title: Quorum-sensing regulators control virulence gene expression in Vibrio cholerae.
abstract: The production of virulence factors including cholera toxin and the toxin-coregulated pilus in the human pathogen Vibrio cholerae is strongly influenced by environmental conditions. The well-characterized ToxR signal transduction cascade is responsible for sensing and integrating the environmental information and controlling the virulence regulon. We show here that, in addition to the known components of the ToxR signaling circuit, quorum-sensing regulators are involved in regulation of V. cholerae virulence. We focused on the regulators LuxO and HapR because homologues of these two proteins control quorum sensing in the closely related luminous marine bacterium Vibrio harveyi. Using an infant mouse model, we found that a luxO mutant is severely defective in colonization of the small intestine. Gene arrays were used to profile transcription in the V. cholerae wild type and the luxO mutant. These studies revealed that the ToxR regulon is repressed in the luxO mutant, and that this effect is mediated by another negative regulator, HapR. We show that LuxO represses hapR expression early in log-phase growth, and constitutive expression of hapR blocks ToxR-regulon expression. Additionally, LuxO and HapR regulate a variety of other cellular processes including motility, protease production, and biofilm formation. Together these data suggest a role for quorum sensing in modulating expression of blocks of virulence genes in a reciprocal fashion in vivo.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Miller
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
authors.forename: Michelle
authors.initials: M
authors.lastname: Dziejman
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Bassler
authors.forename: John J
authors.initials: JJ
authors.lastname: Mekalanos
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002771:Cholera; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D014734:Vibrio cholerae / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C088907:LuxO protein, Vibrio harveyi; D012097:Repressor Proteins; C097244:TCPP protein, Vibrio cholerae; D015534:Trans-Activators; D014157:Transcription Factors; C499324:toxR protein, Vibrio cholerae; C066719:toxR protein, bacteria; C064778:LuxR autoinducer binding proteins