Disentangling competence for genetic transformation and virulence in Streptococcus pneumoniae

Lin, Jingjun; Zhu, Luchang; Lau, Gee W.

doi:10.1007/s00294-015-0520-z

Cited by 33 publications

(32 citation statements)

References 39 publications

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“…In particular, this mechanism allows bacteria to acquire and share genes encoding antibiotic resistance [39]. In addition, competence activation in streptococci also results in the co-expression of genes involved in virulence-associated functions and predation mechanisms, which are essential for their fitness during infection [40, 41]. Inhibiting competence development thus constitutes an interesting target in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS

Talagas¹,

Fontaine²,

Laura³

et al. 2016

PLoS Pathog

100

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In Gram-positive bacteria, cell-to-cell communication mainly relies on extracellular signaling peptides, which elicit a response either indirectly, by triggering a two-component phosphorelay, or directly, by binding to cytoplasmic effectors. The latter comprise the RNPP family (Rgg and original regulators Rap, NprR, PrgX and PlcR), whose members regulate important bacterial processes such as sporulation, conjugation, and virulence. RNPP proteins are increasingly considered as interesting targets for the development of new antibacterial agents. These proteins are characterized by a TPR-type peptide-binding domain, and except for Rap proteins, also contain an N-terminal HTH-type DNA-binding domain and display a transcriptional activity. Here, we elucidate the structure-function relationship of the transcription factor ComR, a new member of the RNPP family, which positively controls competence for natural DNA transformation in streptococci. ComR is directly activated by the binding of its associated pheromone XIP, the mature form of the comX/sigX-inducing-peptide ComS. The crystal structure analysis of ComR from Streptococcus thermophilus combined with a mutational analysis and in vivo assays allows us to propose an original molecular mechanism of the ComR regulation mode. XIP-binding induces release of the sequestered HTH domain and ComR dimerization to allow DNA binding. Importantly, we bring evidence that this activation mechanism is conserved and specific to ComR orthologues, demonstrating that ComR is not an Rgg protein as initially proposed, but instead constitutes a new member of the RNPP family. In addition, identification of XIP and ComR residues important for competence activation constitutes a crucial step towards the design of antagonistic strategies to control gene exchanges among streptococci.

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Section: Introductionmentioning

confidence: 99%

Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS

Talagas¹,

Fontaine²,

Laura³

et al. 2016

PLoS Pathog

100

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“…Since DprA interacts directly with ComE~P to mediate the shut‐off of pneumococcal competence, there is a direct link between DprA and pneumococcal fitness. It has been suggested that the link between competence and fitness provides a selective pressure for maintenance of an intact com regulon, which in turn provides the adaptive benefit of transformation (Lin et al, ). Here, we have shown that the high cellular levels of DprA are crucial for optimal competence shut‐off and for the fitness of transformants.…”

Section: Discussionmentioning

confidence: 99%

Fine‐tuning cellular levels of DprA ensures transformant fitness in the human pathogen Streptococcus pneumoniae

Johnston

Mortier‐Barrière

Khemici

et al. 2018

Molecular Microbiology

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Natural genetic transformation is a widespread mechanism of horizontal gene transfer. It involves the internalization of exogenous DNA as single strands and chromosomal integration via homologous recombination, promoting acquisition of new genetic traits. Transformation occurs during a distinct physiological state called competence. In Streptococcus pneumoniae, competence is controlled by ComDE, a two-component system induced by an exported peptide pheromone. DprA is universal among transformable species, strongly induced during pneumococcal competence, and crucial for pneumococcal transformation. Pneumococcal DprA plays three crucial roles in transformation and competence. Firstly, DprA protects internalized DNA from degradation. Secondly, DprA loads the homologous recombinase RecA onto transforming DNA to promote transformation. Finally, DprA interacts with the response regulator ComE to shut-off competence. Here, we explored the effect of altering the cellular levels of DprA on these three roles. High cellular levels of DprA were not required for the primary role of DprA as a transformation-dedicated recombinase loader or for protection of transforming DNA. In contrast, full expression of dprA was required for optimal competence shut-off and transformant fitness. High cellular levels of DprA thus ensure the fitness of pneumococcal transformants by mediating competence shut-off. This promotes survival and propagation of transformants, maximizing pneumococcal adaptive potential.

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“…This mechanism of DNA uptake may result in important changes in the bacterial genetic background, which may lead to the emergence of bacterial subpopulations carrying different genetic traits in relation to the parental generation 3 . When S. pneumoniae enter in the competent state, the autolysin—considered an important S. pneumoniae virulence factor—is activated.…”

Section: Introductionmentioning

confidence: 99%

The virulence of Streptococcus pneumoniae partially depends on dprA

Chang

et al. 2017

Brazilian Journal of Microbiology

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Streptococcus pneumoniae is one of the most frequent opportunistic pathogens worldwide. DNA processing protein A (DprA) is an important factor involved in bacterial uptake and DNA integration into bacterial genome, but its role in S. pneumoniae virulence remains unclear. The aim of this study was to characterize the effects of the pneumococcal dprA gene on the pathogenesis of S. pneumoniae. To construct a dprA-deficient pneumococcal strain, the dprA gene of the S. pneumoniae strain D39 was inactivated. The virulence of this dprA-deficient strain, designated ΔD39, was compared with that of the wild-type strain by evaluating their respective capabilities to adhere to human pulmonary epithelial cells (PEC-A549) and by analyzing their choline-binding protein expression levels. In addition, the expression profiles of genes associated with virulence and host survival assays were also conducted with the mutant and the wild-type strain. Our results indicate that the capability of ΔD39 to adhere to the PEC-A549 airway cells was significantly lower (p < 0.01) compared with D39. Additionally, the 100-KD choline-binding protein was not detected in ΔD39. The addition of competence-stimulating peptide (CSP) lead to a significantly reduction of psaA mRNA expression in the dprA-deficient mutant and an increased level of psaA transcripts in the wild-type strain (p < 0.01). The median survival time of mice intraperitoneally infected with ΔD39 was significantly higher (p < 0.01) than that of mice infected with D39. The results of this study suggest that DprA has a significant effect on virulence characteristics of S. pneumoniae by influencing the expression of choline-binding protein and PsaA.

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Disentangling competence for genetic transformation and virulence in Streptococcus pneumoniae

Cited by 33 publications

References 39 publications

Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS

Structural Insights into Streptococcal Competence Regulation by the Cell-to-Cell Communication System ComRS

Fine‐tuning cellular levels of DprA ensures transformant fitness in the human pathogen Streptococcus pneumoniae

The virulence of Streptococcus pneumoniae partially depends on dprA

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