Infectious diseases have influenced population genetics and the evolution of the structure of the human genome in part by selecting for host susceptibility alleles that modify pathogenesis. Norovirus infection is associated with approximately 90% of epidemic non-bacterial acute gastroenteritis worldwide. Here, we show that resistance to Norwalk virus infection is multifactorial. Using a human challenge model, we showed that 29% of our study population was homozygous recessive for the alpha(1,2)fucosyltransferase gene (FUT2) in the ABH histo-blood group family and did not express the H type-1 oligosaccharide ligand required for Norwalk virus binding. The FUT2 susceptibility allele was fully penetrant against Norwalk virus infection as none of these individuals developed an infection after challenge, regardless of dose. Of the susceptible population that encoded a functional FUT2 gene, a portion was resistant to infection, suggesting that a memory immune response or some other unidentified factor also affords protection from Norwalk virus infection.

We characterized the binding of 8 Noroviruses (NORs) to histo-blood group antigens (HBGAs) in human saliva using recombinant NOR (rNOR) capsid proteins. Among the 8 rNORs tested, 6 formed viruslike particles (VLPs) when the capsid proteins were expressed in insect cells, all of which revealed variable binding activities with saliva; the remaining 2 rNORs did not form VLPs, and the proteins did not bind, or bound weakly, to saliva. Four distinct binding patterns were associated with different histo-blood types, defined by Lewis, secretor, and ABO types. Three patterns (VA387, NV, and MOH) recognized secretors, and 1 pattern (VA207) recognized Lewis-positive nonsecretors. The 3 secretor-recognizing patterns were defined as A/B (MOH), A/O (NV), and A/B/O (VA387) binders. Oligosaccharides containing the Lewis and ABH antigenic epitopes were involved in binding. Our findings suggest that different strains of NORs may recognize different human HBGAs on intestinal epithelial cells as receptors for infection.

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ABO histo-blood group type and secretor status are two genetically determined factors that contribute to resistance and susceptibility to Norwalk virus (NV). Archived serum samples but not saliva samples are available from NV and many other norovirus challenge studies and outbreaks. A person's ABO phenotype is easily determined from their archived sera, but the individual's secretor phenotype cannot easily be ascertained without saliva. We now report that a person's secretor genotype can also be determined from the archived serum samples. Of the 51 volunteers who participated in a NV challenge study, all eight non-secretors were resistant to NV infection, all of the 42 NV-infected volunteers were secretor positive, and a single uninfected secretor was histo-blood group type B. In agreement with a previous report, secretor status was most predictive of risk of NV infection. The methods described in this report should rapidly improve our knowledge of the associations between carbohydrate antigen expression and susceptibility to different strains of the non-cultivatable noroviruses by enabling retrospective studies from previously collected volunteer challenge and outbreak sera.

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