The majority of human blood types, including the secretor, ABO and Lewis blood types are determined by three unique types of saccharides (). The α-1, 2 Fuc (H epitope) is the determinant of the secretor blood type, this saccharide is added to the precursor of the HBGAs by the α-1, 2 fucosyl transferase encoded by FUT2. The two saccharides, α-GalNAc and α-Gal (the A/B epitopes), are the determinants for the A/B blood types and are added to the H antigen by the A/B enzymes, respectively. The Lewis antigens are determined by the α-1, 3/4 Fuc saccharides called the Lewis epitopes that are added to the precursor by the α-1, 3/4 fucosyl transferase encoded by FUT3. Importantly, these three types of saccharides are also the major interacting sites of human NoVs 21
and thus might function as multi-selection factors of human NoVs.
Figure 2 Model of NoV-HBGA interaction. (a) Schematic of a HBGA product with the five saccharides indicated in different shapes and colors. The three major saccharide determinants of human blood types, H, A/B, and Lewis epitopes are indicated. R represents the (more ...)
We propose a new model, developed using available structural and functional analyses, in which human NoVs are sorted into three groups: the H-, A/B- and Lewis-binding groups based on the major interacting residues of the α-1, 2 Fuc, α-GalNAc/α-Gal, and α-1,3/4 Fuc saccharides, respectively (). The two GII strains, VA387 (GII.4) and VA207 (GII.9), belong to the H- and Lewis-binding groups, respectively. In addition, a number of GII strains revealed binding activities to the A and B secretors but not O secretors and non-secretors, such as MOH (GII.5) 5
, suggesting that they target the A/B epitopes as the major residues. However, these strains have not been analyzed by co-crystallization. These NoVs should be grouped in the A/B binding group.
A similar grouping principle based on the major vs. minor binding saccharides may apply to GI NoVs. For example, the well characterized NoV Boxer (GI.8)5
shows a similar binding pattern as that of VA207 and therefore is assigned to the Lewis-binding group. However, owing to the different genetic background and the distinct structures, amino acid composition, and binding modes of the HBGA binding interfaces between GI and GII, the assignment of binding groups for other GI strains might be different. For example, the Norwalk virus could be grouped in the A/B binding group because it targets α-GalNAc on the A antigen as its major binding residue17,20
. However, the Norwalk virus also targets β-Gal on the H antigen as the major interacting residue (). Therefore, further functional and structural analyses are necessary to confirm that similar grouping principle would fit in the GI NoVs.
This proposed model emphasizes the critical roles of the major binding residues that are also the determinants of the three major human HBGA families (the ABO, secretor and Lewis families). Thus, the proposed model is likely to represent all possible repertoires of HBGAs interacting with NoVs and possibly other microbial pathogens of humans as well. The inclusion of one to two minor residues in the classification of the three binding groups, including the residues of the precursors of the HBGAs, provides further power to explain additional variations of NoV-HBGA interaction that could have biological significance.
With further information on the structure and function of the HBGA-binding interfaces of NoVs representing more binding patterns and/or binding groups, this model will be subjected to further refinement or modification. For example, as described above, the Norwalk virus is grouped in the A/B binding group, but it apparently has an alternative binding mode. Thus the final assignment of this strain could be dependent on a comparison of the binding modes of related strains in this genogroup. In addition, variation of binding affinity to the A antigen was found among different GII.4 epidemic variants 22
. Whether these variants should be classified in subgroups within the H-binding group needs to be determined. Furthermore, variable binding affinities of NoVs with similar genetic backgrounds to different antigens were reported 22–29
and need further study. Finally, GII.3 NoVs revealed an intermediate binding pattern between the A/B- and H-binding groups. They bind weakly to the H antigen in addition to strongly binding the A/B antigen5
. Whether these strains should be grouped in the A/B- or H-binding groups needs to be determined. Thus, while the classification of the three binding groups provides a valuable tool, variations or exceptions exist. Further studies to characterize the observed variations, particularly those possibly associated with the minor binding residues, and their impacts on the clinical outcomes and epidemiology are of high importance.