Abstract
Human strains of rotavirus A (RVAs) recognize fucosylated glycans belonging to histo-blood group antigens (HBGAs) through their spike protein VP8*. Lack of these ligands due to genetic polymorphisms is associated with resistance to gastroenteritis caused by P[8] genotype RVAs. With the aim to delineate the contribution of HBGAs in the process, we analyzed the glycan specificity of VP8* proteins from various P genotypes. Binding to saliva of VP8* from P[8] and P[4] genotypes required expression of both FUT2 and FUT3 enzymes, whilst binding of VP8* from the P[14] genotype required FUT2 and A enzymes. We further defined a glycan motif, GlcNAcβ3Galβ4GlcNAc, recognized by P[6] clinical strains. Conversion into Lewis antigens by the FUT3 enzyme impaired recognition, explaining their lower binding to saliva of Lewis positive phenotype. In addition, the presence of neutralizing antibodies was associated with the presence of the FUT2 wild type allele in sera from young healthy adults. Nonetheless, in vitro infection of transformed cell lines was independent of HBGAs expression, indicating that HBGAs are not human RV receptors. The match between results from saliva-based binding assays and the epidemiological data indicates that the polymorphism of human HBGAs controls susceptibility to RVAs, although the exact mechanism remains unclear.
Highlights
Rotavirus (RV) is the leading cause of severe acute gastroenteritis in infants and children less than 5 years of age
With the aim to delineate the relative contribution of Histo-Blood Group Antigens (HBGAs) in the infection process and to explore the consequences of HBGAs polymorphism on the virus transmission and efficacy of the available vaccines, we investigated the HBGA specificity of VP8* proteins from strains of various P genotypes, including the vaccine strains and the effect of HBGAs synthesis blockade on the in vitro infection of susceptible cells
We started by studying the binding of recombinant VP8* proteins from human strains to HBGAs by saliva-based binding assay since human saliva contains mucins that bear HBGAs, similar to those present at the surface of the small intestine37
Summary
Rotavirus (RV) is the leading cause of severe acute gastroenteritis in infants and children less than 5 years of age. Two other structural proteins are used for strain classification: VP7 (G - Glycoprotein) and VP4 (P - Protease Sensitive) found on the outmost surfaces of the virions1 Genes encoding these proteins enable the definition of G and P genotypes respectively. Recent studies suggested that the cell attachment protein VP8* can interact with Histo-Blood Group Antigens (HBGAs), namely the ABH and Lewis antigens. These are complex carbohydrates found on the surface of many cell types, including epithelial intestinal cells and as free molecules in biologic fluids, such as saliva and milk. Other studies documented that P[9], P[14] and P[25] strains interact with the A antigen and that this interaction is involved in the infection in vitro
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