PMID- 37655966 OWN - NLM STAT- MEDLINE DCOM- 20230920 LR - 20230920 IS - 1949-0984 (Electronic) IS - 1949-0976 (Print) IS - 1949-0976 (Linking) VI - 15 IP - 2 DP - 2023 Dec TI - Activation of Nod2 signaling upon norovirus infection enhances antiviral immunity and susceptibility to colitis. PG - 2249960 LID - 10.1080/19490976.2023.2249960 [doi] LID - 2249960 AB - Over 90% of epidemic non-bacterial gastroenteritis are caused by human noroviruses (NoVs), which persist in a substantial subset of people allowing their spread worldwide. This has led to a significant number of endemic cases and up to 70,000 children deaths in developing countries. NoVs are primarily transmitted through the fecal-oral route. To date, studies have focused on the influence of the gut microbiota on enteric viral clearance by mucosal immunity. In this study, the use of mouse norovirus S99 (MNoV_S99) and CR6 (MNoV_CR6), two persistent strains, allowed us to provide evidence that the norovirus-induced exacerbation of colitis severity relied on bacterial sensing by nucleotide-binding oligomerization domain 2 (Nod2). Consequently, Nod2-deficient mice showed reduced levels of gravity of Dextran sodium sulfate (DSS)-induced colitis with both viral strains. And MNoV_CR6 viremia was heightened in Nod2(-/-) mice in comparison with animals hypomorphic for Atg16l1, which are prone to aggravated inflammation under DSS. Accordingly, the infection of macrophages derived from WT mice promoted the phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and NOD2's expression levels. Higher secretion of Tumor Necrosis Factor alpha (TNFalpha) following NOD2 activation and better viral clearance were measured in these cells. By contrast, reduced levels of pSTAT1 and blunted downstream secretion of TNFalpha were found in Nod2-deficient macrophages infected by MNoV_S99. Hence, our results uncover a previously unidentified virus-host-bacterial interplay that may represent a novel therapeutic target for treating noroviral origin gastroenteritis that may be linked with susceptibility to several common illnesses such as Crohn's disease. FAU - Muharram, Ghaffar AU - Muharram G AUID- ORCID: 0000-0003-4309-8450 AD - Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, U1019 - UMR 9017 - CIIL -Centre d'Infection et d'Immunite de Lille, Lille, France. FAU - Thepaut, Marion AU - Thepaut M AD - Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, U1019 - UMR 9017 - CIIL -Centre d'Infection et d'Immunite de Lille, Lille, France. FAU - Lobert, Pierre-Emmanuel AU - Lobert PE AD - Laboratory of Cell Physiology, INSERM U1003, University of Lille, Lille, France. FAU - Grandjean, Teddy AU - Grandjean T AD - Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, U1019 - UMR 9017 - CIIL -Centre d'Infection et d'Immunite de Lille, Lille, France. FAU - Boulard, Olivier AU - Boulard O AD - Faculte de Medecine, CHU Lille, Laboratoire de Virologie, Univ. Lille, Lille, France. FAU - Delacre, Myriam AU - Delacre M AD - Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, U1019 - UMR 9017 - CIIL -Centre d'Infection et d'Immunite de Lille, Lille, France. FAU - Wakeford, Emmrich AU - Wakeford E AD - Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, U1019 - UMR 9017 - CIIL -Centre d'Infection et d'Immunite de Lille, Lille, France. FAU - Wheeler, Richard AU - Wheeler R AD - TERI (Tumor Escape, Resistance and Immunity), Centre de recherche en cancerologie de Lyon, Centre Leon Berard, Universite de Lyon, Universite Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Lyon, France. FAU - Poulin, Lionel Franz AU - Poulin LF AD - Faculte de Medecine, CHU Lille, Laboratoire de Virologie, Univ. Lille, Lille, France. FAU - Boneca, Ivo Gomperts AU - Boneca IG AD - TERI (Tumor Escape, Resistance and Immunity), Centre de recherche en cancerologie de Lyon, Centre Leon Berard, Universite de Lyon, Universite Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Lyon, France. FAU - Lafont, Frank AU - Lafont F AD - Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, Lille, U1019 - UMR 9017 - CIIL -Centre d'Infection et d'Immunite de Lille, Lille, France. FAU - Michallet, Marie-Cecile AU - Michallet MC AD - Institut Pasteur, Universite Paris Cite CNRS UMR6047, INSERM U1306, Unite de Biologie et genetique de la paroi bacterienne, Paris, France. FAU - Hober, Didier AU - Hober D AD - Laboratory of Cell Physiology, INSERM U1003, University of Lille, Lille, France. FAU - Cadwell, Ken AU - Cadwell K AD - Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, NY, USA. AD - Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA. AD - Division of Gastroenterology and Hepatology, Department of Medicine, New York University Langone Health, New York, NY, USA. FAU - Chamaillard, Mathias AU - Chamaillard M AD - Faculte de Medecine, CHU Lille, Laboratoire de Virologie, Univ. Lille, Lille, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Gut Microbes JT - Gut microbes JID - 101495343 RN - 0 (Nod2 protein, mouse) RN - 0 (Nod2 Signaling Adaptor Protein) SB - IM MH - Animals MH - Mice MH - *Caliciviridae Infections/immunology MH - *Colitis/chemically induced/virology MH - *Gastroenteritis/immunology/virology MH - *Gastrointestinal Microbiome MH - *Nod2 Signaling Adaptor Protein/metabolism PMC - PMC10478738 OTO - NOTNLM OT - Antiviral immunity OT - colitis OT - macrophages NOD2 OT - norovirus OT - signaling COIS- K.C. has received research support from Pfizer, Takeda, Pacific Biosciences, Genentech, and AbbVie; consulted for or received honoraria from Vedanta, Genentech, and AbbVie; and holds U.S. patent 10,722,600 and provisional patent 62/935,035 and 63/157,225. EDAT- 2023/09/01 12:43 MHDA- 2023/09/04 06:43 PMCR- 2023/09/01 CRDT- 2023/09/01 09:32 PHST- 2023/09/04 06:43 [medline] PHST- 2023/09/01 12:43 [pubmed] PHST- 2023/09/01 09:32 [entrez] PHST- 2023/09/01 00:00 [pmc-release] AID - 2249960 [pii] AID - 10.1080/19490976.2023.2249960 [doi] PST - ppublish SO - Gut Microbes. 2023 Dec;15(2):2249960. doi: 10.1080/19490976.2023.2249960.