Counteractive Balancing of Transcriptome Expression Involving CodY and CovRS in Streptococcus pyogenes

Kreth, Jens; Chen, Zhiyun; Ferretti, Joseph J.; Malke, Horst

doi:10.1128/jb.00061-11

Cited by 45 publications

(39 citation statements)

References 70 publications

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“…Thus, CovR single amino acid replacements in the serotype M3 strain under study here appear to balance augmented immune activation associated with pilus expression with increased immune evasion via IL-8 degradation and degradation of neutrophil extracelluar traps. It was recently reported that covRS inactivation in the GAS serotype M49 strain NZ131 resulted in increased pilus production [53]. Bioinformatic analysis of the published genome [54] reveals that strain NZ131 also contains five putative CovR binding sites in the nra/cpb intergenic region in this strain, similar to what is observed in strain MGAS10870.…”

Section: Discussionsupporting

confidence: 60%

Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis

et al. 2011

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Sequencing of invasive strains of group A streptococci (GAS) has revealed a diverse array of single nucleotide polymorphisms in the gene encoding the control of virulence regulator (CovR) protein. However, there is limited information regarding the molecular mechanisms by which CovR single amino acid replacements impact GAS pathogenesis. The crystal structure of the CovR C-terminal DNA-binding domain was determined to 1.50 Å resolution and revealed a three-stranded β-sheet followed by a winged helix-turn-helix DNA binding motif. Modeling of the CovR protein-DNA complex indicated that CovR single amino acid replacements observed in clinical GAS isolates could directly alter protein-DNA interaction and impact protein structure. Isoallelic GAS strains that varied by a single amino acid replacement in the CovR DNA binding domain had significantly different transcriptomes compared to wild-type and to each other. Similarly, distinct recombinant CovR variants had differential binding affinity for DNA from the promoter regions of several virulence factor-encoding genes. Finally, mice that were challenged with GAS CovR isoallelic strains had significantly different survival times, which correlated with the transcriptome and protein-DNA binding studies. Taken together, these data provide structural and functional insights into the critical and distinct effects of variation in the CovR protein on GAS pathogenesis.

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Section: Discussionsupporting

confidence: 60%

Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis

et al. 2011

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“…A significant difference in adcA transcripts was not previously identified using DNA microarrays in either the exponential or stationary phases of growth [23]. The predicted 515 amino acid protein (Spy49_0549) has a putative signal peptide, a histidine rich motif, and is annotated as a zinc binding transporter [25].…”

Section: Resultsmentioning

confidence: 99%

CodY-mediated regulation of Streptococcus pyogenes exoproteins

et al. 2012

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BackgroundThe production of Streptococcus pyogenes exoproteins, many of which contribute to virulence, is regulated in response to nutrient availability. CodY is a transcriptional regulator that controls gene expression in response to amino acid availability. The purpose of this study was to identify differences in the expression of streptococcal exoproteins associated with deletion of the codY gene.ResultsWe compared the secreted proteins produced by wild-type S. pyogenes to a codY mutant in the post-exponential phase of growth. We used both one and two-dimensional gel electrophoresis to separate exoproteins. Proteins that were significantly different in abundance upon repeated analysis were identified with tandem mass spectrometry. The production of the secreted cysteine protease SpeB, a secreted chromosomally encoded nuclease (SdaB), and a putative adhesion factor (Spy49_0549) were more abundant in supernatant fluids obtained from the codY mutant. In addition, hyaluronidase (HylA), CAMP factor (Cfa), a prophage encoded nuclease (Spd-3), and an uncharacterized extracellular protein (Spy49_0015) were less abundant in supernatant fluids obtained from the codY mutant strain. Enzymatic assays showed greater DNase activity in culture supernatants isolated in the post-exponential phase of growth from the codY mutant strain compared to the wild-type strain. Because extracellular nucleases and proteases can influence biofilm formation, we also measured the ability of the strains to form biofilms during growth with both rich medium (Todd Hewitt yeast extract; THY) and chemically defined media (CDM). No difference was observed with rich media but with CDM the biofilms formed by the codY mutant strain had less biomass compared to the wild-type strain.ConclusionsOverall, the results indicate that CodY alters the abundance of a select group of S. pyogenes exoproteins, including DNases, a protease, and hylauronidase, which together may alleviate starvation by promoting dissemination of the pathogen to nutrient rich environments and by hydrolysis of host macromolecules.

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“…A global regulator of metabolism found in nearly all low G+C Gram-positive bacteria, CodY controls at least 200 genes in Bacillus (127), Clostridium (128), Staphylococcus (129, 130), Streptococcus (131, 132), Lactococcus (133), and Listeria (134). Lactobacillus spp.…”

Section: Metabolite-responsive Global Regulators That Influence Virulmentioning

confidence: 99%

“…That is, CovR can be a positive or negative regulator of some virulence-associated genes, depending on environmental conditions. By repressing the covRS operon, CodY seems to work at cross-purposes with CovRS and can therefore appear to be a reciprocal activator or inhibitor of virulence (132). How this complicated arrangement plays out in vivo is uncertain, but during growth of S. pyogenes in human blood in vitro , many genes are subject to regulation by CodY but not necessarily in the same way as in laboratory growth media (131).…”

Section: Metabolite-responsive Global Regulators That Influence Virulmentioning

confidence: 99%

Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria

2015

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Pathogenic bacteria must contend with immune systems that actively restrict the availability of nutrients and cofactors, and create a hostile growth environment. To deal with these hostile environments, pathogenic bacteria have evolved or acquired virulence determinants that aid in the acquisition of nutrients. This connection between pathogenesis and nutrition may explain why regulators of metabolism in nonpathogenic bacteria are used by pathogenic bacteria to regulate both metabolism and virulence. Such coordinated regulation is presumably advantageous because it conserves carbon and energy by aligning synthesis of virulence determinants with the nutritional environment. In Gram-positive bacterial pathogens, at least three metabolite-responsive global regulators, CcpA, CodY, and Rex, have been shown to coordinate the expression of metabolism and virulence genes. In this chapter, we discuss how environmental challenges alter metabolism, the regulators that respond to this altered metabolism, and how these regulators influence the host-pathogen interaction.

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Counteractive Balancing of Transcriptome Expression Involving CodY and CovRS in Streptococcus pyogenes

Cited by 45 publications

References 70 publications

Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis

Distinct Single Amino Acid Replacements in the Control of Virulence Regulator Protein Differentially Impact Streptococcal Pathogenesis

CodY-mediated regulation of Streptococcus pyogenes exoproteins

Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria

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