Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators

ABSTRACT Adaptation of group A Streptococcus (GAS) to its human host is mediated by two-component systems that transduce external stimuli to regulate bacterial physiology. Among such systems, CsrRS (also known as CovRS) is the most extensively characterized for its role in regulating ∼10% of the GAS...

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Autores principales:	Meredith B. Finn, Kathryn M. Ramsey, Simon L. Dove, Michael R. Wessels
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	Streptococcus pyogenes chromatin immunoprecipitation two-component system virulence regulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/dd3673ad85fd473f988ceff06545bb13
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spelling	oai:doaj.org-article:dd3673ad85fd473f988ceff06545bb132021-11-10T18:37:52ZIdentification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators10.1128/mBio.01642-212150-7511https://doaj.org/article/dd3673ad85fd473f988ceff06545bb132021-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01642-21https://doaj.org/toc/2150-7511ABSTRACT Adaptation of group A Streptococcus (GAS) to its human host is mediated by two-component systems that transduce external stimuli to regulate bacterial physiology. Among such systems, CsrRS (also known as CovRS) is the most extensively characterized for its role in regulating ∼10% of the GAS genome, including several virulence genes. Here, we show that extracellular magnesium and the human antimicrobial peptide LL-37 have opposing effects on the phosphorylation of the response regulator CsrR by the receptor kinase CsrS. Genetic inactivation of CsrS phosphatase or kinase activity, respectively, had similar but more pronounced effects on CsrR phosphorylation compared to growth in magnesium or LL-37. These changes in CsrR phosphorylation were correlated with the repression or activation of CsrR-regulated genes as assessed by NanoString analysis. Chromatin immunoprecipitation and DNA sequencing (ChIP-seq) revealed CsrR occupancy at CsrRS-regulated promoters and lower-affinity associations at many other locations on the GAS chromosome. Because ChIP-seq did not detect CsrR occupancy at promoters associated with some CsrR-regulated genes, we investigated whether these genes might be controlled indirectly by intermediate regulators whose expression is modulated by CsrR. Transcriptional profiling of mutant strains deficient in the expression of either of two previously uncharacterized transcription regulators in the CsrR regulon indicated that one or both proteins participated in the regulation of 22 of the 42 CsrR-regulated promoters for which no CsrR association was detected by ChIP-seq. Taken together, these results illuminate CsrRS-mediated regulation of GAS gene expression through modulation of CsrR phosphorylation, CsrR association with regulated promoters, and the control of intermediate transcription regulators. IMPORTANCE Group A Streptococcus (GAS) is an important public health threat as a cause of sore throat, skin infections, life-threatening invasive infections, and the postinfectious complications of acute rheumatic fever, a leading cause of acquired heart disease. This work characterizes CsrRS, a GAS system for the detection of environmental signals that enables adaptation of the bacteria for survival in the human throat by regulating the production of products that allow the bacteria to resist clearance by the human immune system. CsrRS consists of two proteins: CsrS, which is on the bacterial surface to detect specific stimuli, and CsrR, which receives signals from CsrS and, in response, represses or activates the expression of genes coding for proteins that enhance bacterial survival. Some of the genes regulated by CsrR encode proteins that are themselves regulators of gene expression, thereby creating a regulatory cascade.Meredith B. FinnKathryn M. RamseySimon L. DoveMichael R. WesselsAmerican Society for MicrobiologyarticleStreptococcus pyogeneschromatin immunoprecipitationtwo-component systemvirulence regulationMicrobiologyQR1-502ENmBio, Vol 12, Iss 4 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Streptococcus pyogenes chromatin immunoprecipitation two-component system virulence regulation Microbiology QR1-502
spellingShingle	Streptococcus pyogenes chromatin immunoprecipitation two-component system virulence regulation Microbiology QR1-502 Meredith B. Finn Kathryn M. Ramsey Simon L. Dove Michael R. Wessels Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators
description	ABSTRACT Adaptation of group A Streptococcus (GAS) to its human host is mediated by two-component systems that transduce external stimuli to regulate bacterial physiology. Among such systems, CsrRS (also known as CovRS) is the most extensively characterized for its role in regulating ∼10% of the GAS genome, including several virulence genes. Here, we show that extracellular magnesium and the human antimicrobial peptide LL-37 have opposing effects on the phosphorylation of the response regulator CsrR by the receptor kinase CsrS. Genetic inactivation of CsrS phosphatase or kinase activity, respectively, had similar but more pronounced effects on CsrR phosphorylation compared to growth in magnesium or LL-37. These changes in CsrR phosphorylation were correlated with the repression or activation of CsrR-regulated genes as assessed by NanoString analysis. Chromatin immunoprecipitation and DNA sequencing (ChIP-seq) revealed CsrR occupancy at CsrRS-regulated promoters and lower-affinity associations at many other locations on the GAS chromosome. Because ChIP-seq did not detect CsrR occupancy at promoters associated with some CsrR-regulated genes, we investigated whether these genes might be controlled indirectly by intermediate regulators whose expression is modulated by CsrR. Transcriptional profiling of mutant strains deficient in the expression of either of two previously uncharacterized transcription regulators in the CsrR regulon indicated that one or both proteins participated in the regulation of 22 of the 42 CsrR-regulated promoters for which no CsrR association was detected by ChIP-seq. Taken together, these results illuminate CsrRS-mediated regulation of GAS gene expression through modulation of CsrR phosphorylation, CsrR association with regulated promoters, and the control of intermediate transcription regulators. IMPORTANCE Group A Streptococcus (GAS) is an important public health threat as a cause of sore throat, skin infections, life-threatening invasive infections, and the postinfectious complications of acute rheumatic fever, a leading cause of acquired heart disease. This work characterizes CsrRS, a GAS system for the detection of environmental signals that enables adaptation of the bacteria for survival in the human throat by regulating the production of products that allow the bacteria to resist clearance by the human immune system. CsrRS consists of two proteins: CsrS, which is on the bacterial surface to detect specific stimuli, and CsrR, which receives signals from CsrS and, in response, represses or activates the expression of genes coding for proteins that enhance bacterial survival. Some of the genes regulated by CsrR encode proteins that are themselves regulators of gene expression, thereby creating a regulatory cascade.
format	article
author	Meredith B. Finn Kathryn M. Ramsey Simon L. Dove Michael R. Wessels
author_facet	Meredith B. Finn Kathryn M. Ramsey Simon L. Dove Michael R. Wessels
author_sort	Meredith B. Finn
title	Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators
title_short	Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators
title_full	Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators
title_fullStr	Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators
title_full_unstemmed	Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators
title_sort	identification of group a <named-content content-type="genus-species">streptococcus</named-content> genes directly regulated by csrrs and novel intermediate regulators
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/dd3673ad85fd473f988ceff06545bb13
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Identification of Group A <named-content content-type="genus-species">Streptococcus</named-content> Genes Directly Regulated by CsrRS and Novel Intermediate Regulators

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