Abstract Title
PB2 variants beyond the 627 domain contribute to replication variation of avian influenza A viruses from avian species to mammals
Abstract
Influenza A viruses (IAVs) cause outbreaks in birds, humans, and lower mammals, with wild aquatic birds, particularly from the orders Anseriformes and Charadriiformes, acting as primary reservoirs. These viruses are linked to those circulating in domestic poultry and lower mammals and to all documented human pandemic strains. However, few wild avian IAV variants have naturally spilled over into mammals, and the molecular mechanisms underlying this remain incompletely understood. Our recent study found two closely related avian IAVs—A/blue-winged teal/Ohio/12OS2244/2012(H4N6) and A/blue-winged teal/Ohio/15OS5426/2015(H4N6)—exhibit distinct replication and transmission abilities in swine, despite similar receptor binding abilities (Zhang et al.JVirol.2020.94(24):e00847-2). We hypothesize variation in the RNA polymerase contributes to these differential replicative abilities in swine. Sixteen H4N6 genetic recombinants were generated by swapping genes between the viruses, and their growth kinetics were assessed in primary swine respiratory cells and avian DF-1 cells. While all recombinant viruses replicated efficiently in avian DF-1 cells, only a subset with polymorphic PB1 or PB2 genes from OS2244 showed efficient replication in swine cells. This concurred with minigenome assays showing the OS2244 PB2 gene supported enhanced polymerase activity in mammalian cells. Molecular characterization revealed identical 627 domains, but an amino acid substitution in the PB2 N1-linker domain. Further experiments will elucidate how this substitution affects RNA polymerase host factors interactions, influencing mammalian replication. Overall, this study demonstrates that PB2 variations beyond the 627 domain can significantly impact replication difference between mammalian and avian hosts.
Co-Author(s)
Emily Giri1,2,3, Xiaojian Zhang1,2,3, Jacqueline M. Nolting4, and Xiu-Feng Henry Wan1,2,3,5
1Center for Influenza and Emerging Infectious Diseases, University of Missouri, Columbia, Missouri, USA; 2Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri, USA; 3Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA; 4Department of Veterinary Preventive Medicine, Ohio State University, Columbus, Ohio, USA; 5Department of Electrical Engineering & Computer Science, University of Missouri, Columbia, Missouri, USA.
Abstract Category
Avian influenza in mammals, pandemic preparedness, and one health