Abstract
Strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. Rotaviruses (RVs), which cause life-threatening gastroenteritis in infants and children, display significant genotype-dependent variations in glycan recognition resulting from sequence alterations in the VP8* domain of the spike protein VP4. The structural basis of this genotype-dependent glycan specificity, particularly in human RVs, remains poorly understood. Here, from crystallographic studies, we show how genotypic variations configure a novel binding site in the VP8* of a neonate-specific bovine-human reassortant to uniquely recognize either type I or type II precursor glycans, and to restrict type II glycan binding in the bovine counterpart. Such a distinct glycan-binding site that allows differential recognition of the precursor glycans, which are developmentally regulated in the neonate gut and abundant in bovine and human milk provides a basis for age-restricted tropism and zoonotic transmission of G10P[11] rotaviruses.
Highlights
Strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis
Recent studies have shown that recognition of sialoglycans is necessary for most ARVs10–12, human RV (HRV) exhibit genotype-dependent variations in glycan specificity10,13–15, which could be the basis for host tropism, host adaptation and zoonosis
Neonatal infections are largely asymptomatic, G10P[11] infections are associated with severe gastrointestinal symptoms such as feed intolerance, necrotizing enterocolitis and abdominal distension in some settings19 An asymptomatic HRV strain 116E with a P[11] genotype has recently been licensed for use as a vaccine in India20
Summary
Strain-dependent variation of glycan recognition during initial cell attachment of viruses is a critical determinant of host specificity, tissue-tropism and zoonosis. For rotaviruses (RVs), which are the major causative agents of life-threatening gastroenteritis in children under the age of 5 years and result in 453,000 deaths worldwide annually, recognition of specific cellular glycans for initial cell attachment is mediated by the distally located VP8* domain of the spike protein VP4 (refs 3,4). This protein along with the glycoprotein VP7 constitutes the outermost layer of the three concentric capsid layers that enclose the genome consisting of 11 double-stranded RNA segments. The infectivity of the vaccine P[11] HRV 116E was abrogated by the polyacrylamide (PAA)conjugated poly-N-acetyl-D-lactosamine in human milk, and Lycopersicon esculentum-positive infant saliva
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