Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice

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 alpha 2-3 glycosidic bonds, while human-adapted hemagglutinins bind alpha 2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with alpha 2-6 or mixed alpha 2-6/alpha 2-3 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 alpha 2-6, alpha 2-3, or alpha 2-3/alpha 2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing alpha 2-3 to alpha 2-6 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.