Secreted non-structural protein 1 of norovirus counteracts IFN-l immunity and is a vaccine target.

Human noroviruses (HNoVs) are highly contagious enteric pathogens that cause gastroenteritis. Current vaccine approaches which are of limited efficacy target the viral capsid protein. We recently identified tuft cells as the target of intestinal murine norovirus (MNoV) infection, and mapped non-structural protein 1 (NS1) as a viral determinant of tuft cell tropism. Here, we discovered that NS1 is an unconventionally secreted viral protein. NS1 secretion is essential for intestinal MNoV infection in mice, and dispensable for extra-intestinal infection or viral replication in vitro. MNoV infection globally represses the intestinal interferon-lambda (IFN-?) response. Importantly, vaccinating animals with recombinant NS1 provides superior protection to a similar capsid protein vaccination strategy. These findings represent novel aspect of NoV intestinal pathogenesis controlled by a secreted viral immune evasion factor and shed lights into the future HNoV vaccine development.