Two-Component Signal Transduction Systems in the Human Pathogen Streptococcus agalactiae

Thomas, Lamar S.; Cook, Laura C. C.

doi:10.1128/iai.00931-19

Cited by 36 publications

(24 citation statements)

References 110 publications

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“…The major regulator of host-pathogen interaction in ß-hemolytic streptococci is the transcriptional factor CovR belonging to the PhoP family of bacterial response regulator [19,20]. Targeted analysis in GBS demonstrated that CovR directly represses the transcription of the PLOS GENETICS cyl operon encoding the ß-h/c toxin, the bibA gene, and the PI-1 pili operon [21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

The CovR regulatory network drives the evolution of Group B Streptococcus virulence

et al. 2021

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Virulence of the neonatal pathogen Group B Streptococcus is under the control of the master regulator CovR. Inactivation of CovR is associated with large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, transcriptome analyses suggested a plasticity of the CovR signaling pathway in clinical isolates leading to phenotypic heterogeneity in the bacterial population. In this study, we characterized the CovR regulatory network in a strain representative of the CC-17 hypervirulent lineage responsible of the majority of neonatal meningitis. Transcriptome and genome-wide binding analysis reveal the architecture of the CovR network characterized by the direct repression of a large array of virulence-associated genes and the extent of co-regulation at specific loci. Comparative functional analysis of the signaling network links strain-specificities to the regulation of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, to mutations in CovR-regulated promoters, and to variability in CovR activation by phosphorylation. This regulatory adaptation occurs at the level of genes, promoters, and of CovR itself, and allows to globally reshape the expression of virulence genes. Overall, our results reveal the direct, coordinated, and strain-specific regulation of virulence genes by the master regulator CovR and suggest that the intra-species evolution of the signaling network is as important as the expression of specific virulence factors in the emergence of clone associated with specific diseases.

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Section: Introductionmentioning

confidence: 99%

The CovR regulatory network drives the evolution of Group B Streptococcus virulence

et al. 2021

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“…The number of TCSs per species tends to be higher in environmental species that are exposed to fluctuations in the natural environment and that possess larger genomes. Some clinically-significant examples are presented in Table 1 [ 15 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ].…”

Section: Introductionmentioning

confidence: 99%

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

Phillips‐Jones

2021

Molecules

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There is an urgent need to find new antibacterial agents to combat bacterial infections, including agents that inhibit novel, hitherto unexploited targets in bacterial cells. Amongst novel targets are two-component signal transduction systems (TCSs) which are the main mechanism by which bacteria sense and respond to environmental changes. TCSs typically comprise a membrane-embedded sensory protein (the sensor histidine kinase, SHK) and a partner response regulator protein. Amongst promising targets within SHKs are those involved in environmental signal detection (useful for targeting specific SHKs) and the common themes of signal transmission across the membrane and propagation to catalytic domains (for targeting multiple SHKs). However, the nature of environmental signals for the vast majority of SHKs is still lacking, and there is a paucity of structural information based on full-length membrane-bound SHKs with and without ligand. Reasons for this lack of knowledge lie in the technical challenges associated with investigations of these relatively hydrophobic membrane proteins and the inherent flexibility of these multidomain proteins that reduces the chances of successful crystallisation for structural determination by X-ray crystallography. However, in recent years there has been an explosion of information published on (a) methodology for producing active forms of full-length detergent-, liposome- and nanodisc-solubilised membrane SHKs and their use in structural studies and identification of signalling ligands and inhibitors; and (b) mechanisms of signal sensing and transduction across the membrane obtained using sensory and transmembrane domains in isolation, which reveal some commonalities as well as unique features. Here we review the most recent advances in these areas and highlight those of potential use in future strategies for antibiotic discovery. This Review is part of a Special Issue entitled “Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents” edited by Mary K. Phillips-Jones.

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“…The major regulator of host-pathogen interaction in ß-hemolytic streptococci is the transcriptional factor CovR belonging to the PhoP family of bacterial response regulator (18,19). Targeted analysis in GBS demonstrated that CovR directly represses the transcription of the cyl operon encoding the ß-h/c toxin, the bibA gene, and the PI-1 pili operon (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

Mazzuoli

Daunesse

Varet

et al. 2021

Preprint

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Virulence of the neonatal pathogen Group B Streptococcus depends on the master regulator CovR. Inactivation of CovR leads to large-scale transcriptome remodeling and impairs almost every step of the interaction between the pathogen and the host. However, comparative analyses suggested a plasticity of the CovR signalling pathway in clinical isolates, probably due to the host selective pressure and leading to phenotypic heterogeneity in the bacterial population. Here, we characterize the CovR regulatory network in a strain representative of the hypervirulent lineage responsible of the majority of late-onset meningitidis. Genome-wide binding and transcriptome analysis demonstrated that CovR acts as a direct and global repressor of virulence genes, either as a primary regulator or with specialized co-regulators. Remarkably, CovR directly regulates genes of the pan-genome, including the two specific hypervirulent adhesins and horizontally acquired genes, as well as core-genes showing mutational biases in the population. Parallel analysis of the CovR network in a second isolate links strain-specificities to micro-evolutions in CovR-regulated promoters and to broad difference due to variability in CovR activation by phosphorylation. Our results highlight the direct, coordinated, and strain-specific regulation of virulence genes by CovR. This intra-species evolution of the signalling network reshapes bacterial-host interactions, increasing the potential for adaptation and the emergence of clone associated with specific diseases.

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Two-Component Signal Transduction Systems in the Human Pathogen Streptococcus agalactiae

Cited by 36 publications

References 110 publications

The CovR regulatory network drives the evolution of Group B Streptococcus virulence

The CovR regulatory network drives the evolution of Group B Streptococcus virulence

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

The CovR regulatory network drives the evolution of Group BStreptococcusvirulence

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