Introduction: Previous work implicated histo-blood group antigens (HBGA) as cellular rotavirus receptors, mainly for rare P[9] and P[14] human rotaviruses, and the HBGA relation with childhood rotavirus susceptibility is unclear1,2. Internal N-acetylneuraminic acid (Sia) on ganglioside GM1 is a receptor for several human rotaviruses3. Animal rotaviruses typically use terminal Sia. The VP8* subunit of rotavirus VP4 binds these glycans.
Objectives: To conduct structure-function analyses of HBGA and Sia for VP8* binding and usage as rotavirus receptors. Human rotaviruses of common P types i.e. Wa P[8]), RV-3 (P[6]), ST-3 (P[6]), DS-1(P[4]); rare P types i.e. K8 (P[9]) and HAL1166 (P[14]); and animal rotaviruses were studied.
Results and conclusions: NMR studies showed interactions of DS-1 and RV-3 VP8* with type A HBGA, involving the HBGA-defining fucose moiety. Thus, VP8* on RV-3 can bind both internal Sia and type A HBGA to facilitate cell entry3. K8 and HAL1166 VP8* also bound type A HBGA, but without engaging the fucose. K8 VP8* binding affinity was less than HAL1166 VP8*4. Substantial rearrangement of the K8 VP8* glycan binding groove upon type A HBGA binding was evident in crystal structures. This is this first observation of intrinsic VP8* flexibility, which may (i) explain its ability to recognise both Sia and HBGA, and (ii) facilitate cross-species infection5. Further NMR studies showed Wa VP8* did not bind type A HBGA, and no VP8* bound to Lewisb or H type-1 antigens. VP8*-cell binding and infectivity studies reflected these findings, with type A HBGA inhibiting DS-1, RV-3, ST-3, K8 and HAL1166 but not Wa, and Lewisb and H type-1 antigens having no effect4. Preliminary analysis indicates RV ganglioside usage may relate to the rotavirus-cell entry pathway used2.
1Hu et al., Nature 485: 256, 2012; 2Coulson, Curr Opin Virol 15:90, 2015; 3Fleming et al., J Virol 88:4558, 2014; 4Bohm et al., Nat Commun 6:5907, 2015; 5Yu et al., ChemBioChem 10.1002/cbic.201500360, 2015