Linking the nutritional status of Streptococcus pyogenes to alteration of transcriptional gene expression: The action of CodY and RelA

Malke, Horst; Steiner, Kerstin; McShan, W. Michael; Ferretti, Joseph J.

doi:10.1016/j.ijmm.2005.11.008

Cited by 102 publications

(123 citation statements)

References 65 publications

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“…First identified in Bacillus subtilis as a factor that represses stationary phase genes during exponential growth in rich medium (11), CodY is now known to provide a critical regulatory link between metabolism and pathogenesis in bacteria important for human health (5,6,(12)(13)(14)(15)(16). CodY is activated as a DNA-binding protein in vitro by at least two classes of metabolites: the branched-chain amino acids [BCAAs; i.e., isoleucine, leucine, and valine (ILV)] and GTP (17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Hierarchical expression of genes controlled by theBacillus subtilisglobal regulatory protein CodY

Brinsmade

Alexander

Livny

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

119

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Global regulators that bind strategic metabolites allow bacteria to adapt rapidly to dynamic environments by coordinating the expression of many genes. We report an approach for determining gene regulation hierarchy using the regulon of the Bacillus subtilis global regulatory protein CodY as proof of principle. In theory, this approach can be used to measure the dynamics of any bacterial transcriptional regulatory network that is affected by interaction with a ligand. In B. subtilis, CodY controls dozens of genes, but the threshold activities of CodY required to regulate each gene are unknown. We hypothesized that targets of CodY are differentially regulated based on varying affinity for the protein's many binding sites. We used RNA sequencing to determine the transcription profiles of B. subtilis strains expressing mutant CodY proteins with different levels of residual activity. In parallel, we quantified intracellular metabolites connected to central metabolism. Strains producing CodY variants F71Y, R61K, and R61H retained varying degrees of partial activity relative to the WT protein, leading to gene-specific, differential alterations in transcript abundance for the 223 identified members of the CodY regulon. Using liquid chromatography coupled to MS, we detected significant increases in branched-chain amino acids and intermediates of arginine, proline, and glutamate metabolism, as well as decreases in pyruvate and glycerate as CodY activity decreased. We conclude that a spectrum of CodY activities leads to programmed regulation of gene expression and an apparent rerouting of carbon and nitrogen metabolism, suggesting that during changes in nutrient availability, CodY prioritizes the expression of specific pathways.BCAA | ILV | RNA-seq | metabolite analysis

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mentioning

confidence: 99%

Hierarchical expression of genes controlled by theBacillus subtilisglobal regulatory protein CodY

Brinsmade

Alexander

Livny

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

103

119

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“…GAS produces many actively secreted proteins that target the host cell, including numerous proteases, lipases, and immunomodulatory proteins. GAS alters the level of production of these virulence factors in response to changes in external stimuli, resulting in significant transcriptome remodeling (7,8). Therefore, GAS is likely to have differing tissue-specific gene expression patterns that are influenced by the host microenvironment.…”

mentioning

confidence: 99%

“…Therefore, GAS is likely to have differing tissue-specific gene expression patterns that are influenced by the host microenvironment. Several studies have investigated GAS transcriptome changes that occur during culture in laboratory media, saliva, blood, and with host cells (7,9,10). However, these types of studies lack the ability to capture the complex host-pathogen interactions that take place during infection of an intact host.…”

mentioning

confidence: 99%

Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

Shea

Virtaneva

Kupko

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Relatively little is understood about the dynamics of global hostpathogen transcriptome changes that occur during bacterial infection of mucosal surfaces. To test the hypothesis that group A Streptococcus (GAS) infection of the oropharynx provokes a distinct host transcriptome response, we performed genome-wide transcriptome analysis using a nonhuman primate model of experimental pharyngitis. We also identified host and pathogen biological processes and individual host and pathogen gene pairs with correlated patterns of expression, suggesting interaction. For this study, 509 host genes and seven biological pathways were differentially expressed throughout the entire 32-day infection cycle. GAS infection produced an initial widespread significant decrease in expression of many host genes, including those involved in cytokine production, vesicle formation, metabolism, and signal transduction. This repression lasted until day 4, at which time a large increase in expression of host genes was observed, including those involved in protein translation, antigen presentation, and GTP-mediated signaling. The interactome analysis identified 73 host and pathogen gene pairs with correlated expression levels. We discovered significant correlations between transcripts of GAS genes involved in hyaluronic capsule production and host endocytic vesicle formation, GAS GTPases and host fibrinolytic genes, and GAS response to interaction with neutrophils. We also identified a strong signal, suggesting interaction between host γδ T cells and genes in the GAS mevalonic acid synthesis pathway responsible for production of isopentenyl-pyrophosphate, a short-chain phospholipid that stimulates these T cells. Taken together, our results are unique in providing a comprehensive understanding of the host-pathogen interactome during mucosal infection by a bacterial pathogen.epithelial growth factor receptor | host pathogen | microarray | Streptococcus pyogenes | transcriptome

