Viral Fitness Landscapes in Diverse Host Species Reveal Multiple Evolutionary Lines for the NS1 Gene of Influenza A Viruses

Abstract

Summary: Influenza A viruses (IAVs) have a remarkable tropism in their ability to circulate in both mammalian and avian species. The IAV NS1 protein is a multifunctional virulence factor that inhibits the type I interferon host response through a myriad of mechanisms. How NS1 has evolved to enable this remarkable property across species and its specific impact in the overall replication, pathogenicity, and host preference remain unknown. Here we analyze the NS1 evolutionary landscape and host tropism using a barcoded library of recombinant IAVs. Results show a surprisingly great variety of NS1 phenotypes according to their ability to replicate in different hosts. The IAV NS1 genes appear to have taken diverse and random evolutionary pathways within their multiple phylogenetic lineages. In summary, the high evolutionary plasticity of this viral protein underscores the ability of IAVs to adapt to multiple hosts and aids in our understanding of its global prevalence. : Muñoz-Moreno et al. report that influenza A virus NS1 undergoes diverse and unpredictable evolutionary pathways based on its different phylogenetic lineages. A high-throughput approach using a barcoded library is used to test the interactions between NS1-recombinant viruses and to study their preference for specific or multiple hosts. Keywords: influenza virus, orthomyxovirus, NS1 evolution, IFN response, innate immunity, barcoded library