Abstract
The 2009/2010 pandemic influenza virus (H1N1pdm) contains an avian-lineage PB2 gene that lacks E627K and D701N substitutions important in the pathogenesis and transmission of avian-origin viruses in humans or other mammals. Previous studies have shown that PB2-627K is not necessary because of a compensatory Q591R substitution. The role that PB2-701N plays in the H1N1pdm phenotype is not well understood. Therefore, PB2-D701N was introduced into an H1N1pdm virus (A/New York/1682/2009 (NY1682)) and analyzed in vitro and in vivo. Mini-genome replication assay, in vitro replication characteristics in cell lines, and analysis in the mouse and ferret models demonstrated that PB2-D701N increased virus replication rates and resulted in more severe pathogenicity in mice and more efficient transmission in ferrets. In addition, compared to the NY1682-WT virus, the NY1682-D701N mutant virus induced less IFN-λ and replicated to a higher titer in primary human alveolar epithelial cells. These findings suggest that the acquisition of the PB2-701N substitution by H1N1pdm viruses may result in more severe disease or increase transmission in humans.
Highlights
Influenza A viruses are important human and animal pathogens that cause frequent epidemics and epizootics, and emergence of novel viruses in humans and animals continue to pose a pandemic threat
After 6 h or 18 h incubation at 33oC, 37oC, or 39oC, luciferase production was assayed. At both time points and all temperatures, the PB2-D701N substitution resulted in a significantly higher level of relative luciferase activity compared to the PB2-WT (p
The increased RNA polymerase activity conferred by PB2-D701N was fairly modest in comparison to other mutations (e.g., E627K, and E158G) [8], seemingly small differences in RNA polymerase activity may still influence transmission or pathogenesis
Summary
Influenza A viruses are important human and animal pathogens that cause frequent epidemics and epizootics, and emergence of novel viruses in humans and animals continue to pose a pandemic threat. Transmission and pathogenesis of influenza A viruses are polygenic traits influenced by the interaction of viral components with host cells. The RdRp and the NP are major determinants of host species-specificity, transmission, and pathogenesis. The 2009 influenza A pandemic was caused by H1N1 subtype viruses (H1N1pdm), which have a triple reassortant RNA polymerase and NP gene constellation that contains avian (PB2, and PA), human (PB1) and swine (NP) lineage gene segments [1,2,3]. It is anticipated that additional adaptations will evolve in the H1N1pdm viruses unique triple reassortant gene constellation as it adapts to humans, and these changes have the potential to enhance its virulence and/or transmission
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