Intestinal antiviral signaling is controlled by autophagy gene Epg5 independent of the microbiota. Epg5

Mutations in the autophagy gene EPG5 are responsible for Vici syndrome, a human genetic disease characterized by combined immunodeficiency. Previously, we found that a mutation in Epg5 in mice is associated with hyperinflammation in the lungs mediated by IL-1β and TNF, resulting in resistance to influenza. Here, we find that disruption of Epg5 results in protection against multiple enteric viruses including norovirus and rotavirus. Gene expression analysis reveals IFN-λ responsive genes as a key alteration. Further, mice lacking Epg5 exhibit substantial alterations of the intestinal microbiota. Surprisingly, germ-free mouse studies indicate Epg5-associated inflammation of both the intestine and lung is microbiota-independent. Genetic studies support IFN-λ signaling as the primary mediator of resistance to enteric viruses, but not of microbial dysbiosis in Epg5 mice. This study unveils an important role for autophagy gene Epg5 in host organism protection by modulating intestinal IFN-λ responses that is unexpectedly independent of the microbiota.