Influenza viruses with receptor-binding neuraminidases
Hooper, Kathryn Ann
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University of Washington Abstract Influenza viruses with receptor-binding neuraminidases Kathryn A. Hooper Chair of the Supervisory Committee: Assistant Member Jesse D. Bloom Division of Basic Sciences and Computational Biology, Fred Hutchinson Cancer Research Center For the vast majority of influenza viruses characterized to date, the two main surface proteins have opposing and mutually exclusive functions. Hemagglutinin (HA) is the viral entry protein, mediating attachment of the virus to the host cell via sialic acid-receptors and fusion of the viral and endosomal membranes. In contrast, neuraminidase (NA) is the viral exit protein, and is a sialidase that cleaves receptors from the surface of the producing cell to facilitate viral release. In the last few years, a growing body of evidence has shown that the receptor binding and receptor cleaving activities need not be mutually exclusive, and that single amino-acid mutations can allow NA to act as the receptor-binding protein. These mutations are D151G in N2 subtype NAs and G147R in N1 subtype NAs. Here I describe the characterization of the G147R N1 NA mutation in Chapter II which was serendipitously discovered as a tissue-culture adaptation mutation. In Chapter III, I examine the effect of the G147R mutation in the background of naturally circulating viruses from three different viral lineages. I find that the receptor-binding NA mutation has no effect on the fitness of a pandemic human H1N1 virus in cell culture or in a mouse model of pathogenesis. The presence of the receptor-binding NA also does not affect sensitivity of the virus to neutralization by an anti-HA IgG, although it does slightly protect against neutralization by the Fab domain of the antibody. The physiological relevance of escape from anti-HA Fab, however, remains unclear. Overall, the identification of NA receptor-binding mutations represents a new aspect of influenza virus biology which warrants further investigation. The first NA-binding mutation was discovered when viruses failed to behave as expected in traditional hemagglutination inhibition assays. The acquisition of this D151G mutation by many recent H3N2 strains has remained a problem for the determination of vaccine efficacy in anti-sera hemagglutination inhibition assays. My work extended the finding that receptor-binding mutations can occur in N2 subtype NAs to the N1 subtype, as well. This suggests that the overall spectrum of NA-binding mutations may be much greater than is currently understood. Furthermore, because the N1 binding mutation does not significantly compromise the fitness of a recent human virus, my work also suggests that NA-binding mutations may have the potential to become more widespread in the future.