Mutations in H5N1 Influenza Virus Hemagglutinin that Confer Binding to Human Tracheal Airway Epithelium 英文参考文献.docVIP

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Mutations in H5N1 Influenza Virus Hemagglutinin that Confer Binding to Human Tracheal Airway Epithelium 英文参考文献.doc

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Mutations in H5N1 Influenza Virus Hemagglutinin that Confer Binding to Human Tracheal Airway Epithelium 英文参考文献

MutationsinH5N1InfluenzaVirusHemagglutininthat ConferBindingtoHumanTrachealAirwayEpithelium GuadalupeAyora-Talavera1.,HollyShelton1.,MargaretA.Scull2,JunyuanRen3,IanM.Jones3, RaymondJ.Pickles2,WendyS.Barclay1* 1DepartmentofVirology,ImperialCollegeLondon,London,UnitedKingdom,2CysticFibrosis/PulmonaryResearchandTreatmentCenter,DepartmentofMicrobiology andImmunology,UniversityofNorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica,3SchoolofBiologicalSciences,UniversityofReading, Whiteknights,Reading,UnitedKingdom Abstract Theemergencein2009ofaswine-originH1N1influenzavirusasthefirstpandemicofthe21stCenturyisatimelyreminder of the international public health impact of influenza viruses, even those associated with mild disease. The widespread distributionofhighlypathogenicH5N1influenzavirusintheavianpopulationhasspawnedconcernthatitmaygiveriseto ahumaninfluenzapandemic.ThemortalityrateassociatedwithoccasionalhumaninfectionbyH5N1virusapproximates 60%,suggestingthatanH5N1pandemicwouldbedevastatingtoglobalhealthandeconomy.Todate,theH5N1virushas notacquiredthepropensitytotransmitefficientlybetweenhumans.Thereasonsbehindthisareunclear,especiallygiven thehighmutationrateassociatedwithinfluenzavirusreplication.HereweusedapanelofrecombinantH5hemagglutinin (HA)variantstodemonstratethepotentialforH5HAtobindhumanairwayepithelium,thepredominanttargettissuefor influenza virus infection and spread. While parental H5 HA exhibited limited binding to human tracheal epithelium, introductionofselectedmutationsconvertedthebindingprofiletothatofacurrenthumaninfluenzastrainHA.Strikingly, these amino-acid changes required multiple simultaneous mutations in the genomes of naturally occurring H5 isolates. Moreover,H5HAsbearingintermediatesequencesfailedtobindairwaytissuesandlikelyrepresentmutationsthatarean evolutionary ‘‘dead end.’’ We conclude that, although genetic changes that adapt H5 to human airways can be demonstrated, they may not readily arise during natural virus