Identification of Amino Acids in HA and PB2 Critical for the Transmission of H5N1 Avian Influenza Vi.docx
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Identification of Amino Acids in HA and PB2 Critical for the Transmission of H5N1 Avian Influenza Vi.docx
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IdentificationofAminoAcidsinHAandPB2CriticalfortheTransmissionofH5N1AvianInfluenzaVi
IdentificationofAminoAcidsinHAandPB2CriticalfortheTransmissionofH5N1AvianInfluenzaVirusesinaMammalianHost
H5N1influenzaviruseshavecausedover400humaninfectionsin15countriesandcontinuetocirculateinpoultryandwildbirds.Mosthumaninfectionsresultedfromdirectcontactwithvirus-contaminatedpoultryorpoultryproducts.ItwouldbedisastrousifH5N1virusesacquiredtheabilitytoefficientlytransmitamonghumans,becausethemortalityratemayexceed60%.However,thegeneticbasisfortransmissionofH5N1influenzavirusesislargelyunknown.Here,wedemonstratethattheaminoacidresidueat701ofPB2isaprerequisitefortransmissionofH5N1virusesinamammalianguineapigmodel.Interestingly,wefoundthattheabsenceofglycosylationatresidues158–160oftheHAgeneispivotalfortheH5N1virustobindtohuman-likereceptorsandtotransmitinamammalhost.ThesefindingsareimportantforassessingthepandemicpotentialofH5N1fieldisolates.
YuweiGao1,2,YingZhang1,KyokoShinya3,GuohuaDeng1,YongpingJiang1,ZejunLi1,YuntaoGuan1,GuobinTian1,YanbingLi1,JianzhongShi1,LilingLiu1,XianyingZeng1,ZhigaoBu1,XianzhuXia2,YoshihiroKawaoka3,4,5*,HualanChen1*
1AnimalInfluenzaLaboratoryoftheMinistryofAgricultureandNationalKeyLaboratoryofVeterinaryBiotechnology,HarbinVeterinaryResearchInstitute,ChineseAcademyofAgriculturalSciences,Harbin,People'sRepublicofChina,2The11thInstitute,AcademyofMilitaryMedicalSciences,Changchun,People'sRepublicofChina,3TheInternationalCenterforMedicalResearchandTreatment,KobeUniversity,Kobe,Japan,4DivisionofVirology,DepartmentofMicrobiologyandImmunology;InternationalResearchCenterforInfectiousDiseases,InstituteofMedicalScience,UniversityofTokyo,Tokyo,Japan,5DepartmentofPathobiologicalSciences,UniversityofWisconsin-Madison,Madison,Wisconsin,UnitedStatesofAmerica
Abstract
Since2003,H5N1influenzaviruseshavecausedover400knowncasesofhumaninfectionwithamortalityrategreaterthan60%.Mostofthesecasesresultedfromdirectcontactwithvirus-contaminatedpoultryorpoultryproducts.Althoughonlylimitedhuman-to-humantransmissionhasbeenreportedtodate,itisfearedthatefficienthuman-to-humantransmissionofH5N1viruseshasthepotentialtocauseapandemicofdisastrousproportions.ThegeneticbasisforH5N1viraltransmissionamonghumansislargelyunknown.Inthisstudy,weusedguineapigsasamammalianmodeltostudythetransmissionofsixdifferentH5N1avianinfluenzaviruses.Wefoundthattwoviruses,A/duck/Guangxi/35/2001(DKGX/35)andA/bar-headedgoose/Qinghai/3/2005(BHGQH/05),weretransmittedfrominoculatedanimalstonaïvecontactanimals.Ourmutagenesisanalysisrevealedthattheaminoacidasparagine(Asn)atposition701inthePB2proteinwasaprerequisiteforDKGX/35transmissioninguineapigs.Inaddition,anaminoacidchangeinthehemagglutinin(HA)protein(Thr160Ala),resultinginthelossofglycosylationat158–160,wasresponsibleforHAbindingtosialylatedglycansandwascriticalforH5N1virustransmissioninguineapigs.TheseaminoacidschangesinPB2andHAcouldserveasimportantmolecularmarkersforassessingthepandemicpotentialofH5N1fieldisolates.
AuthorSummary
H5N1influenzaviruseshavecausedover400humaninfectionsin15countriesandcontinuetocirculateinpoultryandwildbirds.Mosthumaninfectionsresultedfromdirectcontactwithvirus-contaminatedpoultryorpoultryproducts.ItwouldbedisastrousifH5N1virusesacquiredtheabilitytoefficientlytransmitamonghumans,becausethemortalityratemayexceed60%.However,thegeneticbasisfortransmissionofH5N1influenzavirusesislargelyunknown.Here,wedemonstratethattheaminoacidresidueat701ofPB2isaprerequisitefortransmissionofH5N1virusesinamammalianguineapigmodel.Interestingly,wefoundthattheabsenceofglycosylationatresidues158–160oftheHAgeneispivotalfortheH5N1virustobindtohuman-likereceptorsandtotransmitinamammalhost.ThesefindingsareimportantforassessingthepandemicpotentialofH5N1fieldisolates.
Citation:
GaoY,ZhangY,ShinyaK,DengG,JiangY,etal.(2009)IdentificationofAminoAcidsinHAandPB2CriticalfortheTransmissionofH5N1AvianInfluenzaVirusesinaMammalianHost.PLoSPathog5(12):
e1000709.doi:
10.1371/journal.ppat.1000709
Editor:
BarbaraSherry,NorthCarolinaStateUniversity,UnitedStatesofAmerica
Received:
August26,2009;Accepted:
November24,2009;Published:
December24,2009
Copyright:
©2009Gaoetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.
