Type I and III interferons synergize with TNF to promote virally-triggered damage to the intestinal epithelium
Year: 2026
Type: preprint
Abstract: Excessive cell death in the epithelium due to prolonged immune activation is associated with intestinal diseases such as Crohn’s disease. Mice with mutations in the Crohn’s disease susceptibility gene Atg16l1 are susceptible to inflammation associated with intestinal epithelial cell (IEC) death, including loss of antimicrobial Paneth cells triggered by infection with murine norovirus (MNV). Here, we show that intestinal disease downstream of MNV depends on IFN-α/β and IFN-λ signaling in IECs. In mouse organoids, IFNs synergize with TNF to induce RIPK1-dependent cell death, amplified by ATG16L1 deficiency. We further show that human intestinal organoids harboring the ATG16L1 risk allele exhibit heightened sensitivity to TNF and IFN co-stimulation and to serum from severe COVID-19 patients. Our findings reveal that virally triggered cytokines including IFNs exacerbate epithelial vulnerability in genetically predisposed hosts.
Institutions: Lyon 1 Université, École Normale Supérieure de Lyon, Centre National de la Recherche Scientifique, Institut de Génomique Fonctionnelle de Lyon, New York University, University of Pennsylvania, The University of Melbourne, Peter Doherty Institute, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, St. Jude Children's Research Hospital, Institute of Science Tokyo
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7123346389