Influenza A viruses exhibit extreme diversity as exemplified by the multiple serotypes of the hemagglutinin (HA, H1-H18) and neuraminidase (NA, N1-N11) surface antigens. To date, only three of the possible 198 combinations found in avian and other animal reservoirs have been associated with human pandemics (H1N1, H2N2, H3N2). However, ever increasing anxiety about the potential for infections by infections of zoonotic origin have heightened concern about emergence of a human transmissible virus that could devastate the human population. The emergence of H5N1, H6N1, H7N7, H7N9, H9N2, and H10N8 viruses in the human population are constant reminders of this possibility. Influenza B viruses with its two distinct lineages further increase the health and economic burden of seasonal influenza worldwide. This proposal seeks to elucidate, at the structural level, key sites of vulnerability on influenza virus that can be utilized to develop therapeutics as well as improved vaccines. Antibody-mediated neutralization of influenza virus is a complex combinatorial problem for the human immune system as it is presented with diverse, highly variable and constantly evolving viruses. While neutralizing antibodies against human flu are traditionally regarded as being strain specific, recent advances have shown that much broader responses can be mounted that give valuable insights into conserved sites of vulnerability. We are therefore amassing compelling evidence that a sustained, cross- serotype response can be mounted against influenza and this vital information can now be harnessed for design of small molecules, peptides, and proteins to target these key sites of vulnerability, thereby blocking influenza infection. No effective drugs are currently available for preventing the entry of influenza virus. Thus, we will elucidate common features for recognition of sites of vulnerability of pandemic and emerging influenza viruses from crystal structures of diverse HAs with broadly neutralizing antibodies and sialosides that are mimics of the natural receptor. A combined biophysical, biochemical, and chemical approach employing state- of-the-art structural biology, glycan arrays, and chemical biology will be used to provide key insights into influenza virus neutralization that enable design of novel therapeutics to control and combat future influenza pandemics and seasonal epidemics.
We will determine sites of vulnerability on influenza virus from structural studies of influenza hemagglutinin in complex with broadly neutralizing antibodies and sialoside receptors. Recurring themes of recognition will provide a platform for design of small molecules, peptides, and small proteins as potential therapeutics to prevent influenza virus infection.
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