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Journal of Virology, April 2009, p. 3754-3761, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02596-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Li Qi,1 John C. Kash,1 Vivien G. Dugan,1 Ruixue Wang,1 Guozhong Jin,1 Robert E. Cunningham,2 and Jeffery K. Taubenberger1*

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,1 Department of Biophysics, Armed Forces Institute of Pathology, Rockville, Maryland 208502

Received 16 December 2008/ Accepted 28 January 2009

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.

* Corresponding author. Mailing address: Laboratory of Infectious Diseases, NIAID, NIH, 33 North Drive, MSC 3203, Bethesda, MD 20892-3203. Phone: (301) 443-5960. Fax: (301) 480-1696. E-mail: taubenbergerj{at}niaid.nih.gov

{triangledown} Published ahead of print on 11 February 2009.

Journal of Virology, April 2009, p. 3754-3761, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02596-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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