Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment

ABSTRACT Upon entry into the host cell cytosol, the facultative intracellular pathogen Listeria monocytogenes coordinates the expression of numerous essential virulence factors by allosteric binding of glutathione (GSH) to the Crp-Fnr family transcriptional regulator PrfA. Here, we report that robus...

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Autores principales:	Jonathan L. Portman, Samuel B. Dubensky, Bret N. Peterson, Aaron T. Whiteley, Daniel A. Portnoy
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	glutathione c-di-AMP gram-positive bacteria stringent response virulence virulence regulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0450fd164b444d849a55969f36405c99
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spelling	oai:doaj.org-article:0450fd164b444d849a55969f36405c992021-11-15T15:51:50ZActivation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment10.1128/mBio.01595-172150-7511https://doaj.org/article/0450fd164b444d849a55969f36405c992017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01595-17https://doaj.org/toc/2150-7511ABSTRACT Upon entry into the host cell cytosol, the facultative intracellular pathogen Listeria monocytogenes coordinates the expression of numerous essential virulence factors by allosteric binding of glutathione (GSH) to the Crp-Fnr family transcriptional regulator PrfA. Here, we report that robust virulence gene expression can be recapitulated by growing bacteria in a synthetic medium containing GSH or other chemical reducing agents. Bacteria grown under these conditions were 45-fold more virulent in an acute murine infection model and conferred greater immunity to a subsequent lethal challenge than bacteria grown in conventional media. During cultivation in vitro, PrfA activation was completely dependent on the intracellular levels of GSH, as a glutathione synthase mutant (ΔgshF) was activated by exogenous GSH but not reducing agents. PrfA activation was repressed in a synthetic medium supplemented with oligopeptides, but the repression was relieved by stimulation of the stringent response. These data suggest that cytosolic L. monocytogenes interprets a combination of metabolic and redox cues as a signal to initiate robust virulence gene expression in vivo. IMPORTANCE Intracellular pathogens are responsible for much of the worldwide morbidity and mortality from infectious diseases. These pathogens have evolved various strategies to proliferate within individual cells of the host and avoid the host immune response. Through cellular invasion or the use of specialized secretion machinery, all intracellular pathogens must access the host cell cytosol to establish their replicative niches. Determining how these pathogens sense and respond to the intracellular compartment to establish a successful infection is critical to our basic understanding of the pathogenesis of each organism and for the rational design of therapeutic interventions. Listeria monocytogenes is a model intracellular pathogen with robust in vitro and in vivo infection models. Studies of the host-sensing and downstream signaling mechanisms evolved by L. monocytogenes often describe themes of pathogenesis that are broadly applicable to less tractable pathogens. Here, we describe how bacteria use external redox states as a cue to activate virulence.Jonathan L. PortmanSamuel B. DubenskyBret N. PetersonAaron T. WhiteleyDaniel A. PortnoyAmerican Society for Microbiologyarticleglutathionec-di-AMPgram-positive bacteriastringent responsevirulencevirulence regulationMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	glutathione c-di-AMP gram-positive bacteria stringent response virulence virulence regulation Microbiology QR1-502
spellingShingle	glutathione c-di-AMP gram-positive bacteria stringent response virulence virulence regulation Microbiology QR1-502 Jonathan L. Portman Samuel B. Dubensky Bret N. Peterson Aaron T. Whiteley Daniel A. Portnoy Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment
description	ABSTRACT Upon entry into the host cell cytosol, the facultative intracellular pathogen Listeria monocytogenes coordinates the expression of numerous essential virulence factors by allosteric binding of glutathione (GSH) to the Crp-Fnr family transcriptional regulator PrfA. Here, we report that robust virulence gene expression can be recapitulated by growing bacteria in a synthetic medium containing GSH or other chemical reducing agents. Bacteria grown under these conditions were 45-fold more virulent in an acute murine infection model and conferred greater immunity to a subsequent lethal challenge than bacteria grown in conventional media. During cultivation in vitro, PrfA activation was completely dependent on the intracellular levels of GSH, as a glutathione synthase mutant (ΔgshF) was activated by exogenous GSH but not reducing agents. PrfA activation was repressed in a synthetic medium supplemented with oligopeptides, but the repression was relieved by stimulation of the stringent response. These data suggest that cytosolic L. monocytogenes interprets a combination of metabolic and redox cues as a signal to initiate robust virulence gene expression in vivo. IMPORTANCE Intracellular pathogens are responsible for much of the worldwide morbidity and mortality from infectious diseases. These pathogens have evolved various strategies to proliferate within individual cells of the host and avoid the host immune response. Through cellular invasion or the use of specialized secretion machinery, all intracellular pathogens must access the host cell cytosol to establish their replicative niches. Determining how these pathogens sense and respond to the intracellular compartment to establish a successful infection is critical to our basic understanding of the pathogenesis of each organism and for the rational design of therapeutic interventions. Listeria monocytogenes is a model intracellular pathogen with robust in vitro and in vivo infection models. Studies of the host-sensing and downstream signaling mechanisms evolved by L. monocytogenes often describe themes of pathogenesis that are broadly applicable to less tractable pathogens. Here, we describe how bacteria use external redox states as a cue to activate virulence.
format	article
author	Jonathan L. Portman Samuel B. Dubensky Bret N. Peterson Aaron T. Whiteley Daniel A. Portnoy
author_facet	Jonathan L. Portman Samuel B. Dubensky Bret N. Peterson Aaron T. Whiteley Daniel A. Portnoy
author_sort	Jonathan L. Portman
title	Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment
title_short	Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment
title_full	Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment
title_fullStr	Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment
title_full_unstemmed	Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment
title_sort	activation of the <italic toggle="yes">listeria monocytogenes</italic> virulence program by a reducing environment
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/0450fd164b444d849a55969f36405c99
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Activation of the <italic toggle="yes">Listeria monocytogenes</italic> Virulence Program by a Reducing Environment

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