The two faces of Janus: virulence gene regulation by CovR/S in group A streptococci

Churchward, Gordon

doi:10.1111/j.1365-2958.2007.05649.x

Cited by 112 publications

(122 citation statements)

References 60 publications

(108 reference statements)

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“…The CovR response regulator has been shown to repress trxSR transcription in two different microarray studies using different GAS strains (10,15). At several target promoters, CovR binds to conserved ATTARA motifs or TTA repeats to mediate direct repression of transcription (7). The presence of a consensus CovR binding site immediately downstream of P Spy1307 suggests that CovR might directly repress its transcription (Fig.…”

Section: Vol 76 2008 Trxr Regulates Mga and Virulence In M1 Gas 4663mentioning

confidence: 99%

“…The best characterized TCS in GAS is the CovRS/CsrRS system that functions as a repressor of many known and putative virulence genes, including those encoding capsule synthesis (hasABC), streptolysin S (sagA), streptokinase (ska), and streptodornase (sdn) (7,12,15,21). CovRS has been shown to regulate transcription of 15% of the GAS genome either directly or indirectly and is responsive to nonphysiological concentrations of Mg 2ϩ and various stress conditions likely to be encountered during infection of the human host (11,15,17,18).…”

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confidence: 99%

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TrxR, a New CovR-Repressed Response Regulator That Activates the Mga Virulence Regulon in Group A Streptococcus

et al. 2008

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Coordinate regulation of virulence factors by the group A streptococcus (GAS) Streptococcus pyogenes is important in this pathogen's ability to cause disease. To further elucidate the regulatory network in this human pathogen, the CovR-repressed two-component system (TCS) trxSR was chosen for further analysis based on its homology to a virulence-related TCS in Streptococcus pneumoniae. In a murine skin infection model, an insertion mutation in the response regulator gene, trxR, led to a significant reduction in lesion size, lesion severity, and lethality. Curing the trxR mutation restored virulence comparable to the wild-type strain. The trxSR operon was defined in vivo, and CovR was found to directly repress its promoter in vitro. DNA microarray analysis established that TrxR activates transcription of Mga-regulated virulence genes, which may explain the virulence attenuation of the trxR mutant. This regulation appears to occur by activation of the mga promoter, Pmga, as demonstrated by analysis of a luciferase reporter fusion. Complementation of the trxR mutant with trxR on a plasmid restored expression of Mga regulon genes and restored virulence in the mouse model to wild-type levels. TrxR is the first TCS shown to regulate Mga expression. Because it is CovR repressed, TrxR defines a new pathway by which CovR can influence Mga to affect pathogenesis in the GAS.

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Section: Vol 76 2008 Trxr Regulates Mga and Virulence In M1 Gas 4663mentioning

confidence: 99%

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confidence: 99%

TrxR, a New CovR-Repressed Response Regulator That Activates the Mga Virulence Regulon in Group A Streptococcus

et al. 2008

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“…Although the exact mechanism of signal transduction in the case of CovRS has not been established, different modes have been proposed for its modulation (21). It is thought that CovS, the cognate sensor kinase, phosphorylates the conserved aspartate residue on the CovR for its activation; however, phosphorylation has never been demonstrated in vivo or in vitro.…”

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confidence: 99%

“…It has also been proposed that under certain stress conditions, CovS may inactivate CovR by dephosphorylation (22). In addition, low-molecular-weight phosphodonors, such as acetyl-phosphate or carbamoyl phosphate, can also phosphorylate CovR and activate the response regulator (21). Interestingly, S. mutans does not possess the cognate sensor kinase CovS, and the molecular mechanisms of CovR activation are currently unknown.…”

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confidence: 99%

CovR Alleviates Transcriptional Silencing by a Nucleoid-Associated Histone-Like Protein in Streptococcus mutans

