ToxR Antagonizes H-NS Regulation of Horizontally Acquired Genes to Drive Host Colonization

• Published in: PLoS pathogens Vol. 12; no. 4; p. e1005570
• Main Authors: Kazi, Misha I, Conrado, Aaron R, Mey, Alexandra R, Payne, Shelley M, Davies, Bryan W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2016; Public Library of Science (PLoS)
• Subjects: Animals; Bacterial Proteins - genetics; Base Sequence; Binding sites (Biochemistry); Biofilms; Biology and Life Sciences; Blotting, Northern; Cholera; Cholera - genetics; Chromatin Immunoprecipitation; Defects; Deoxyribonucleic acid; DNA; DNA-Binding Proteins - genetics; Gene expression; Gene Expression Regulation, Bacterial - genetics; Gene Transfer, Horizontal; Genetic aspects; Genetic regulation; Genomes; Health aspects; Medicine and Health Sciences; Mice; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Pandemics; Pathogenesis; Pathogens; Plasmids; Promoters (Genetics); Properties; Proteins; Research and Analysis Methods; Reverse Transcriptase Polymerase Chain Reaction; Transcription factors; Transcription Factors - genetics; Vibrio cholerae; Vibrio cholerae - pathogenicity; Virulence - genetics; Virulence Factors - genetics
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005570

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.