Noroviruses and Histo-blood Groups: the Impact of Common Host Genetic Polymorphisms on Virus Transmission and Evolution

Noroviruses (NoVs) are recognized as a leading cause of human gastroenteritis worldwide. Infection occurs following the ingestion of contaminated food or, most often, through direct contact from person to person. However, not all individuals are equally sensitive to these viruses. Indeed, NoVs use glycans of the ABH and Lewis histo-blood group antigen family (HBGAs) as attachment factors. At the epithelial level, the synthesis of these HBGAs requires the action of several glycosyltransferases that are encoded by the ABO, FUT2, and FUT3 genes. The combined polymorphism at these three loci dictates sensitivity to NoV infection because the attachment profile to these glycans varies among strains. Structural analysis of the capsid protein interaction with HBGAs reveals distinct modes of binding for strains of genogroups I and II but high conservation within each genogroup, whereas minor amino acid changes are sufficient to generate modifications of HBGA-binding specificities or affinities. Such modifications therefore induce changes in the spectrum of susceptible individuals. Studies of NoV-HBGA interactions together with phylogenetic analyses and the epidemiologic survey of strains indicate that NoV transmission and evolution depend on both the establishment of herd immunity and the genetic resistance of many individuals, which confers herd innate protection by restricting NoV circulation.