Biswas

Mohapatra

2012

J Bacteriol

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In Streptococcus mutans, the global response regulator CovR plays an important role in biofilm formation, stress tolerance response, and caries production. We have previously demonstrated that CovR activates a large gene cluster, which is a part of a genomic island, TnSmu2. In this article, we have further characterized CovR at the molecular level to understand the gene activation mechanism. Toward this end, we mapped the transcription start site of the operon that lies upstream of the SMU.1348 gene (P SMU.1348 ), the first gene of the cluster. We constructed a transcriptional reporter fusion and showed that CovR induces expression from P SMU.1348 . We also demonstrated that purified CovR protects the sequence surrounding the ؊10 region of P SMU.1348 . In an in vitro transcription assay, we showed that histone-like protein (HLP), a homologue of Escherichia coli HU protein, represses transcription from P SMU.1348 . In vivo overexpression of HLP in trans also represses transcription from P SMU.1348 . Addition of CovR to the HLP-repressed P SMU.1348 resulted in increased transcription from the promoter, suggesting a role for CovR in countering HLP silencing. Moreover, addition of SMU.1349, a transcriptional activator of the operon, to the in vitro assay further stimulated the transcription. Based on our in vivo and in vitro results, we propose a model for transcriptional activation of the operon.

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“…CovR/S regulates approximately 15% of the genes in GAS, including virulence genes, such as the has operon (hyaluronic acid capsule synthesis), ska (streptokinase), sagA (streptolysin S), and speB (cysteine protease) (17,20,27,33). CovS is thought to be the cognate sensor kinase for the phosphorylation or dephosphorylation of CovR (11); environmental stimuli, particularly during periods of stress, are recognized by CovS, which in turn regulates the activity of the global response regulator CovR (13). CovR regulates the expression of common sets of genes in different strains, but the repertoire of genes regulated by CovR may vary between strains (12, 50).…”

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confidence: 99%

Modulation ofcovRExpression inStreptococcus mutansUA159

2008

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The biofilm-forming Streptococcus mutans is a gram-positive bacterium that resides in the human oral cavity and is considered to be the primary etiological agent in the formation of dental caries. The global response regulator CovR, which lacks a cognate sensor kinase, is essential for the pathogenesis and biofilm formation of this bacterium, but it is not clear how covR expression is regulated in S. mutans. In this communication, we present the results of our studies examining various factors that regulate the expression of covR in S. mutans UA159. The results of Southern hybridization and PCR analysis indicated that CovR is an orphan response regulator in various isolates of S. mutans. The transcriptional start site for covR was found to be 221 base pairs upstream of the ATG start codon, and site-directed mutagenesis of the upstream TATAAT box confirmed our findings. The expression of covR is growth phase dependent, with maximal expression observed during exponential-growth phase. While changes to the growth temperature did not significantly affect the expression of covR, increasing the pH or the concentration of Mg 2؉ in the growth medium leads to an increase in covR expression. The results of semiquantitative reverse transcriptase PCR analysis and in vivo transcriptionalfusion reporter assays indicated that CovR autoregulates its own expression; this was verified by the results of electrophoretic mobility shift assays and DNase I protection assays, which demonstrated direct binding of CovR to the promoter region. Apparently, regulation by Mg 2؉ and the autoregulation of covR are not linked. A detailed analysis of the regulation of CovR may lead to a better understanding of the pathogenesis of S. mutans, as well as providing further insight into the prevention of dental caries.

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The two faces of Janus: virulence gene regulation by CovR/S in group A streptococci

Cited by 112 publications

References 60 publications

TrxR, a New CovR-Repressed Response Regulator That Activates the Mga Virulence Regulon in Group A Streptococcus

TrxR, a New CovR-Repressed Response Regulator That Activates the Mga Virulence Regulon in Group A Streptococcus

CovR Alleviates Transcriptional Silencing by a Nucleoid-Associated Histone-Like Protein in Streptococcus mutans

Modulation ofcovRExpression inStreptococcus mutansUA159

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