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 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.
Qi
Li
L
Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 208921, USA.
Kash
John C
JC
Dugan
Vivien G
VG
Wang
Ruixue
R
Jin
Guozhong
G
Cunningham
Robert E
RE
Taubenberger
Jeffery K
JK
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
D019267:Hemagglutinin Glycoproteins, Influenza Virus; C483468:hemagglutinin, human influenza A virus; D019158:N-Acetylneuraminic Acid