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About: As with many other viruses, the initial cell attachment of rotaviruses, major causative agent of infantile gastroenteritis, is mediated by interactions with specific cellular glycans(1–4). The distally located VP8* domain of the rotavirus spike protein VP4(5) mediates such interactions. The existing paradigm is that ‘sialidase-sensitive’ animal rotavirus strains bind to glycans with terminal sialic acid (Sia), whereas ‘sialidase-insensitive’ human rotavirus (HR) strains bind to glycans with internal Sia such as GM1(3). Although the involvement of Sia in the animal strains is firmly supported by crystallographic studies(1,3,6,7), it is not yet known how VP8* of HRs interacts with Sia and whether their cell attachment necessarily involves sialoglycans. We found that VP8* of a HR strain specifically recognizes A-type histo-blood group antigen (HBGA) using a glycan array screen comprised of 511 glycans, and that virus infectivity in HT-29 cells is abrogated by anti-Atype antibodies as well as significantly enhanced in CHO cells genetically modified to express the A-type HBGA, providing a novel paradigm for initial cell attachment of HR. HBGAs are genetically determined glycoconjugates present in mucosal secretions, epithelial and on red blood cells(8), and are recognized as susceptibility and cell attachment factors for gastric pathogens like H. pylori(9) and noroviruses(10). Our crystallographic studies show that the A-type HBGA binds to the HR VP8* at the same location as the Sia in the VP8* of animal rotavirus, and suggest how subtle changes within the same structural framework allow for such receptor switching. These results raise the possibility that host susceptibility to specific HR strains and pathogenesis are influenced by genetically controlled expression of different HBGAs among the world’s population.

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