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

Kazi, Misha I.; Conrado, Aaron R.; Mey, Alexandra R.; Payne, Shelley M.; Davies, Bryan William

doi:10.1371/journal.ppat.1005570

Cited by 44 publications

(64 citation statements)

References 114 publications

(175 reference statements)

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“…Since many of these phenotypes have also been associated with ToxR, these results suggest that ToxR regulates many of its gene targets indirectly. This conclusion is supported by the aforementioned ChIP-seq studies indicating that ToxR directly regulated just 39 genes (49). The gene encoding LeuO was among the 39 genes identified in the ChIP-seq data set, confirming our previous reports that ToxR directly regulated leuO transcription (10,11).…”

Section: Discussionsupporting

confidence: 89%

“…This conclusion is supported by microarray studies which implicated ToxR in the regulation of Ͼ150 genes in V. cholerae, including genes involved in cellular transport, energy metabolism, motility, iron uptake, and outer membrane proteins (30). This conclusion is further supported by a recently published ToxR chromatin immunoprecipitation sequencing (ChIP-seq) study showing that ToxR can function as an H-NS antagonist (49). We previously showed that ToxR directly activated leuO expression in response to environmental cues by a process that was dependent upon the presence of the periplasmic domain of ToxR (10,11).…”

Section: Discussionmentioning

confidence: 68%

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Vibrio cholerae LeuO Links the ToxR Regulon to Expression of Lipid A Remodeling Genes

et al. 2016

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Vibrio cholerae is an intestinal pathogen that causes the diarrheal disease cholera. Colonization of the intestine depends upon the expression of genes that allow V. cholerae to overcome host barriers, including low pH, bile acids, and the innate immune system. ToxR is a major contributor to this process. ToxR is a membrane-spanning transcription factor that coordinates gene expression in response to environmental cues. In previous work we showed that ToxR upregulated leuO expression in response to bile salts. LeuO is a LysR family transcription factor that contributes to acid tolerance, bile resistance, and biofilm formation in V. cholerae. Here, we investigated the function of ToxR and LeuO in cationic antimicrobial peptide (CAMP) resistance. We report that ToxR and LeuO contribute to CAMP resistance by regulating carRS transcription. CarRS is a two-component regulatory system that positively regulates almEFG expression. AlmEFG confers CAMP resistance by glycinylation of lipid A. We found that the expression of carRS and almEFG and the polymyxin B MIC increased in mutants lacking toxRS or leuO. Conversely, leuO overexpression decreased the polymyxin B MIC. Furthermore, we found that LeuO directly bound to the carRS promoter and that ToxR-dependent activation of leuO transcription regulated carRS transcription in response to bile salts. Our results suggest that LeuO functions downstream of ToxR to modulate carRS expression in response to environmental cues. This study extends the functional role of ToxR and LeuO in environmental adaptation to include cell surface remodeling and CAMP resistance. Vibrio cholerae is a Gram-negative facultative human pathogen and the causative agent of the diarrheal disease cholera. V. cholerae is native to aquatic ecosystems, where it often associates with chitinous aquatic organisms (reviewed in reference 1). People acquire V. cholerae by ingestion of contaminated food or water. Following ingestion, V. cholerae colonizes the small intestine, where it produces virulence factors that result in a severe secretory diarrhea that is the hallmark of the disease cholera. The secretory diarrhea then contributes to V. cholerae transmission to new hosts and dissemination into the aquatic ecosystem.The ability of V. cholerae to rapidly transition between the aquatic ecosystem and the host is essential for its success as a pathogen. Colonization of the human gastrointestinal tract is mediated by transcriptional responses that facilitate adaptation to dynamic environments in the gastrointestinal tract. Following ingestion, V. cholerae activates the expression of virulence factors that are essential for both colonization and disease development. This includes the production of the enterotoxin cholera toxin (CT) and an adhesin called the toxin coregulated pilus (TCP) (2, 3). The expression of many V. cholerae virulence genes is coordinately regulated by the ToxR regulon (4). The ToxR regulon is divided into two branches: the ToxT-dependent branch and the ToxT-independent branch. In the ToxT-depe...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 68%

