title: ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization.
abstract: The virulence regulator ToxR initiates and coordinates gene expression needed by Vibrio cholerae to colonize the small intestine and cause disease. Despite its prominence in V. cholerae virulence, our understanding of the direct ToxR regulon is limited to four genes: toxT, ompT, ompU and ctxA. Here, we determine ToxR's genome-wide DNA-binding profile and demonstrate that ToxR is a global regulator of both progenitor genome-encoded genes and horizontally acquired islands that encode V. cholerae's major virulence factors and define pandemic lineages. We show that ToxR shares more than a third of its regulon with the histone-like nucleoid structuring protein H-NS, and antagonizes H-NS binding at shared binding locations. Importantly, we demonstrate that this regulatory interaction is the critical function of ToxR in V. cholerae colonization and biofilm formation. In the absence of H-NS, ToxR is no longer required for V. cholerae to colonize the infant mouse intestine or for robust biofilm formation. We further illustrate a dramatic difference in regulatory scope between ToxR and other prominent virulence regulators, despite similar predicted requirements for DNA binding. Our results suggest that factors in addition to primary DNA structure influence the ability of ToxR to recognize its target promoters.
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Misha I
authors.initials: MI
authors.lastname: Kazi
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Conrado
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Mey
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.|Institute of Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Shelley M
authors.initials: SM
authors.lastname: Payne
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.|Institute of Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Davies
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics*; D001483:Base Sequence; D015152:Blotting, Northern; D002771:Cholera / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D022761:Gene Transfer, Horizontal; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D014734:Vibrio cholerae / Q000472:pathogenicity*; D014774:Virulence / Q000235:genetics*; D037521:Virulence Factors / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C031908:H-NS protein, bacteria; D014157:Transcription Factors; D037521:Virulence Factors; C499324:toxR protein, Vibrio cholerae