title: Role of sialic acid binding specificity of the 1918 influenza virus hemagglutinin protein in virulence and pathogenesis for mice.
abstract: The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via alpha2-3 glycosidic bonds, while human-adapted hemagglutinins bind alpha2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with alpha2-6 or mixed alpha2-6/alpha2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either alpha2-6, alpha2-3, or alpha2-3/alpha2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing alpha2-3 to alpha2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity.
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208921, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qi
authors.forename: John C
authors.initials: JC
authors.lastname: Kash
authors.forename: Vivien G
authors.initials: VG
authors.lastname: Dugan
authors.forename: Ruixue
authors.initials: R
authors.lastname: Wang
authors.forename: Guozhong
authors.initials: G
authors.lastname: Jin
authors.forename: Robert E
authors.initials: RE
authors.lastname: Cunningham
authors.forename: Jeffery K
authors.initials: JK
authors.lastname: Taubenberger
mesh_terms: D000818:Animals; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000378:metabolism*; D053118:Influenza A Virus, H1N1 Subtype / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000821:virology*; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D014774:Virulence; D053585:Virus Attachment
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus; D019158:N-Acetylneuraminic Acid