Identifying host specificity determinants in Influenza viruses
Mutations in a swine influenza virus allowed it to emerge in humans, leading to the swine flu” pandemic of 2009. But it remains unclear what molecular factors permitted the virus to cross the species barrier and avoid human immune recognition. We used a computational approach to look for amino acid signatures that distinguish the pandemic strain from a typical seasonal human flu strain and from other swine strains. We focused on alterations in the hemagglutinin protein, which allows the virus to bind and enter host cells. Compared with typical seasonal flu viruses, the pandemic strain showed different amino acid residues around sites that the human immune system uses to recognize the virus changes that likely allowed this strain to escape immune recog- nition. Most differences in the sequences of the pandemic strain and normal swine flu viruses were found near receptor-binding sites, suggesting that these mutations may have influenced how well the pandemic virus binds to human cells. We then experimentally altered two amino acids in a swine strain to make it more similar to the pandemic strain. These changes affected binding to red blood cells and made the virus more virulent in mice.We are currently in the process of applying the computational tools that we have developed to other influenza strains, including H5N1.
