The NS1 protein of influenza A virus suppresses interferon-regulated activation of antigen-presentation and immune-proteasome pathways

J Gen Virol. 2011 Sep;92(Pt 9):2093-2104. doi: 10.1099/vir.0.032060-0. Epub 2011 May 18.

Abstract

The NS1 protein of influenza virus counters host antiviral defences primarily by antagonizing the type I interferon (IFN) response. Both the N-terminal dsRNA-binding domain and the C-terminal effector domain are required for optimal suppression of host responses during infection. To better understand the regulatory role of the NS1 effector domain, we used an NS1-truncated mutant virus derived from human H1N1 influenza isolate A/Texas/36/91 (Tx/91) and assessed global transcriptional profiles from two independent human lung cell-culture models. Relative to the wild-type Tx/91-induced gene expression, the NS1 mutant virus induced enhanced expression of innate immune genes, specifically NF-κB signalling-pathway genes and IFN-α and -β target genes. We queried an experimentally derived IFN gene set to gauge the proportion of IFN-responsive genes that are suppressed specifically by NS1. We show that the C-terminally truncated NS1 mutant virus is less efficient at suppressing IFN-regulated gene expression associated with activation of antigen-presentation and immune-proteasome pathways. This is the first report integrating genomic analysis from two independent human culture systems, including primary lung cells, using genetically similar H1N1 influenza viruses that differ only in the length of the NS1 protein.

Publication types

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

MeSH terms

  • Antigen Presentation*
  • Cells, Cultured
  • Epithelial Cells / immunology
  • Epithelial Cells / virology
  • Gene Expression Profiling
  • Humans
  • Influenza A Virus, H1N1 Subtype / genetics
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Interferon-alpha / antagonists & inhibitors*
  • Interferon-beta / antagonists & inhibitors*
  • Mutant Proteins / genetics
  • Mutant Proteins / immunology
  • Mutant Proteins / metabolism
  • NF-kappa B / antagonists & inhibitors
  • Proteasome Inhibitors*
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / immunology
  • Viral Nonstructural Proteins / metabolism*
  • Virulence Factors / immunology
  • Virulence Factors / metabolism*

Substances

  • INS1 protein, influenza virus
  • Interferon-alpha
  • Mutant Proteins
  • NF-kappa B
  • Proteasome Inhibitors
  • Viral Nonstructural Proteins
  • Virulence Factors
  • Interferon-beta