A Secreted Viral Nonstructural Protein Determines Intestinal Norovirus Pathogenesis

Cell Host Microbe. 2019 Jun 12;25(6):845-857.e5. doi: 10.1016/j.chom.2019.04.005. Epub 2019 May 23.


Murine norovirus (MNoV) infects a low percentage of enteric tuft cells and can persist in these cells for months following acute infection. Both tuft-cell tropism and resistance to interferon-λ (IFN-λ)-mediated clearance during persistent infection requires the viral nonstructural protein 1/2 (NS1/2). We show that processing of NS1/2 yields NS1, an unconventionally secreted viral protein that is central for IFN-λ resistance. MNoV infection globally suppresses intestinal IFN-λ responses, which is attributable to secreted NS1. MNoV NS1 secretion is triggered by caspase-3 cleavage of NS1/2, and a secreted form of human NoV NS1 is also observed. NS1 secretion is essential for intestinal infection and resistance to IFN-λ in vivo. NS1 vaccination alone protects against MNoV challenge, despite the lack of induction of neutralizing anti-capsid antibodies previously shown to confer protection. Thus, despite infecting a low number of tuft cells, NS1 secretion allows MNoV to globally suppress IFN responses and promote persistence.

Keywords: IFN-λ; NS1; norovirus; secretion; vaccine.

Publication types

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

MeSH terms

  • Animals
  • Caliciviridae Infections / pathology*
  • Caliciviridae Infections / virology*
  • Cytokines / antagonists & inhibitors*
  • Disease Models, Animal
  • Gastroenteritis / pathology
  • Gastroenteritis / virology
  • Humans
  • Immune Evasion*
  • Mice
  • Norovirus / growth & development*
  • Norovirus / pathogenicity*
  • Viral Nonstructural Proteins / metabolism*
  • Virulence Factors / metabolism


  • Cytokines
  • Viral Nonstructural Proteins
  • Virulence Factors
  • interferon-lambda protein, mouse