title: Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands.
abstract: Group A rotaviruses are major intestinal pathogens that express potential alpha4beta1 and alpha4beta7 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 alpha4beta1 as a cellular receptor. In this study a new potential alpha4beta1, alpha4beta7 and alpha9beta1 integrin ligand sequence, Tyr-Gly-Leu, was identified in VP4. It was shown that several human and monkey rotaviruses bound alpha4beta1 and alpha4beta7, but not alpha9beta1. Binding to alpha4beta1 mediated the infectivity and growth of monkey rotaviruses, and binding to alpha4beta7 mediated their infectivity. A porcine rotavirus interacted with alpha4 integrins at a post-binding stage to facilitate infection. Activation of alpha4beta1 increased rotavirus infectivity. Cellular treatment with peptides containing the alpha4 integrin ligand sequences Tyr-Gly-Leu and Ile-Asp-Ala eliminated virus binding to alpha4 integrins and infectivity. In contrast, rotavirus recognition of alpha4 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 alpha4beta1 was demonstrated with rotavirus reassortants. Swapping and point mutagenesis of alpha4 surface loops showed that rotaviruses required the same alpha4 residues and domains for binding as the natural alpha4 integrin ligands: mucosal addressin cell adhesion molecule-1, fibronectin and vascular cell adhesion molecule-1. Several rotaviruses are able to use alpha4beta7 and alpha4beta1 for cell binding or entry, through the recognition of the same alpha4-subunit domains as natural alpha4 ligands.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Kate L
authors.initials: KL
authors.lastname: Graham
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Fleming
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Halasz
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Hewish
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Hadya S
authors.initials: HS
authors.lastname: Nagesha
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Holmes
authors.affiliation: The University of California, Davis, UC Davis Medical Center, Research III, Suite 3300, 4645 2nd Avenue, Sacramento, CA 95817, USA.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Coulson
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D011485:Protein Binding; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D012401:Rotavirus / Q000502:physiology*
chemical_list: D000956:Antigens, Viral; D036022:Capsid Proteins; D039041:Integrin alpha4beta1; D016023:Integrins; D011991:Receptors, Virus; C060339:VP4 protein, Rotavirus; C050779:VP7 protein, Rotavirus; C113256:integrin alpha 9 beta 1; C071777:integrin alpha4beta7