Innate immune sensing of rotavirus by intestinal epithelial cells leads to diarrhea

Diarrhea is the predominant symptom of acute gastroenteritis resulting from enteric infections and a leading cause of death in infants and young children. However, the role of the host response in diarrhea pathogenesis is unclear. Using rotavirus and neonatal mice as a model, we found that oral inoculation of UV-inactivated replication-defective rotavirus consistently induced watery diarrhea by robust activation of cytosolic double-stranded RNA sensing pathways and type III interferon (IFN-λ) secretion. Diarrhea was significantly diminished in mice lacking the IFN-λ receptor. Mechanistically, IFN-λ signaling downregulates the expression of Dra, a chloride and bicarbonate exchanger, which contributes to reduced water absorption. We confirmed these findings in mice inoculated with reovirus, as well as in donor-derived human intestinal organoids and human biopsy samples. Our data highlight a mechanism of rapid diarrhea induction by host innate immune sensing in the gastrointestinal tract and suggest that diarrhea induction is an active host defense strategy to eliminate the pathogen. • Inactivated enteric viruses can induce diarrhea in newborn mice • IFN-λ is necessary and sufficient to induce diarrhea • dsRNA sensing via MAVS in intestinal epithelial cells mediates diarrhea development • IFN-λ downregulation of Cl − channel at the brush border mediates diarrhea in vivo Hou et al. demonstrate in an infant mouse model that innate immune sensing of enteric viruses induces IFN-λ signaling, which downregulates an apical chloride exchanger that leads to increased intestinal fluid secretion and diarrhea. This suggests that diarrhea induction may be an active host defense strategy to eliminate the pathogen.