Activation of Nod2 signaling upon norovirus infection enhances antiviral immunity and susceptibility to colitis.

Gut microbes 2023 Dec

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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 (TNFα) following NOD2 activation and better viral clearance were measured in these cells. By contrast, reduced levels of pSTAT1 and blunted downstream secretion of TNFα 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.

Citation

Ghaffar Muharram, Marion Thépaut, Pierre-Emmanuel Lobert, Teddy Grandjean, Olivier Boulard, Myriam Delacre, Emmrich Wakeford, Richard Wheeler, Lionel Franz Poulin, Ivo Gomperts Boneca, Frank Lafont, Marie-Cécile Michallet, Didier Hober, Ken Cadwell, Mathias Chamaillard. Activation of Nod2 signaling upon norovirus infection enhances antiviral immunity and susceptibility to colitis. Gut microbes. 2023 Dec;15(2):2249960