Specific norovirus interaction with Lewis x and Lewis a on human intestinal inflammatory mucosa during refractory inflammatory bowel disease

Abstract

ABSTRACTInflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is related to immunological and microbial factors with the possible implication of enteric viruses. We characterize the interaction between human noroviruses (HuNoVs) and blood group antigens in refractory CD and UC using HuNoV Virus Like Particles (VLPs) and histological tissues. Immunohistochemistry was conducted on inflammatory tissue samples from the small intestine, colon and rectum in 15 CD and 9 UC patients. Analysis of the regenerative mucosa of the colon and rectum revealed strong expression of sialylated Lewis a (sLea) and Lewis x (sLex) antigens, and HuNoV VLP binding in the absence of ABO antigen expression in both UC and CD. Competition experiments using sialidase, lectins and monoclonal antibodies demonstrated that HuNoV attachment mostly involved Lea and to a lesser extent, Lex moieties on regenerative mucosa in both UC and CD. Further studies will be required to understand the implications of specific HuNoV binding to regenerative mucosa in refractory IBD.IMPORTANCEInflammatory Bowel Disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are progressive diseases affecting millions of people each year. Flare-ups during IBD result in severe mucosal alterations of the small intestine (CD), colon and rectum (CD and UC). Immunohistochemical analysis of CD and UC samples showed strong expression of known tumoral markers, Sialyl-Lewis a (CA19.9) and Sialyl-Lewis x (CD15s) antigens on colonic and rectal regenerative mucosa, concurrent with strong human norovirus (HuNov) VLP GII.4 affinity. Sialidase treatment and competition experiments using HBGA-specific monoclonal antibodies and lectins clearly demonstrated the implication of the Lewis a moiety, and to a lesser extent Lewis x, in HuNov recognition in regenerative mucosa of CD and UC tissues. Further studies are required to explore the possible implications of enteric viruses in the impairment of epithelial repair and dysregulation of inflammatory pathways during severe IBD.