IFN-I and IL-22 mediate protective effects of intestinal viral infection

Products derived from bacterial members of the gut microbiota evoke immune signaling pathways from the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. Recently, we demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities upon depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and IL-22 producing innate lymphoid cells (ILCs), which in turn promote pSTAT3 signaling in intestinal epithelial cells and protection from intestinal injury. Additionally, we demonstrate that MNV provides a striking IL-22 dependent protection against early life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.