Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ

Commensal microbes profoundly impact host immunity to enteric viral infections 1 . We have shown that the bacterial microbiota and host antiviral cytokine interferon-λ (IFN-λ) determine the persistence of murine norovirus in the gut 2 , 3 . However, the effects of the virome in modulating enteric infections remain unexplored. Here, we report that murine astrovirus can complement primary immunodeficiency to protect against murine norovirus and rotavirus infections. Protection against infection was horizontally transferable between immunocompromised mouse strains by co-housing and fecal transplantation. Furthermore, protection against enteric pathogens corresponded with the presence of a specific strain of murine astrovirus in the gut, and this complementation of immunodeficiency required IFN-λ signalling in gut epithelial cells. Our study demonstrates that elements of the virome can protect against enteric pathogens in an immunodeficient host. This study highlights the impact of the gut virome on host immunity by showing that a specific strain of murine astrovirus in the gut of immunodeficient mice protects them against norovirus and rotavirus infections, and that this protection depends on interferon-λ signalling in gut epithelial cells.