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FORIMMEDIATERELEASE March13,2017 Pre-existingimmunitytodenguevirusshapesZika-specificTcellresponse StudyemphasizestheimportanceofTcellstoprotectagainstZika;theneedfor broadlyprotectivevaccine LAJOLLA,CA—AlthoughZikaanddengueareconsidereddifferentvirus“species,”theyare socloselyrelatedthattheimmunesystemtreatsZikajustlikeanotherversionofdengue, reportresearchersatLaJollaInstituteforAllergyandImmunology.Theirlateststudy, publishedintheMarch13,2017,advanceonlineeditionofNatureMicrobiology,showsthat pre-existingimmunitytodenguevirusmodulatesthemagnitudeandbreadthofthe immunesystem’sTcellresponsetoZika. Caption:Zikaand dengue overlap in many regionsofthe world.Image: Courtesy of La Jolla Institute for Allergy and Immunology “Essentially,whatwefoundisthatinthecontextofpriordengueinfections,subsequent Zikainfectionselicitanimmuneresponseverysimilartoinfectionswithanothertypeof denguevirus,”AssociateProfessorSujanShresta,Ph.D.,thestudy’sleadauthor. “Weshowforthefirsttimeahighdegreeofcross-reactivityattheTcelllevel.”Their findingshaveimportantimplicationsforZikavaccinedevelopmentandalsosuggestthat humangeneticdifferencesthatinfluenceTcellresponsesmightimpacthowpeoplereactto Zikainfection. Whileinrecentdecadesdenguehadbeensteadilyexpandingaroundtheglobe,Zikahad remainedrelativelyunknownuntilthe2015/2016outbreakscatapultedthevirusintothe public’sconsciousness.ThevastmajorityofpeopleinfectedwithZikanevershowanyor onlymildsymptoms,buttheviruscancausedevastatingdevelopmentaldisordersand braindefectsinunbornbabies.IthasalsobeenlinkedtoGuillain-BarreSyndromeinadults, adisorderinwhichtheimmunesystemattackspartoftheperipheralnervoussystem causingmuscleweakness,pain,balanceissuesandevenparalysis. “Itmayhavedisappearedfromtheheadlines,butZikaisheretostay,”saysShresta.“Before withdengueweonlyhadtoworryaboutvirus-carryingmosquitos,butthechallengewith Zikaisthatitcanbetransmittedsexuallyandthereforecantravelanywhere.Plus80 percentofinfectedpeopleareasymptomaticandtheviruscanpersistinsemenformany months.WehavetolearnhowtolivewithZikaandco-circulationofbothdengueandZika inmanycountries.” Indeed,forcluesonhowtotameZika,Shrestaandherteamlookedtodenguevirus.In mostcases,infectionwithdengueviruscausesamild,flu-likeillness,butforreasonsnot yetfullyunderstood,inasmallnumberofcases,thediseaseturnsintothelife-threatening denguehemorrhagicfever,characterizedbybleedinganddangerouslylowbloodpressure, whichcansendthevictimintoshock. Denguecomesinfourflavorsorserotypesandinfectionwithoneserotypedoesnotleadto lifelongimmunitytotheotherthree.Infact,themainriskfactorforseverediseaseisa secondaryinfectionwithadifferentserotype.Theculpritisthoughttobe"antibody- dependentenhancement"orADEforshort:antibodiesdevelopedagainstoneserotypethat areunabletopreventinfectionwithanotherserotype,butinsteadexacerbatethesecond infectionbyhelpingthevirusslipintoimmunecells. Sincerecentstudieshadshownthatantibodiesisolatedfromdengue-infecteddonorcould havebothpotentneutralizingactivitiesagainstanotherserotypeandinduceADE,Shresta exploredwhethersimilarcross-reactivityexistsontheTcelllevel.“AsZikaanddengueco- circulateinmanyregionsoftheworld,itiscriticaltostartexploringtheprotectiveversus potentiallypathogenicinfluenceofTcellsinducedbypriordengueexposureonZika infection,”shesays. Fortheirstudy,postdoctoralresearcherandfirstauthorJinshengWen,Ph.D.,analyzed theCD8+TcellresponsetoZikavirusinmicethathadbeeneitherpre-exposedto dengueorhadseenneithervirusbefore.CD8+orkillerTcellsrecognizedvirus fragmentsor“epitopes”,thataredisplayedonthesurfaceofinfectedcellstosignalthe immunesystemthatthecellisinfectedandneedstobedestroyed. WenfoundthatpriorinfectionwithdengueshapedthesubsequentCD8+Tcellresponseto Zika.Thepoolofcross-reactivememoryCD8+Tcells—Tcellsthatwereabletorecognize bothdengueandZikaepitopes—expandedattheexpenseofTcellsthatonlyrecognized Zikaepitopes.Incontrast,theanti-ZikaCD8+responseinnaïveanimalswasbroad, includingamixofZika-specificanddengue/Zikacross-reactiveCD8+Tcells.“The implicationisthatinpeoplewithpriordengueinfectionstheTcellresponsetoZikawillbe different,”explainsShresta. ImmunizationwithZika-specificorZika/denguecross-reactivepeptidesprotectedmice againstsubsequentinfectionwithZika.Furtherexperimentsrevealedthattheprotection wasdependentonTcells.“Thissuggeststhatvaccinedevelopmentshouldfocusoneliciting astrongTcellresponseandnotjustastrongantibodyresponse,”saysShresta. TheworkwasfundedinpartbytheNationalInstitutesofHealth(AI116813)andtheLa JollaInstituteforAllergyandImmunology. Fullcitation: JinshengWen,WilliamWeihaoTang,NicholasSheets,JuliaEllison,AlessandroSette, KennethKim,andSujanShresta.IdentificationofZikaVirusEpitopesReveals ImmunodominantandProtectiveRolesforDengueCross-ReactiveCD8+TcellsinHLA transgenicmice.NatureMicrobiology,2017.Doi:10.1038/NMICROBIOL.2017.36 AboutLaJollaInstitute LaJollaInstituteforAllergyandImmunologyisdedicatedtounderstandingtheintricacies andpoweroftheimmunesystemsothatwemayapplythatknowledgetopromotehuman healthandpreventawiderangeofdiseases.Sinceitsfoundingin1988asanindependent, nonprofitresearchorganization,theInstitutehasmadenumerousadvancesleading towardsitsgoal:lifewithoutdisease®.
