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


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.

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Figure 1: VP8* structure of HAL1166 P[14] human rotavirus strain and structural comparison with other VP8* structures.
Figure 2: Structural analysis of P[14] VP8*–A-type HBGA interactions.
Figure 3: HAL1166 rotavirus specifically recognizes A-type HBGA.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The coordinates and structure factors for the P[14] VP8* structures are deposited in the Protein Data Bank under accession numbers 4DRR (apo), 4DRV (with A-type trisaccharide) and 4DS0 (with A-type tetrasaccharide). Raw glycan array data are available at http://www.functionalglycomics.org/glycomics/ublicdata/selectedScreens.jsp.


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We acknowledge the support from NIH grants AI36040 (to B.V.V.P.), AI 080656 and P30 DK56338 (to M.K.E.), GM62116 (to the Consortium for Functional Glycomics), and the Robert Welch foundation (Q1279) to B.V.V.P. We thank R. Atmar and S. Shanker for helpful discussions and BCM X-ray core facility for data collection.

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L.H. carried out expression, purification, crystallization, diffraction data collection and structure determination. L.H., S.E.C., R.C. and N.W.C.-P. contributed to virus infectivity assays in HT29, CHO cells and haemagglutination assays and data analyses. D.F.S. contributed to glycan array experiments and analysis. J.L.P. provided parental and genetically modified CHO cells and advice. M.K.E. provided supervision and advice on cell infectivity assays and analysis. L.H. and B.V.V.P. analysed and interpreted the structural data. B.V.V.P. contributed to the overall direction of the project and wrote the manuscript with input from other authors.

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Correspondence to B. V. Venkataram Prasad.

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Hu, L., Crawford, S., Czako, R. et al. Cell attachment protein VP8* of a human rotavirus specifically interacts with A-type histo-blood group antigen. Nature 485, 256–259 (2012). https://doi.org/10.1038/nature10996

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