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J. Virol. doi:10.1128/JVI.00769-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

N-Linked glycosylation attenuates H3N2 influenza viruses

St. Jude Children's Research Hospital, Department of Infectious Diseases and Animal Resources Center, Memphis, Tennessee 38105, University of California San Francisco, Department of Pediatrics and Cardiovascular Research Institute, San Francisco, California 94043

^* To whom correspondence should be addressed. Email: jon.mccullers{at}stjude.org.

	Abstract

Over the last 4 decades H3N2 subtype influenza A viruses have gradually acquired additional potential sites for glycosylation within the globular head of the hemagglutinin (HA) protein. Here we have examined the biological effect of additional glycosylation on the virulence of H3N2 influenza viruses. We created otherwise isogenic reassortant viruses by site-directed mutagenesis that contain additional potential sites for glycosylation and examined the effect on virulence in naïve Balb/c, C57Bl/6, and surfactant protein-D (SP-D) deficient mice. The introduction of additional sites was consistent with the sequence of acquisition in the globular head over the past 39 years beginning with 2 sites in 1968 to the 7 sites found in contemporary influenza viruses circulating in 2000. Decreased morbidity and mortality, as well as lower viral lung titers, were seen in mice as the level of potential glycosylation of the viruses increased. This correlated with decreased evidence of viral mediated lung damage and increased in vitro inhibition of hemagglutination by surfactant protein-D (SP-D). SP-D deficient animals displayed an inverse pattern of disease, such that more highly glycosylated viruses elicited disease equivalent to or exceeding the wildtype. We conclude from these data that increased glycosylation of influenza viruses results in decreased virulence, which is at least partly mediated by SP-D induced clearance from the lung. The continued exploration of interactions between highly glycosylated viruses and surfactant proteins may lead to an improved understanding of the biology within the lung and strategies for viral control.

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