Avian influenza A virus mutations

Research Project: Avian Influenza A Virus Mutations

Avian influenza A virus mutations as signatures of human infection

PU research team:
Dr Mohammad Asif Khan (Principal Investigator), Dr Thomas J August (Adjunct Faculty, Johns Hopkins), Tan Swan (Research Assistant), and Hadia Syahirah (Research Assistant).

Project summary:
A compelling question in the search for a control of avian influenza virus infection is the identity of the amino acid sequences that facilitate infection of humans. H7N9 is a recent example of a subtype that has infected birds and poultry for decades with global distribution, but only this year evolved to infects humans. The possibility that H7N9 or another influenza virus may mutate to more readily infect humans or, even worse, achieve human-to-human transmission, underscores the need for greater understanding of how avian strains adapt to human infection. Several previous studies have described mutations observed in human influenza A. However, a comprehensive evaluation of human host tropism of the virus is lacking and the current experimental data do not reliably predict the potential for human infection of a given virus.

We have developed a methodology for comparing viruses from avian and human hosts to identify sequences that are predictive of human infection. The hypothesis was that mutations of avian influenza A viruses that are also present with high incidence in human viruses are likely associated with the ability of viruses to infect humans. This was tested by the quantitative analysis of the nonamer positions, overlapping eight (1-9, 2-10, 3-11, etc), of the entire H7N9 available proteome. The goal was to demonstrate the scope of mutational changes in protein structure, to avoid the possibility of error in the sequencing of any particular viral sample, and to eliminate the complication of nonsense mutations that are not under selective pressure. A total of 13 signature positions distributed at sites of HA, M1, M2, NP, PA, PA-X, PB1, and PB2 were identified, where the human viruses contained mutations of the corresponding avian virus sequences. The data support the conclusion that human influenza viruses result from existing avian virus mutations with chance adaptive fitness in human cells.

This quantitative evaluation of specific amino acid sequences that distinguish viruses with the capability of transmission to humans provides new approaches for the surveillance and possible prevention of viruses with the greatest potential for human infection. We are currently marketing this to potential industry partners for deployment as a surveillance solution for influenza A virus.