title: The Vibrio parahaemolyticus Type III Secretion Systems manipulate host cell MAPK for critical steps in pathogenesis.
abstract: BACKGROUND
  Vibrio parahaemolyticus is a food-borne pathogen causing inflammation of the gastrointestinal epithelium. Pathogenic strains of this bacterium possess two Type III Secretion Systems (TTSS) that deliver effector proteins into host cells. In order to better understand human host cell responses to V. parahaemolyticus, the modulation of Mitogen Activated Protein Kinase (MAPK) activation in epithelial cells by an O3:K6 clinical isolate, RIMD2210633, was investigated. The importance of MAPK activation for the ability of the bacterium to be cytotoxic and to induce secretion of Interleukin-8 (IL-8) was determined.
  
  
  RESULTS
  V. parahaemolyticus deployed its TTSS1 to induce activation of the JNK, p38 and ERK MAPK in human epithelial cells. VP1680 was identified as the TTSS1 effector protein responsible for MAPK activation in Caco-2 cells and the activation of JNK and ERK by this protein was important in induction of host cell death. V. parahaemolyticus actively induced IL-8 secretion in a response mediated by TTSS1. A role for VP1680 and for the ERK signalling pathway in the stimulation of IL-8 production in epithelial cells by V. parahaemolyticus was established. Interestingly, TTSS2 inhibited IL-8 mRNA transcription at early stages of interaction between the bacterium and the cell.
  
  
  CONCLUSIONS
  This study demonstrated that V. parahaemolyticus activates the three major MAPK signalling pathways in intestinal epithelial cells in a TTSS1-dependent manner that involves the TTSS1 effector VP1680. Furthermore VP1680 and JNK and ERK activation were needed for maximal cytotoxicity of the bacterium. It was shown that V. parahaemolyticus is a strong inducer of IL-8 secretion and that induction reflects a balance between the effects of TTSS1 and TTSS2. Increases in IL-8 secretion were mediated by TTSS1 and VP1680, and augmented by ERK activation. These results shed light on the mechanisms of bacterial pathogenesis mediated by TTSS and suggest significant roles for MAPK signalling during infection with V. parahaemolyticus.
authors.affiliation: Discipline of Microbiology, School of Natural Sciences, National University of Ireland, Galway, University Road, Galway, Ireland.
authors.forename: Ksenia
authors.initials: K
authors.lastname: Matlawska-Wasowska
authors.forename: Rebecca
authors.initials: R
authors.lastname: Finn
authors.forename: Ana
authors.initials: A
authors.lastname: Mustel
authors.forename: Conor P
authors.initials: CP
authors.lastname: O'Byrne
authors.forename: Alan W
authors.initials: AW
authors.lastname: Baird
authors.forename: Eleanor T
authors.initials: ET
authors.lastname: Coffey
authors.forename: Aoife
authors.initials: A
authors.lastname: Boyd
mesh_terms: D016923:Cell Death; D002460:Cell Line; D004847:Epithelial Cells / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D021381:Protein Transport; D015854:Up-Regulation; D014736:Vibrio parahaemolyticus / Q000378:metabolism* / Q000472:pathogenicity*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D016209:Interleukin-8; D026901:Membrane Transport Proteins; D037521:Virulence Factors; D020928:Mitogen-Activated Protein Kinases