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

Cell Rep. 2019 Dec 17;29(12):3997-4009.e5. doi: 10.1016/j.celrep.2019.11.070.


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.

Keywords: IFN response; NS1 evolution; barcoded library; influenza virus; innate immunity; orthomyxovirus.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dogs
  • Female
  • Host Specificity / genetics*
  • Host-Pathogen Interactions / genetics*
  • Immunity, Innate
  • Influenza A virus / genetics
  • Influenza A virus / pathogenicity*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Mutation*
  • Orthomyxoviridae Infections / genetics
  • Orthomyxoviridae Infections / pathology
  • Orthomyxoviridae Infections / virology*
  • Phylogeny
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication*


  • INS1 protein, influenza virus
  • Viral Nonstructural Proteins