2’-Fucosyllactose Inhibits Human Norovirus Replication in Human Intestinal Enteroids

Abstract

ABSTRACTHuman noroviruses (HuNoVs) are the leading cause of acute gastroenteritis worldwide. Currently, there are no targeted antivirals for the treatment of HuNoV infection. Histo-blood group antigens (HBGAs) on the intestinal epithelium are cellular attachment factors for HuNoVs; molecules that block the binding of HuNoVs to HBGAs thus have the potential to be developed as antivirals. Human milk oligosaccharides (HMOs) are glycans in human milk with structures analogous to HBGAs. HMOs have been shown to act as decoy receptors to prevent the attachment of multiple enteric pathogens to host cells. Previous X-ray crystallography studies have demonstrated the binding of HMO 2’-fucosyllactose (2’FL) in the same pocket as HBGAs for some HuNoV strains. We evaluated the effect of 2’FL on the replication of a globally dominant GII.4 Sydney [P16] HuNoV strain using human intestinal enteroids (HIEs) from adults and children. A significant reduction in GII.4 Sydney [P16] replication was seen in duodenal and jejunal HIEs from multiple adult donors, all segments of the small intestine from an adult organ donor and in two pediatric duodenal HIEs. However, 2’FL did not inhibit HuNoV replication in two infant jejunal HIEs that had significantly lower expression of α1-2-fucosylated glycans. 2’FL can be synthesized in large scale, and safety and tolerance have been assessed previously. Our data suggest that 2’FL has the potential to be developed as a therapeutic for HuNoV gastroenteritis.IMPORTANCEHuman noroviruses infect the gastrointestinal tract and are a leading cause of acute gastroenteritis worldwide. Common symptoms of norovirus include diarrhea, vomiting and stomach cramps. Virus shedding and symptoms are prolonged and debilitating in immunocompromised patients. Currently, there are no approved vaccines or targeted antivirals for treating human norovirus infection. Human intestinal enteroids derived from intestinal stem cells allow the successful replication of norovirus in the laboratory and can be used as a physiologically relevant model system to evaluate antivirals. We discovered that 2’fucosyllactose (2’FL), an oligosaccharide naturally occurring in human milk, inhibits norovirus replication in HIEs from multiple donors and thus has the potential to be developed as a therapeutic for human norovirus. These findings have high translational potential since 2’FL from several manufacturers have GRAS (generally recognized as safe) status and can be synthesized on a large scale for immediate application.