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“…The positive regulation of Mga and CovR by CodY positively affect the expression of six virulence factors (hyaluronate synthase A, immunoglobulin G degrading endopeptidase, pyrogenic exotoxin H, C5a peptidase, a cell surface proteinase, and a collagen-like surface protein). However, the same report showed that the regulation of Mga and CovR by CodY has been shown to occur at the mid-exponential phase of cell growth [47], while our cells were harvested at early stationary phase. Interestingly, at early stationary phase CodY has also been shown to act as a guanosine 5-triphosphatebinding protein [48] that senses the intracellular guanosine 5-triphosphate concentration as an indicator of nutritional limitations.…”

Section: Down-regulation Of Two Regulators Of Virulence Factorsmentioning

confidence: 72%

“…We also observed the down regulation of a transcriptional repressor, CodY, as was also seen by Graham et al [46] when wild-type GAS was exposed to human blood. Interestingly, Malke et al [47] have shown that CodY is a growth phase-dependent positive transcriptional regulator of Mga, a positive multiple regulator, and CovR, which is a member of the two-component global regulatory system CovRS. The positive regulation of Mga and CovR by CodY positively affect the expression of six virulence factors (hyaluronate synthase A, immunoglobulin G degrading endopeptidase, pyrogenic exotoxin H, C5a peptidase, a cell surface proteinase, and a collagen-like surface protein).…”

Section: Down-regulation Of Two Regulators Of Virulence Factorsmentioning

confidence: 99%

Group A streptococcus cell‐associated pathogenic proteins as revealed by growth in hyaluronic acid‐enriched media

et al. 2007

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Northumbria University has developed Northumbria Research Link (NRL) to enable users to access the University's research output. Copyright © and moral rights for items on NRL are retained by the individual author(s) and/or other copyright owners. Single copies of full items can be reproduced, displayed or performed, and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided the authors, title and full bibliographic details are given, as well as a hyperlink and/or URL to the original metadata page. The content must not be changed in any way. Full items must not be sold commercially in any format or medium without formal permission of the copyright holder. The full policy is available online: http://nrl.northumbria.ac.uk/policies.html This document may differ from the final, published version of the research and has been made available online in accordance with publisher policies. To read and/or cite from the published version of the research, please visit the publisher's website (a subscription may be required.) Group A streptococcus (GAS), also know as Streptococcus pyogenes, is a human pathogen and can cause several fatal invasive diseases such as necrotising fasciitis, the so-called flesh-eating disease, and toxic shock syndrome. The destruction of connective tissue and the hyaluronic acid (HA) therein, is a key element of GAS pathogenesis. We therefore propagated GAS in HA-enriched growth media in an attempt to create a simple biological system that could reflect some elements of GAS pathogenesis. Our results show that several recognised virulence factors were up-regulated in HA-enriched media, including the M1 protein, a collagen-like surface protein and the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase, which has been shown to play important roles in streptococcal pathogenesis. Interestingly, two hypothetical proteins of unknown function were also up-regulated and detailed bioinformatics analysis showed that at least one of these hypothetical proteins is likely to be involved in pathogenesis. It was therefore concluded that this simple biological system provided a valuable tool for the identification of potential GAS virulence factors. RESEARCH ARTICLE Group

show abstract

Linking the nutritional status of Streptococcus pyogenes to alteration of transcriptional gene expression: The action of CodY and RelA

Cited by 102 publications

References 65 publications

Hierarchical expression of genes controlled by theBacillus subtilisglobal regulatory protein CodY

Hierarchical expression of genes controlled by theBacillus subtilisglobal regulatory protein CodY

Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus

Group A streptococcus cell‐associated pathogenic proteins as revealed by growth in hyaluronic acid‐enriched media

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