Rotaviruses interact with α4β7 and α4β1 integrins by binding the same integrin domains as natural ligands

Abstract

Group A rotaviruses are major intestinal pathogens that express potentialα4β1 andα4β7 integrin ligand sequences Leu–Asp–Val and Leu–Asp–Ile in their outer capsid protein VP7, and Ile–Asp–Ala in their spike protein VP4. Monkey rotavirus SA11 can use recombinantα4β1 as a cellular receptor. In this study a new potentialα4β1,α4β7 andα9β1 integrin ligand sequence, Tyr–Gly–Leu, was identified in VP4. It was shown that several human and monkey rotaviruses boundα4β1 andα4β7, but notα9β1. Binding toα4β1 mediated the infectivity and growth of monkey rotaviruses, and binding toα4β7 mediated their infectivity. A porcine rotavirus interacted withα4 integrins at a post-binding stage to facilitate infection. Activation ofα4β1 increased rotavirus infectivity. Cellular treatment with peptides containing theα4 integrin ligand sequences Tyr–Gly–Leu and Ile–Asp–Ala eliminated virus binding toα4 integrins and infectivity. In contrast, rotavirus recognition ofα4 integrins was unaffected by a peptide containing the sequence Leu–Asp–Val or by a mutation in the VP7 Leu–Asp–Val sequence. VP4 involvement in rotavirus recognition ofα4β1 was demonstrated with rotavirus reassortants. Swapping and point mutagenesis ofα4 surface loops showed that rotaviruses required the sameα4 residues and domains for binding as the naturalα4 integrin ligands: mucosal addressin cell adhesion molecule-1, fibronectin and vascular cell adhesion molecule-1. Several rotaviruses are able to useα4β7 andα4β1 for cell binding or entry, through the recognition of the sameα4-subunit domains as naturalα4 ligands.