencephalitisvirusvaccineasprophy-laxisagainstAustralianencephalitis:evaluationinamousemodel.J.Med.Virol.61:259–265.

9.Cardosa,M.J.,S.Gordon,S.Hirsch,T.A.Springer,andJ.S.Porter eld.

1986.InteractionofWestNileviruswithprimarymurinemacrophages:roleofcellactivationandreceptorsforantibodyandcomplement.J.Virol.57:952–959.

10.Cardosa,M.J.,J.S.Porter eld,plementreceptormediatesenhanced avivirusreplicationinmacrophages.J.Exp.Med.158:258–263.

11.Casali,antibodiesP.,andandtheA.humanL.Notkins.B-cell1989.repertoire.CD5 Immunol.Blymphocytes,Today10:polyreactive364–368.12.Diamond,M.,T.Roberts,D.Edgil,B.Lu,J.Ernst,andE.Harris.2000.Modulationofdenguevirusinfectioninhumancellsbyalpha,beta,andgammainterferons.J.Virol.74:4957–4966.

13.Diamond,M.S.,D.Edgil,T.G.Roberts,B.Lu,andE.Harris.2000.Infectionofhumancellsbydenguevirusismodulatedbydifferentcelltypesandviralstrains.J.Virol.74:7814–7823.

14.

Ebel,G.D.,A.P.DupuisIII,K.Ngo,D.Nicholas,E.Kauffman,S.A.Jones,D.Young,J.Maffei,P.Y.Shi,K.Bernard,andL.Kramer.2001.PartialgeneticcharacterizationofWestNilevirusstrains,NewYorkState,2000.Emerg.Infect.Dis.7:650–653.

15.

Eldadah,A.H.,andN.Nathanson.1967.PathogenesisofWestNilevirusencephalitisinmiceandrats.II.Virusmultiplication,evolutionofimmuno- uorescence,anddevelopmentofhistologicallesionsinthebrain.Am.J.Epidemiol.86:776–790.

16.Eldadah,A.H.,N.Nathanson,andR.Sarsitis.1967.PathogenesisofWestNilevirusencephalitisinmiceandrats.I.In uenceofageandspeciesonmortalityandinfection.Am.J.Epidemiol.86:765–775.

17.Gollins,S.,andJ.Porter eld.1984.Flavivirusinfectionenhancementinmacrophages:radioactiveandbiologicalstudiesontheeffectofantibodyandviralfate.J.Gen.Virol.65:1261–1272.

18.Gollins,S.,andJ.Porter eld.1986.Theuncoatingandinfectivityofthe avivirusWestNileoninteractionwithcells:effectsofpHandammoniumchloride.J.Gen.Virol.67:1941–1950.

19.Grif n,D.,B.Levine,W.Tyor,S.Ubol,andP.Despres.1997.Theroleofantibodyinrecoveryfromalphavirusencephalitis.Immunol.Rev.159:155–161.

20.Grif n,D.E.,B.Levine,W.R.Tyor,andD.N.Irani.1992.Theimmuneresponseinviralencephalitis.Semin.Immunol.4:111–119.

21.Grif n,D.E.,S.Ubol,P.Despres,T.Kimura,andA.Byrnes.2001.Roleofantibodiesincontrollingalphavirusinfectionofneurons.Curr.Top.Micro-biol.Immunol.260:191–200.

22.

Halevy,M.,Y.Akov,D.Ben-Nathan,D.Kobiler,chmi,andS.Lustig.1994.LossofactiveneuroinvasivenessinattenuatedstrainsofWestNilevirus:pathogenicityinimmunocompetentandSCIDmice.Arch.Virol.137:355–370.

23.Halstead,S.B.,C.N.Venkateshan,M.K.Gentry,rsen.1984.Heterogeneityofinfectionenhancementofdengue2strainsbymonoclonalantibodies.J.Immunol.132:1529–1532.

24.Hubalek,Z.,andJ.Halouzka.1999.WestNilefever—areemergingmos-quito-borneviraldiseaseinEurope.Emerg.Infect.Dis.5:643–650.

25.Kimura-Kuroda,J.,andK.Yasui.1988.ProtectionofmiceagainstJapaneseencephalitisvirusbypassiveadministrationwithmonoclonalantibodies.J.Immunol.141:3606–3610.

26.Kramer,L.D.,andK.A.Bernard.2001.WestNilevirusinfectioninbirdsandmammals.Ann.N.Y.Acad.Sci.951:84–93.

27.

Lanciotti,R.S.,A.J.Kerst,R.S.Nasci,M.S.Godsey,C.J.Mitchell,H.M.Savage,N.Komar,N.A.Panella,B.C.Allen,K.E.Volpe,B.S.Davis,andJ.T.Roehrig.2000.RapiddetectionofWestNilevirusfromhumanclinicalspecimens, eld-collectedmosquitoes,andaviansamplesbyaTaqManre-versetranscriptase-PCRassay.J.Clin.Microbiol.38:4066–4071.

28.

Lanciotti,R.S.,J.T.Roehrig,V.Deubel,J.Smith,M.Parker,K.Steele,B.Crise,K.E.Volpe,M.B.Crabtree,J.H.Scherret,R.A.Hall,J.S.Mac-Kenzie,C.B.Cropp,B.Panigrahy,E.Ostlund,B.Schmitt,M.Malkinson,C.Banet,J.Weissman,N.Komar,H.M.Savage,W.Stone,T.McNamara,andD.J.Gubler.1999.OriginoftheWestNilevirusresponsibleforanoutbreakofencephalitisinthenortheasternUnitedStates.Science286:2333–2337.

29.Levine,B.,J.M.Hardwick,B.D.Trapp,T.O.Crawford,R.C.Bollinger,andD.E.Grif n.1991.Antibody-mediatedclearanceofalphavirusinfectionfromneurons.Science254:856–860.

30.LiconLuna,R.M.,E.Lee,A.Mullbacher,R.V.Blanden,ngman,ckofbothFasligandandperforinprotectsfrom avi-virus-mediatedencephalitisinmice.J.Virol.76:3202–3211.

31.Litwin,J.A.,S.Yokota,T.Hashimoto,andH.D.Fahimi.1984.LightmicroscopicimmunocytochemicaldemonstrationofperoxisomalenzymesinEponsections.Histochemistry81:15–22.

32.

Mathews,J.H.,andJ.T.Roehrig.1984.ElucidationofthetopographyanddeterminationoftheprotectiveepitopesontheEglycoproteinofSaintLouisencephalitisvirusbypassivetransferwithmonoclonalantibodies.J.Immu-nol.132:1533–1537.

33.

Matthews,A.E.,S.R.Weiss,M.J.Shlomchik,L.G.Hannum,J.L.Gombold,andY.Paterson.2001.AntibodyisrequiredforclearanceofinfectiousmurinehepatitisvirusA59fromthecentralnervoussystem,butnottheliver.J.Immunol.167:5254–5263.

Downloaded from at Sun Yat-Sen University on March 1, 2010