Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Annual influenza A virus epidemics are also very significant, resulting in up to 49,000 deaths in the U.S. per year. Pandemic strains of influenza emerge periodically and are thought to be derived ultimately from avian influenza A viruses. The recent 2009 pandemic influenza virus emerged by reassortment of two pre-existing swine influenza virus lineages. The first lineage is the Eurasian avian-like swine lineage that emerged from an avian influenza virus in toto. The second lineage is the triple-reassortant H1N2 swine influenza virus containing gene segments derived from avian, human, and classical swine influenza viruses. The natural reservoir of influenza A viruses is thought to be wild waterfowl. Genetically and antigenically diverse influenza A viruses circulate in wild birds and viral strains from this pool can adapt to new hosts, including humans and domestic animals. Influenza A viruses are also significant pathogens for agriculturally important animals like poultry, swine, and horses. Understanding the mechanisms of host switching are very important for surveillance and pandemic preparedness. Understanding the molecular basis underlying the annual evolution of human influenza will aid in vaccine strain selection. The emergence of new pandemic influenza A viruses requires overcoming barriers to cross-species transmission as viruses move from animal reservoirs into humans. This complicated process is driven by both individual gene mutations and genome reassortments. The viral polymerase complex, composed of the proteins PB1, PB2, and PA, is a major factor controlling host adaptation, and reassortment events involving polymerase gene segments occurred with past pandemic viruses. The ability of polymerase reassortment to restore the activity of an avian influenza virus polymerase that is normally impaired in human cells was investigated in collaboration with Andrew Mehle and Jennifer Doudna at the University of California, Berkeley. These studies showed that the substitution of human-origin PA subunits into an avian influenza virus polymerase alleviates restriction in human cells and increases polymerase activity in vitro. Reassortants with 2009 pandemic H1N1 PA proteins were the most active. Mutational analyses demonstrated that the majority of the enhancing activity in human PA results from a threonine-to-serine change at residue 552. Reassortant viruses with avian polymerases and human PA subunits, or simply the T552S mutation, displayed faster replication kinetics in culture and increased pathogenicity in mice compared to those containing a wholly avian polymerase complex. Thus, the acquisition of a human PA subunit, or the signature T552S mutation, is a potential mechanism to overcome the species-specific restriction of avian polymerases and increase virus replication.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$361,386
Indirect Cost
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State
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Ambroggio, Xavier I; Dommer, Jennifer; Gopalan, Vivek et al. (2013) HASP server: a database and structural visualization platform for comparative models of influenza A hemagglutinin proteins. BMC Bioinformatics 14:197
Mehle, Andrew; Dugan, Vivien G; Taubenberger, Jeffery K et al. (2012) Reassortment and mutation of the avian influenza virus polymerase PA subunit overcome species barriers. J Virol 86:1750-7
Shi, Mang; Jagger, Brett W; Wise, Helen M et al. (2012) Evolutionary conservation of the PA-X open reading frame in segment 3 of influenza A virus. J Virol 86:12411-3
Wang, Ruixue; Schwartzman, Louis M; Memoli, Matthew J et al. (2011) Detection of seasonal H3N2 influenza A virus by type-specific TaqMan minor groove binder probe assay. Diagn Microbiol Infect Dis 70:281-4
Dugan, Vivien G; Dunham, Eleca J; Jin, Guozhong et al. (2011) Phylogenetic analysis of low pathogenicity H5N1 and H7N3 influenza A virus isolates recovered from sentinel, free flying, wild mallards at one study site during 2006. Virology 417:98-105
Taubenberger, Jeffery K; Kash, John C (2010) Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 7:440-51
Kash, John C; Qi, Li; Dugan, Vivien G et al. (2010) Prior infection with classical swine H1N1 influenza viruses is associated with protective immunity to the 2009 pandemic H1N1 virus. Influenza Other Respir Viruses 4:121-7
Wang, Ruixue; Taubenberger, Jeffery K (2010) Methods for molecular surveillance of influenza. Expert Rev Anti Infect Ther 8:517-27
Taubenberger, J K; Morens, D M (2009) Pandemic influenza--including a risk assessment of H5N1. Rev Sci Tech 28:187-202
Morens, David M; Taubenberger, Jeffery K; Fauci, Anthony S (2009) The persistent legacy of the 1918 influenza virus. N Engl J Med 361:225-9

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