Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands

Group A rotaviruses are major intestinal pathogens that express potential 41 and 47 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 recombinant 41 as a cellular receptor. In this study a new potential 41, 47 and 91 integrin ligand sequence, Tyr-Gly-Leu, was identified in VP4. It was shown that several human and monkey rotaviruses bound 41 and 47, but not 91. Binding to 41 mediated the infectivity and growth of monkey rotaviruses, and binding to 47 mediated their infectivity. A porcine rotavirus interacted with 4 integrins at a post-binding stage to facilitate infection. Activation of 41 increased rotavirus infectivity. Cellular treatment with peptides containing the 4 integrin ligand sequences Tyr-Gly-Leu and Ile-Asp-Ala eliminated virus binding to 4 integrins and infectivity. In contrast, rotavirus recognition of 4 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 of 41 was demonstrated with rotavirus reassortants. Swapping and point mutagenesis of 4 surface loops showed that rotaviruses required the same 4 residues and domains for binding as the natural 4 integrin ligands: mucosal addressin cell adhesion molecule-1, fibronectin and vascular cell adhesion molecule-1. Several rotaviruses are able to use 47 and 41 for cell binding or entry, through the recognition of the same 4-subunit domains as natural 4 ligands.