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Role of Influenza Polymerase in Host Adaptation

Influenza A viruses are negative-sense, single-stranded, segmented RNA viruses that infect a wide range of hosts, including humans and many avian species. One mechanism for the instigation of a pandemic is direct infection of humans with an avian virus that contains mutations allowing it to easily infect and spread among humans. Before 1997, direct infection of humans with avian influenza viruses was not considered a threat to human health. However, several cases of human infection with highly pathogenic avian H5N1 influenza viruses occurred in 1997 in Hong Kong showing that direct avian-to-human transmission of influenza can occur. Characterization of the isolated H5N1 viruses indicates mutation at polymerase gene plays a major role for human adaptation. We did further analysis to identify mutations in polymerase genes that enhance the polymerase activity of avian viruses in mammalian hosts. We revealed that PB2 residue 271, which is highly conserved among human, but not avian viruses, contribute for enhanced activity in mammalian cells. This study indicates that there are multiple residues in PB2 that can affect the mammalian host adaptation of avian influenza viruses.

The emergence of new pandemic occurred in 2009. The source of the 2009 pandemic was a Mexican swine-origin reassortant virus of the H1N1 subtype (pH1N1). Several reassortment steps led to the emergence of this virus, which possesses HA, NP, and NS genes of the classical swine lineage, NA and M from the Eurasian swine lineage, a human PB1 that was seeded from an avian virus in approximately 1968, and avian PA and PB2 genes. The avian-origin PB2 contains 591R, which is thought to compensate for the lack of 627K, and 271A, which we revealed to the enhanced polymerase activity in mammalian hosts. In addition to PB2 mutations, we found that the pH1N1 PA gene is a major factor for high pH1N1 polymerase activity in mammalian cells. Analysis using site-directed mutagenesis identified several pH1N1 PA residues that enhance avian polymerase activity in mammalian cells. Our results indicate that in addition to PB2, mutations in PA can also significantly affect viral polymerase activity in mammalian hosts.

  • Bussey KA, Bousse TL, Desmet EA, Kim B, Takimoto T. PB2 residue 271 plays a key role in enhanced polymerase activity of influenza A viruses in mammalian host cells. J. Virol. 84:4395-4406, 2010.
  • Bussey KA, Desmet EA, Mattiacio JL, Hamilton A, Bradel-Tretheway B, Bussey HE, Kim B, Dewhurst S, Takimoto T. PA residues in the 2009 H1N1 pandemic influenza virus enhance avian virus polymerase activity in mammalian cells. J Virol 85:7020-7028, 2011.

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