Glycan recognition in globally dominant human rotaviruses

Liya Hu,Wilhelm Salmen,Sasirekha Ramani,Daniel R Laucirica,Ketki Patil,Allan Chris M Ferreon,Josephine C Ferreon,David F Smith,B V Venkataram Prasad,Banumathi Sankaran,Yi Lasanajak,Mary K Estes,Phoebe S Tsoi,Robert L Atmar

doi:10.1038/s41467-018-05098-4

Liya Hu, Wilhelm Salmen + Show 12 more

Open Access

https://doi.org/10.1038/s41467-018-05098-4

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Abstract

Rotaviruses (RVs) cause life-threatening diarrhea in infants and children worldwide. Recent biochemical and epidemiological studies underscore the importance of histo-blood group antigens (HBGA) as both cell attachment and susceptibility factors for the globally dominant P[4], P[6], and P[8] genotypes of human RVs. How these genotypes interact with HBGA is not known. Here, our crystal structures of P[4] and a neonate-specific P[6] VP8*s alone and in complex with H-type I HBGA reveal a unique glycan binding site that is conserved in the globally dominant genotypes and allows for the binding of ABH HBGAs, consistent with their prevalence. Remarkably, the VP8* of P[6] RVs isolated from neonates displays subtle structural changes in this binding site that may restrict its ability to bind branched glycans. This provides a structural basis for the age-restricted tropism of some P[6] RVs as developmentally regulated unbranched glycans are more abundant in the neonatal gut.

Highlights

Rotaviruses (RVs) cause life-threatening diarrhea in infants and children worldwide
Further modification of ABH histo-blood group antigens (HBGA) can occur by α-1, 3 fucosyltransferase (FUT3); adding an α-Fuc (LeFuc) to the precursor GlcNAc leads to secretor-positive Lewis (Se + Le+) HBGAs (ALeb, BLeb, and Leb)
Our studies show that VP8* of these genotypes engages the type I precursor glycan (Galβ1,3-GlcNAc) at a unique and conserved binding site that is present in all P[4], P[6] and P[8] human RVs (HRVs), and the subtle sequence and structural changes lead to an altered glycan configuration at the reducing end in the neonate-specific P[6] RV, that may play a key role in the age-restricted tropism of some P[6] strains

Summary

Introduction

Rotaviruses (RVs) cause life-threatening diarrhea in infants and children worldwide. Recent biochemical and epidemiological studies underscore the importance of histo-blood group antigens (HBGA) as both cell attachment and susceptibility factors for the globally dominant P[4], P[6], and P[8] genotypes of human RVs. Our crystal structures of P[4] and a neonate-specific P[6] VP8*s alone and in complex with H-type I HBGA reveal a unique glycan binding site that is conserved in the globally dominant genotypes and allows for the binding of ABH HBGAs, consistent with their prevalence. The VP8* of P[6] RVs isolated from neonates displays subtle structural changes in this binding site that may restrict its ability to bind branched glycans. Recent epidemiological studies indicate that infection by RVs strongly correlates with the secretor status of the individual, suggesting that the HBGAs are susceptibility factors for HRVs as well as cell attachment factors. Precursor disaccharides are expressed and the addition of branches and terminal carbohydrates is regulated in a tissue-specific manner during development. Previous crystallographic studies revealed that the VP8* of the P[14] HRV binds to A-type HBGA at a site that

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