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bioRxiv · 10.1101/2025.03.10.642353

Deciphering the role of histo-blood group antigens in bovine rotavirus C infection

Navarro-Lleo, N.·Ramirez-Cardenas, J.·Paredes-Martinez, F.·Serna, S.·Gozalbo-Rovira, R.·Munoz-Garcia, J. C.·Reichardt, N. C.·Casino, P.·Angulo, J.·Rodriguez-Diaz, J.·Buesa, J.
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Abstract

Rotaviruses (RVs) are the main cause of viral diarrhea among infants, small children, and the young of many animal species. Histo-blood group antigens (HBGAs) are potential RV receptors and glycan composition on mucous surfaces influences host susceptibility and cross-species virus transmission. RVs exhibit genotype-dependent glycan binding and differences are due to sequence modifications in the VP8* domain of the spike protein VP4. Nevertheless, the molecular bases for this genotype-dependent glycan specificity, especially in non-A RVs, are not thoroughly understood. This study delves into how genotypic variations configure a novel binding site in the VP8* of a bovine P[3] rotavirus species C (RVC) strain to recognize H type-2 antigen (H2) and its precursor N-acetyl-lactosamine (LacNAc) using glycan binding assays, crystallography, and STD NMR. Results reveal a specific interaction of bovine P[3] RVC VP8* with H2 and LacNAc, more strongly with the latter. In the P[3] RVC VP8*-H2 interaction, the N-acetyl glucosamine moiety displays significant interaction, while galactose participates moderately and fucose binds weakly. Moreover, the bovine VP8* structure, resolved at 3 [A], shows specific structural features which differ from human RVC, as it contains two additional {beta}-strands ({beta}1 and {beta}2) contributing to {beta}-sheet2 and conformational changes that widens the cleft to allow different carbohydrate binding modes. These subtle changes in both sequence and structure explain the H2 precursor recognition, which is ubiquitous in human neonate intestine and in human and bovine milk, providing insights into P[3] RVC tropism and its potential zoonotic transmission. Author SummaryRotavirus C (RVC) represents an emerging pathogen with the ability to infect both humans and animals. It is widely acknowledged that host glycobiology plays a crucial role in determining susceptibility to RVs. Consequently, a better understanding of the interactions between RVs and carbohydrates is essential to know how the virus causes infection and to develop effective preventive strategies. Recent findings have unveiled the capability of the human RVC genotype P[2] to recognize the type A antigen through the VP8* spike protein although little is known about animal RVC strains. In this study, we describe the capacity of bovine P[3] RVC strain to bind H2 and LacNAc, both HBGAs. We also offer the structural explanation for the glycan differential recognition between human and bovine RVC strains. Our findings offer valuable insights into RVC attachment to host cells and its potential implications for species barriers.

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Navarro-Lleo, N., Ramirez-Cardenas, J., Paredes-Martinez, F., Serna, S., Gozalbo-Rovira, R., Munoz-Garcia, J. C., Reichardt, N. C., Casino, P., Angulo, J., Rodriguez-Diaz, J., Buesa, J.. 2025-03-11. Deciphering the role of histo-blood group antigens in bovine rotavirus C infection. https://doi.org/10.1101/2025.03.10.642353

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