Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence

ABSTRACT Staphylococcus aureus causes various diseases ranging from skin and soft tissue infections to life-threatening infections. Adaptation to the different host niches is controlled by a complex network of transcriptional regulators. Global profiling of condition-dependent transcription revealed...

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Autores principales:	Anna Nagel, Stephan Michalik, Michel Debarbouille, Tobias Hertlein, Manuela Gesell Salazar, Hermann Rath, Tarek Msadek, Knut Ohlsen, Jan Maarten van Dijl, Uwe Völker, Ulrike Mäder
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	SaeRS TCS Staphylococcus aureus antisense transcription bicyclomycin proteome transcription termination Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/18531e5a96654e92bd4f0c6a1aa8ed30
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spelling	oai:doaj.org-article:18531e5a96654e92bd4f0c6a1aa8ed302021-11-15T15:58:20ZInhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence10.1128/mBio.01332-182150-7511https://doaj.org/article/18531e5a96654e92bd4f0c6a1aa8ed302018-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01332-18https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus causes various diseases ranging from skin and soft tissue infections to life-threatening infections. Adaptation to the different host niches is controlled by a complex network of transcriptional regulators. Global profiling of condition-dependent transcription revealed adaptation of S. aureus HG001 at the levels of transcription initiation and termination. In particular, deletion of the gene encoding the Rho transcription termination factor triggered a remarkable overall increase in antisense transcription and gene expression changes attributable to indirect regulatory effects. The goal of the present study was a detailed comparative analysis of S. aureus HG001 and its isogenic rho deletion mutant. Proteome analysis revealed significant differences in cellular and extracellular protein profiles, most notably increased amounts of the proteins belonging to the SaeR regulon in the Rho-deficient strain. The SaeRS two-component system acts as a major regulator of virulence gene expression in staphylococci. Higher levels of SaeRS-dependent virulence factors such as adhesins, toxins, and immune evasion proteins in the rho mutant resulted in higher virulence in a murine bacteremia model, which was alleviated in a rho complemented strain. Inhibition of Rho activity by bicyclomycin, a specific inhibitor of Rho activity, also induced the expression of SaeRS-dependent genes, at both the mRNA and protein levels, to the same extent as observed in the rho mutant. Taken together, these findings indicate that activation of the Sae system in the absence of Rho is directly linked to Rho’s transcription termination activity and establish a new link between antibiotic action and virulence gene expression in S. aureus. IMPORTANCE The major human pathogen Staphylococcus aureus is a widespread commensal bacterium but also the most common cause of nosocomial infections. It adapts to the different host niches through a complex gene regulatory network. We show here that the Rho transcription termination factor, which represses pervasive antisense transcription in various bacteria, including S. aureus, plays a role in controlling SaeRS-dependent virulence gene expression. A Rho-deficient strain produces larger amounts of secreted virulence factors in vitro and shows increased virulence in mice. We also show that treatment of S. aureus with the antibiotic bicyclomycin, which inhibits Rho activity and is effective against Gram-negative bacteria, induces the same changes in the proteome as observed in the Rho-deficient strain. Our results reveal for the first time a link between transcription termination and virulence regulation in S. aureus, which implies a novel mechanism by which an antibiotic can modulate the expression of virulence factors.Anna NagelStephan MichalikMichel DebarbouilleTobias HertleinManuela Gesell SalazarHermann RathTarek MsadekKnut OhlsenJan Maarten van DijlUwe VölkerUlrike MäderAmerican Society for MicrobiologyarticleSaeRS TCSStaphylococcus aureusantisense transcriptionbicyclomycinproteometranscription terminationMicrobiologyQR1-502ENmBio, Vol 9, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	SaeRS TCS Staphylococcus aureus antisense transcription bicyclomycin proteome transcription termination Microbiology QR1-502
spellingShingle	SaeRS TCS Staphylococcus aureus antisense transcription bicyclomycin proteome transcription termination Microbiology QR1-502 Anna Nagel Stephan Michalik Michel Debarbouille Tobias Hertlein Manuela Gesell Salazar Hermann Rath Tarek Msadek Knut Ohlsen Jan Maarten van Dijl Uwe Völker Ulrike Mäder Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence
description	ABSTRACT Staphylococcus aureus causes various diseases ranging from skin and soft tissue infections to life-threatening infections. Adaptation to the different host niches is controlled by a complex network of transcriptional regulators. Global profiling of condition-dependent transcription revealed adaptation of S. aureus HG001 at the levels of transcription initiation and termination. In particular, deletion of the gene encoding the Rho transcription termination factor triggered a remarkable overall increase in antisense transcription and gene expression changes attributable to indirect regulatory effects. The goal of the present study was a detailed comparative analysis of S. aureus HG001 and its isogenic rho deletion mutant. Proteome analysis revealed significant differences in cellular and extracellular protein profiles, most notably increased amounts of the proteins belonging to the SaeR regulon in the Rho-deficient strain. The SaeRS two-component system acts as a major regulator of virulence gene expression in staphylococci. Higher levels of SaeRS-dependent virulence factors such as adhesins, toxins, and immune evasion proteins in the rho mutant resulted in higher virulence in a murine bacteremia model, which was alleviated in a rho complemented strain. Inhibition of Rho activity by bicyclomycin, a specific inhibitor of Rho activity, also induced the expression of SaeRS-dependent genes, at both the mRNA and protein levels, to the same extent as observed in the rho mutant. Taken together, these findings indicate that activation of the Sae system in the absence of Rho is directly linked to Rho’s transcription termination activity and establish a new link between antibiotic action and virulence gene expression in S. aureus. IMPORTANCE The major human pathogen Staphylococcus aureus is a widespread commensal bacterium but also the most common cause of nosocomial infections. It adapts to the different host niches through a complex gene regulatory network. We show here that the Rho transcription termination factor, which represses pervasive antisense transcription in various bacteria, including S. aureus, plays a role in controlling SaeRS-dependent virulence gene expression. A Rho-deficient strain produces larger amounts of secreted virulence factors in vitro and shows increased virulence in mice. We also show that treatment of S. aureus with the antibiotic bicyclomycin, which inhibits Rho activity and is effective against Gram-negative bacteria, induces the same changes in the proteome as observed in the Rho-deficient strain. Our results reveal for the first time a link between transcription termination and virulence regulation in S. aureus, which implies a novel mechanism by which an antibiotic can modulate the expression of virulence factors.
format	article
author	Anna Nagel Stephan Michalik Michel Debarbouille Tobias Hertlein Manuela Gesell Salazar Hermann Rath Tarek Msadek Knut Ohlsen Jan Maarten van Dijl Uwe Völker Ulrike Mäder
author_facet	Anna Nagel Stephan Michalik Michel Debarbouille Tobias Hertlein Manuela Gesell Salazar Hermann Rath Tarek Msadek Knut Ohlsen Jan Maarten van Dijl Uwe Völker Ulrike Mäder
author_sort	Anna Nagel
title	Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence
title_short	Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence
title_full	Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence
title_fullStr	Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence
title_full_unstemmed	Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence
title_sort	inhibition of rho activity increases expression of saers-dependent virulence factor genes in <named-content content-type="genus-species">staphylococcus aureus</named-content>, showing a link between transcription termination, antibiotic action, and virulence
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/18531e5a96654e92bd4f0c6a1aa8ed30
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Inhibition of Rho Activity Increases Expression of SaeRS-Dependent Virulence Factor Genes in <named-content content-type="genus-species">Staphylococcus aureus</named-content>, Showing a Link between Transcription Termination, Antibiotic Action, and Virulence

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