Abstract
Influenza A viruses (IAV) can infect a broad range of mammalian and avian species. However, the host innate immune system provides defenses that restrict IAV replication and infection. Likewise, IAV have evolved to develop efficient mechanisms to counteract host antiviral responses to efficiently replicate in their hosts. The IAV PA-X and NS1 non-structural proteins are key virulence factors that modulate innate immune responses and virus pathogenicity during infection. To study the determinants of IAV pathogenicity and their functional co-evolution, we evaluated amino acid differences in the PA-X and NS1 proteins of early (1996–1997) and more recent (since 2016) H5N1 IAV. H5N1 IAV have zoonotic and pandemic potential and represent an important challenge both in poultry farming and human health. The results indicate that amino acid changes occurred over time, affecting the ability of these two non-structural H5N1 IAV proteins to inhibit gene expression and affecting virus pathogenicity. These results highlight the importance to monitor the evolution of these two virulence factors of IAV, which could result in enhanced viral replication and virulence.
Highlights
Influenza A viruses (IAV) belong to the Orthomyxoviridae family of viruses containing an eight-segmented, single-stranded, negative-sense RNA genome
We previously showed that the pandemic H1N1 (pH1N1) IAV that emerged in humans in 2009, has evolved to incorporate amino acid changes in the non-structural 1 (NS1) and polymerase acidic (PA)-X proteins leading to increased and decreased shutoff activity, respectively [36,42]
To analyze whether the NS1 and PA-X proteins of other IAV subtypes evolve over time, the sequences of NS1 and PA-X proteins of H5N1 IAV circulating in avian and human hosts during 1996–1997, when the first avian and human cases were reported, were compared to the NS1 and PA-X proteins of H5N1 IAV circulating since 2016
Summary
Influenza A viruses (IAV) belong to the Orthomyxoviridae family of viruses containing an eight-segmented, single-stranded, negative-sense RNA genome. Loss of PA-X expression increased viral replication, pathogenicity, and host inflammatory response for pH1N1 in mice [32,33] and for H5N1 IAV in mice, Viruses 2021, 13, 1760 chickens, and ducks [34]. Using viral strains of pH1N1, H5N1 HPAIV, and a H9N2 LPAIV, it has been shown that viruses with full-length PA-X (252 amino acids) replicate more efficiently and were more pathogenic in mice than the corresponding viruses with truncated (232 amino acids) PA-X proteins [30]. We have shown that regulation of innate immune responses by IAV NS1 and PA-X proteins determines virus fitness and pathogenesis in vitro and in vivo, respectively [12,35,36,37]. Consistent with our previous findings [36,37], our studies suggest the importance of a co-evolution in the regulation of host gene expression by H5N1 NS1 and PA-X proteins, with effects on viral fitness and pathogenesis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
