Cell attachment protein VP8* of a human rotavirus specifically interacts with A-type histo-blood group antigen

Abstract

This crystallographic study shows the attachment of human rotavirus VP8* to histo blood group A antigen, and suggests how changes within the structure of VP8* could allow switching from sialylated to non-sialylated glycan receptor. Rotaviruses are the major pathogens of infantile gastroenteritis. They attach to the surfaces of cells through interactions with specific cellular glycans. Animal rotaviruses bind to glycans with terminal sialic acid, whereas human rotavirus strains are sialidase insensitive. Venkataram Prasad and colleagues now show that certain human rotavirus strains bind to and infect cells through A-type histo-blood group antigen (HBGA), suggesting that susceptibility to specific human rotavirus strains might be influenced by different blood-group antigens, a phenomenon reported in Helicobacter pylori and norovirus infection. Crystallographic studies show how HBGA binds to the attachment protein of human norovirus (VP8), and suggest how subtle changes in the structure of VP8 might allow receptor switching. As with many other viruses, the initial cell attachment of rotaviruses, which are the major causative agent of infantile gastroenteritis, is mediated by interactions with specific cellular glycans1,2,3,4. The distally located VP8* domain of the rotavirus spike protein VP4 (ref. 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 strains bind to glycans with internal Sia such as GM1 (ref. 3). Although the involvement of Sia in the animal strains is firmly supported by crystallographic studies1,3,6,7, it is not yet known how VP8* of human rotaviruses interacts with Sia and whether their cell attachment necessarily involves sialoglycans. Here we show that VP8* of a human rotavirus 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-A-type antibodies as well as significantly enhanced in Chinese hamster ovary cells genetically modified to express the A-type HBGA, providing a novel paradigm for initial cell attachment of human rotavirus. HBGAs are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells8, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori9 and noroviruses10. Our crystallographic studies show that the A-type HBGA binds to the human rotavirus 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 human rotavirus strains and pathogenesis are influenced by genetically controlled expression of different HBGAs among the world’s population.