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.
Authors
- María Florencia Gómez Castro (ORCID: https://orcid.org/0000-0003-4081-7819)
- Gaopeng Hou (ORCID: https://orcid.org/0000-0003-4753-9743)
- Siyuan Ding (ORCID: https://orcid.org/0000-0002-5338-260X)
- Terence S. Dermody (ORCID: https://orcid.org/0000-0003-1853-8741)
- Xingxing Ren (ORCID: https://orcid.org/0000-0002-8601-5216)
- Shu Zhu (ORCID: https://orcid.org/0000-0002-8163-0869)
- Hinissan P. Kohio
- Juhee Son (ORCID: https://orcid.org/0000-0001-9605-7017)
- Takahiro Kawagishi (ORCID: https://orcid.org/0000-0002-8693-1820)
- Avan Antia (ORCID: https://orcid.org/0000-0002-5092-6173)
- Anna L. DeVeaux (ORCID: https://orcid.org/0000-0003-2558-6637)
- Megan T. Baldridge (ORCID: https://orcid.org/0000-0002-7030-6131)
- Ningguo Feng (ORCID: https://orcid.org/0000-0003-4973-0947)
- Alexa N. Roth (ORCID: https://orcid.org/0000-0002-6649-8265)
- Qiru Zeng
Institutions
- University of Science and Technology of China (CN)
- University of Pittsburgh (US)
- Chinese Academy of Sciences (CN)
- Washington University in St. Louis (US)
- Stanford University (US)
- The University of Osaka (JP)
Publication Details
- Journal
- Cell Host & Microbe
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.chom.2025.02.005
- Citations
- 9
- Primary Topic
- Viral gastroenteritis research and epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 12.57
Funders
- National Institute of Allergy and Infectious Diseases