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RESEARCH PRODUCT

Norovirus-Host Interactions in the course of Inflammatory Bowel Disease

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Inflammatory bowel disease (IBD) affects around 200,000 people in France. This group of conditions includes Crohn's disease (CD), which involves the entire digestive tract, and ulcerative colitis (UC), which involves only the colon and rectum. It is known that immunological, genetic and microbiological factors are at play in IBD, but the role of viruses remains only partially explored. Among viral etiologies, human noroviruses (huNoV) are the main cause of acute viral gastroenteritis worldwide. Norovirus binds to intestinal cells through histo-blood group antigens (HBGA), including ABO and Lewis antigens. The expression of HBGA is dependent upon tissue type and the underlying physiopathological states. In healthy subjects, HBGA are almost exclusively expressed in the small intestine and proximal colon. This thesis aimed to determine HBGA expression and norovirus binding profiles using virus-like particles (VLP) in the inflammatory tissues of 24 patients suffering from IBD flares and 14 non-secretor patients (1 patient suffering from CD and 13 healthy patients). Our goal was to determine HBGA expression in secretors (expressing ABO, Lewis b and Lewis y) and non-secretors (expressing Lewis a and Lewis x), and in healthy patients and patients diagnosed with IBD; and to define the role of HBGA in norovirus binding using huNoV VLP. Binding assays using GII.4 VLP (worldwide predominant genotype) showed VLP binding in the inflamed mucosae of the small intestine, colon, and rectum. Inflammatory mucosae expressed Lewis a and Lewis x antigens in sialylated and non-sialylated forms. Competition experiments revealed that GII.4 VLP binding was due mainly to Lewis a and partially to Lewis x antigens in the absence of ABO antigen expression, which are poorly expressed in regenerative mucosae. In healthy non-secretors, we also showed the abolition of VLP binding when monoclonal antibodies directed against Lewis a antigen were used, demonstrating its implication in norovirus binding in the duodenum of healthy non-secretors. Finally, VLP binding was tissue-specific and genotype-dependent (GII.4, GII.3, GII.17 in our study). In conclusion, inflammatory and regenerative mucosae have the ability to interact with huNoV through the Lewis a antigen. However, the inflammatory mechanisms underlying norovirus attachment in regenerative mucosa remain unexplored. Further studies will be required to understand the mechanisms of inflammation possibly triggered by norovirus infections, and an evaluation of the incidence of norovirus infections and other enteric viruses in IBD is warranted.