Activation of Nod2 signalling upon Norovirus infection enhances antiviral immunity and susceptibility to colitis
Résumé
Over 90% of epidemic nonbacterial gastroenteritis are caused by human Noroviruses (NoV) which are persisting in a substantial subset of people allowing their spread worldwide. It leads 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 sulphate (DSS)-induced colitis with both viral strains. And MNoV_CR6 viremia was heightened in Nod2-/- mice in comparison with animals hypomorphic for Atg16l1, that 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 Transcription1 (STAT1) and NOD2’s expression levels. Higher secretion of Tumor Necrosis Factor alpha (TNF) following NOD2 activation and better viral clearance were measured in these cells. By contrast, reduced levels of pSTAT1 and blunted downstream secretion of TNF 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.
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Activation of Nod2 signalling upon norovirus infection enhances antiviral immunity and susceptibility to colitis_modified manuscript_modified v130823.pdf (302.18 Ko)
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