A secreted viral non-structural protein determines intestinal norovirus pathogenesis

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 require 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. Norovirus is an enteric virus that infects intestinal epithelial tuft cells in mice. Lee et al . discover that murine norovirus NS1 is an unconventionally secreted protein that overcomes IFN- λ -mediated norovirus control and is critical for intestinal infection in mice. Additionally, vaccination with NS1 alone confers protection, suggesting potential vaccine strategies.