Vibrio cholerae LeuO Links the ToxR Regulon to Expression of Lipid A Remodeling Genes

et al. 2016

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“…A similar pattern was observed in independent ChiP-Seq analysis using a different El Tor biotype V. cholerae strain (Fig. 1) [31]. H-NS bound to fewer sites along V. cholerae chromosomes, but occupied longer stretches of DNA compared to E. coli .…”

Section: H-ns Global Regulation and Chromatin Binding In V Choleraesupporting

confidence: 81%

“…Another example is provided by the bitopic regulator ToxR. The cytoplasmic domain of the transmembrane protein ToxR directly activates the transcription of toxT , ompU and ompT (encoding outer membrane proteins) and the vpsL-Q operon while remaining anchored to the inner membrane [31,36]. The bridging activity of H-NS could facilitate chromosome-inner membrane interactions at several sites, allowing ToxR molecules to simultaneously engage multiple target promoters.…”

Section: H-ns Global Regulation and Chromatin Binding In V Choleraementioning

confidence: 99%

H-NS: an overarching regulator of the Vibrio cholerae life cycle

Ayala

Silva

Benítez

2017

Research in Microbiology

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Vibrio cholerae has become a model organism for studies connecting virulence, pathogen evolution and infectious disease ecology. The coordinate expression of motility, virulence and biofilm enhances its pathogenicity, environmental fitness and fecal-oral transmission. The histone-like nucleoid structuring protein negatively regulates gene expression at multiple phases of the V. cholerae life cycle. Here we discuss: (i) the regulatory and structural implications of H-NS chromatin-binding in the two-chromosome cholera bacterium; (ii) the factors that counteract H-NS repression; and (iii) a model for the regulation of the V. cholerae life cycle that integrates H-NS repression, cyclic diguanylic acid signaling and the general stress response.

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“…Notable mutations across the sequential strains first include a G107S mutation in the histone-like protein H-NS, which is in the DNA binding domain of this repressor that controls transcription of genes that encode hemolysin, MARTX, and CT (39). A recent study showed that deletion of hns uncouples virulence gene expression from its normal control by ToxR, which could account in part for the increased toxin production (40).…”

Section: Overproduction Of Secreted Toxins By An Aet Isolate From Haitimentioning

confidence: 99%

Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain

et al. 2016

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bVibrio cholerae O1 El Tor strains have been responsible for pandemic cholera since 1961. These strains have evolved over time, spreading globally in three separate waves. Wave 3 is caused by altered El Tor (AET) variant strains, which include the strain with the signature ctxB7 allele that was introduced in 2010 into Haiti, where it caused a devastating epidemic. In this study, we used phenotypic analysis to compare an early isolate from the Haiti epidemic to wave 1 El Tor isolates commonly used for research. It is demonstrated that the Haiti isolate has increased production of cholera toxin (CT) and hemolysin, increased motility, and a reduced ability to form biofilms. This strain also outcompetes common wave 1 El Tor isolates for colonization of infant mice, indicating that it has increased virulence. Monitoring of CT production and motility in additional wave 3 isolates revealed that this phenotypic variation likely evolved over time rather than in a single genetic event. Analysis of available whole-genome sequences and phylogenetic analyses suggested that increased virulence arose from positive selection for mutations found in known and putative regulatory genes, including hns and vieA, diguanylate cyclase genes, and genes belonging to the lysR and gntR regulatory families. Overall, the studies presented here revealed that V. cholerae virulence potential can evolve and that the currently prevalent wave 3 AET strains are both phenotypically distinct from and more virulent than many El Tor isolates.

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

Cited by 44 publications

References 114 publications

Vibrio cholerae LeuO Links the ToxR Regulon to Expression of Lipid A Remodeling Genes

Vibrio cholerae LeuO Links the ToxR Regulon to Expression of Lipid A Remodeling Genes

H-NS: an overarching regulator of the Vibrio cholerae life cycle

Phenotypic Analysis Reveals that the 2010 Haiti Cholera Epidemic Is Linked to a Hypervirulent Strain

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