Funding:
ThisworkwassupportedbyChineseNationalNaturalScienceFoundation30825032,theChineseNationalKeyBasicResearchProgram(973)2010CB534000,2005CB523005and2005CB523200,bygrantsfromtheChineseNationalS&TPlan2006BAD06A05and2006BAD06A04,byacontractresearchfundfromtheMinistryofEducation,Culture,Sports,ScienceandTechnology,Japan,forProgramofFoundingResearchCentersforEmergingandReemergingInfectiousDiseasesand,inpart,byGrants-in-AidforSpeciallyPromotedResearchandforScientificResearch,byERATO(JapanScienceandTechnologyAgency),andbyNationalInstituteofAllergyandInfectiousDiseasesPublicHealthServiceresearchgrants,USA.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,orpreparationofthemanuscript.
Competinginterests:
Theauthorshavedeclaredthatnocompetinginterestsexist.
*E-mail:
kawaokay@svm.vetmed.wisc.edu(YK);hlchen1@(HC)
Introduction
TheH5N1avianinfluenzaviruses(AIVs)haveattractedextensiveattentionfortheirdeadlyimpactonbothanimalsandhumans.ThenumberofpeoplewhohavebeensubclinicallyinfectedwithH5N1virusesisverylimited[1],andH5N1AIVshavea60%fatalityrateinhumans(WorldHealthOrganization[WHO];http:
//www.who.int).H5N1AIVsfirstsurfacedinChinain1996[2],withchicken-lethalandavirulentstrainsbeingisolatedfromgeeseinGuangdongprovince[3].In1997,areassortantH5N1AIVthatcarriedtheHAgenefromanA/goose/Guangdong/1/96-likeviruscausedanoutbreakofdiseaseinpoultryinHongKongandcrossedoverintohumans,resultingin18casesofinfectionwithsixdeaths[4],[5].In2003and2004,H5N1AIVsinfectedpoultryandhumansinnumerouscountriesofsoutheasternAsia[6].In2005,severalgenotypesofH5N1AIVcausedoutbreaksinwildmigratorybirdsatQinghaiLakeinwesternChina,andonegenotypespreadwidelytodifferentspeciesacrossawidegeographicareathatincludedEuropeandAfrica[7].Todate,H5N1AIVshavecauseddiseaseinmorethan60countries(OfficeInternationaldesEpizooties[OIE];http:
//www.oie.int),withcasesofhumaninfectionbeingreportedin15countries(WorldHealthOrganization[WHO];http:
//www.who.int).Despitesubstantialeffortstocontroltheseoutbreaks,H5N1AIVshavecontinuedtoevolveandspread,perpetuatingthefearofaninfluenzapandemicifthesevirusesacquiretheabilitytotransmitefficientlyamonghumans.UnderstandingthegeneticdeterminantsthatcontrolH5N1AIVtransmissioninmammalianhostswillhelpprotectpublichealth.
Thetransmissibilityofinfluenzavirusesisdeterminedbythevirus,environmentalfactors,andhostfactors[8]–[11].Theviraltraitsgoverningtransmissionefficiencyhavenotbeenwellcharacterized.TheaffinityoftheviralHAproteinforsialicacidα-2,6linkedglycan(α-2,6glycan)isnecessaryfortransmissionofthe1918H1N1influenzavirusbetweenferrets[9].Theviralpolymerasecomplexisalsoinvolvedindeterminingviralhostrange,replicationandpathogenicity[12]–[15]andplaysaroleintransmission[16],[17].Coldanddryenvironmentalconditionsfavorthetransmissionofhumaninfluenzavirusinguineapigs[10],[11].
Hostfactorsalsoaffectreplicationandtransmissionofinfluenzaviruses.Underexperimentalconditions,AIVsdonotreplicateefficientlyinhumans[18],andhumanvirusesdonotreplicateefficientlyinducks[19].Inonestudy,thehumanupperairwaytractwasreportedtocontaincellsthatpredominantlyexpressα-2,6glycan[20],anenvironmentthatfavorsthereplicationandtransmissionofhumaninfluenzaviruses,whichpreferentiallybindtoα-2,6glycans.However,inanotherstudy,viruseswithpreferentialbindingtoα-2,3glycanswerereportedtobindtocellsinthehumanupperrespiratorytract[21].Thefirsthumanisolatesinthe1957and1968pandemicspreferentiallyboundtoα-2,6glycanseventhoughtheirHAswerederivedfromavianviruses,whichpreferentiallyrecognizeα-2,3glycans[22].ThesefindingssuggestthatforviruseswithHAsfromAIVstobeefficientlytransmittedamonghumans,theyneedtopreferentiallybindtoα-2,6glycans[23].
FerretsandguineapigshavebeensuccessfullyusedasmodelstoevaluatethetransmissibilityofAIVsandotherspeciesofinfluenzavirusesinmammalianhosts[8],[9],[11],[16],[17],[24]–[30].H5N1AIVsexhibitvaryinglevelsofreplicationandvirulenceinmammalianmouseandferretmodels[2],[13],[31].Inthisstudy,weusedguineapigsasamammalianmodeltoexaminethereplicationandtransmissionofsixH5N1AIVsthatexhibitdifferentreplicationandvirulencephenotypesinmice.WealsoexploredthegeneticrequirementsforH5N1AIVtransmissioninthismammalianhost.
Results
ReplicationofH
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