title: Multivalent adhesion molecule 7 clusters act as signaling platform for host cellular GTPase activation and facilitate epithelial barrier dysfunction.
abstract: Vibrio parahaemolyticus is an emerging bacterial pathogen which colonizes the gastrointestinal tract and can cause severe enteritis and bacteraemia. During infection, V. parahaemolyticus primarily attaches to the small intestine, where it causes extensive tissue damage and compromises epithelial barrier integrity. We have previously described that Multivalent Adhesion Molecule (MAM) 7 contributes to initial attachment of V. parahaemolyticus to epithelial cells. Here we show that the bacterial adhesin, through multivalent interactions between surface-induced adhesin clusters and phosphatidic acid lipids in the host cell membrane, induces activation of the small GTPase RhoA and actin rearrangements in host cells. In infection studies with V. parahaemolyticus we further demonstrate that adhesin-triggered activation of the ROCK/LIMK signaling axis is sufficient to redistribute tight junction proteins, leading to a loss of epithelial barrier function. Taken together, these findings show an unprecedented mechanism by which an adhesin acts as assembly platform for a host cellular signaling pathway, which ultimately facilitates breaching of the epithelial barrier by a bacterial pathogen.
authors.affiliation: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Jenson
authors.initials: J
authors.lastname: Lim
authors.affiliation: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Stones
authors.affiliation: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Catherine Alice
authors.initials: CA
authors.lastname: Hawley
authors.affiliation: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Charlie Anne
authors.initials: CA
authors.lastname: Watson
authors.affiliation: Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Krachler
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism; D015153:Blotting, Western; D018938:Caco-2 Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002463:Cell Membrane Permeability; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D004926:Escherichia coli / Q000254:growth & development / Q000378:metabolism*; D020549:GTP Phosphohydrolase Activators / Q000378:metabolism*; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D008856:Microscopy, Fluorescence; D015398:Signal Transduction; D014735:Vibrio Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D014736:Vibrio parahaemolyticus / Q000472:pathogenicity; D014774:Virulence; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D018829:Adhesins, Bacterial; D015815:Cell Adhesion Molecules; D020549:GTP Phosphohydrolase Activators; D020741:rho GTP-Binding Proteins