Abstract
Recognition of specific cell surface glycans, mediated by the VP8* domain of the spike protein VP4, is the essential first step in rotavirus (RV) infection. Due to lack of direct structural information of virus-ligand interactions, the molecular basis of ligand-controlled host ranges of the major human RVs (P[8] and P[4]) in P[II] genogroup remains unknown. Here, through characterization of a minor P[II] RV (P[19]) that can infect both animals (pigs) and humans, we made an important advance to fill this knowledge gap by solving the crystal structures of the P[19] VP8* in complex with its ligands. Our data showed that P[19] RVs use a novel binding site that differs from the known ones of other genotypes/genogroups. This binding site is capable of interacting with two types of glycans, the mucin core and type 1 histo-blood group antigens (HBGAs) with a common GlcNAc as the central binding saccharide. The binding site is apparently shared by other P[II] RVs and possibly two genotypes (P[10] and P[12]) in P[I] as shown by their highly conserved GlcNAc-interacting residues. These data provide strong evidence of evolutionary connections among these human and animal RVs, pointing to a common ancestor in P[I] with a possible animal host origin. While the binding properties to GlcNAc-containing saccharides are maintained, changes in binding to additional residues, such as those in the polymorphic type 1 HBGAs may occur in the course of RV evolution, explaining the complex P[II] genogroup that mainly causes diseases in humans but also in some animals.
Highlights
Rotaviruses (RVs) are a major cause of severe gastroenteritis in children under the age of 5, causing 200,000 deaths[1,2,3]and account for 2 million childhood hospital admissions with an estimated cost of over 1 billion US dollars per year[4, 5]
Significant advances in understanding ligand-associated RV host ranges have been made but how such host ligands drive RV evolution leading to the diverse genotypes/genogroups already identified remains unclear
In our recent study of another P[II] RV (P[19]) that is genetically closely related with the other P[II] RVs, we found that P[19] VP8Ãs have a unique property of binding two types of glycans, the mucin core and type 1 histo-blood group antigens (HBGAs) and may use a binding site different from those described above[26], indicating that the P[II] RVs may be evolutionarily distantly related with other genogroups
Summary
Rotaviruses (RVs) are a major cause of severe gastroenteritis in children under the age of 5, causing 200,000 deaths[1,2,3]and account for 2 million childhood hospital admissions with an estimated cost of over 1 billion US dollars per year[4, 5]. It has been shown that RV attachment to cell surface carbohydrates, mediated by the VP8Ã domain of the spike protein VP4, is a required first step of an effective infection [6,7,8,9]. Based on the VP4 sequences, the group A RVs have been grouped into 40 genotypes (P[1]-P[40])[10, 11]. In a study based on the VP8Ã sequence, the different RV genotypes have been grouped into five genogroups (P[I]-P[V])[12]. Different genotypes/genogroups cause diseases in different populations and/or various animal species and each genotype and genogroup may have distinct glycan binding specificities responsible for their host ranges or tropism
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