A North American H7N3 Influenza Virus Supports Reassortment with 2009 Pandemic H1N1 and Induces Disease in Mice without Prior Adaptation.

Abstract

Reassortment between H5 or H9 subtype avian and mammalian influenza A viruses (IAV) can generate a novel virus that causes disease and transmits between mammals. Such information is currently not available for H7 subtype viruses. We evaluated the ability of a low-pathogenicity North American avian H7N3 virus (A/shorebird/Delaware/22/2006) to reassort with mammalian or avian viruses using a plasmid-based competition assay. In addition to genome segments derived from an avian H7N9 virus, the H7N3 virus reassorted efficiently with the PB2, NA, and M segments from the 2009 pandemic H1N1 (PH1N1) virus.In vitro and in vivo evaluation of the H7N3:PH1N1 (7 + 1) reassortant viruses revealed that the PB2, NA, or M segments from PH1N1 largely do not attenuate the H7N3 virus, whereas the PB1, PA, NP, or NS genome segments from PH1N1 do. Additionally, we assessed the functionality of the H7N3:PH1N1 7 + 1 reassortant viruses by measuring the inflammatory response in vivo We found that infection with wild-type H7N3 resulted in increased inflammatory cytokine production relative to that seen with the PH1N1 strain and that the increase was further exacerbated by substitution of PH1N1 PB2 but not NA or M. Finally, we assessed if any adaptations occurred in the individually substituted segments after in vivo inoculation and found no mutations, suggesting that PH1N1 PB2, NA, and M are genetically stable in the background of this H7N3 virus. Taking the data together, we demonstrate that a North American avian H7N3 IAV is genetically and functionally compatible with multiple gene segments from the 2009 pandemic influenza virus strain without prior adaptation. The 2009 pandemic H1N1 virus continues to circulate and reassort with other influenza viruses, creating novel viruses with increased replication and transmission potential in humans. Previous studies have found that this virus can also reassort with H5N1 and H9N2 avian influenza viruses. We now show that several genome segments of the 2009 H1N1 virus are also highly compatible with a low-pathogenicity avian H7N3 virus and that these reassortant viruses are stable and not attenuated in an animal model. These results highlight the potential for reassortment of H1N1 viruses with avian influenza virus and emphasize the need for continued surveillance of influenza viruses in areas of cocirculation between avian, human, and swine viruses.