Lewis fucose is a key moiety for the recognition of histo‐blood group antigens by GI.9 norovirus, as revealed by structural analysis

Abstract

Noroviruses have been identified as major causative agents of acute nonbacterial gastroenteritis in humans. Histo-blood group antigens (HBGAs) are thought to play a major role among the host cellular factors influencing norovirus infection. Genogroup I, genotype 9 (GI.9) is the most recently identified genotype within genogroup I, whose representative strain is the Vancouver 730 norovirus. However, the molecular interactions between host antigens and the GI.9 capsid protein have not been investigated in detail. In this study, we demonstrate that the GI.9 norovirus preferentially binds Lewis antigens over blood group A, B, and H antigens, as revealed by an HBGA binding assay using virus-like particles. We determined the crystal structures of the protruding domain of the GI.9 capsid protein in the presence or absence of Lewis antigens. Our analysis demonstrated that Lewis fucose (a1-3/4 fucose) represents a key moiety for the GI.9 protein-HBGA interaction, thus suggesting that Lewis antigens might play a critical role during norovirus infection. In addition to previously reported findings, our observations may support the future design of antiviral agents and vaccines against noroviruses.

Structural analyses of the GI.4 norovirus by cryo-electron microscopy and X-ray crystallography revealing binding sites for human monoclonal antibodies

“…Interestingly, several residues on the P-loop and His322 on the β4-sheet prior to the P-loop are thought to be involved in the binding of HBGA, based on the structural analysis of the related GI.9 VP1 protein ( 28 ). In contrast, the contribution of the V L domain is rather minor, with CDR1 and CDR3 recognizing the P-loop from one protomer and the S-loop from another protomer.…”

The Role of Histo-Blood Group Antigens and Microbiota in Human Norovirus Replication in Zebrafish Larvae

“…Both fucose residues proved to colocalize with the viral capsid protein VP1, indicating that infection of intestinal epithelial cells is closely related to the presence of fucose at the cell surface. As shown by our enzyme-linked immunosorbent assay (ELISA) and previous literature ( 49 , 50 ), HuNoV virions are able to bind Le X ; thus, collectively our data show that HuNoV does enter and replicate in the HBGA-expressing cells of the intestinal tract of zebrafish, as it does in humans.…”

Glycan Stability and Flexibility: Thermodynamic and Kinetic Characterization of Nonconventional Hydrogen Bonding in Lewis Antigens

“…Many interactions of Lewis antigens with proteins are mediated by Fuc residues. , However, in Le b -protein complexes, the interactions appear to be mediated by the NAc of the GlcNAc residue. Still, not all interactions of Le b with proteins depend on the NAc. , …”

“…Many interactions of Lewis antigens with proteins are mediated by Fuc residues. 34,35 However, in Le b -protein complexes, the interactions appear to be mediated by the The four plots in the left column show 13 C linewidths for Lewis antigens with GlcNAc at the reducing end (Le a -3, Le x -3, Le b -4, Le y -4); the four plots in the middle column show 13 C linewidths for the same antigens that are extended by Gal at the reducing end (Le a -4, Le x -4, Le b -5, Le y -5). The first two plots in the right column show Lewis antigens containing a Fuc → Rha substitution (Le a (Fuc → Rha)-3 Me , Le x (Fuc → Rha)-3 Me ), and the bottom two plots on the right column show Le a -AE and Le x -AE.…”