Activation of the Listeria monocytogenes Virulence Program by a Reducing Environment
Open Access
- 8 November 2017
- journal article
- research article
- Published by American Society for Microbiology in mBio
- Vol. 8 (5), e01595-17
- https://doi.org/10.1128/mbio.01595-17
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 (Δ gshF ) 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.Funding Information
- HHS | National Institutes of Health (1P01 AI063302, 1R01 AI27655)
- the National Science Foundation Graduate Research Fellowship Program (DGE 1106400)
This publication has 68 references indexed in Scilit:
- Mutations of the Listeria monocytogenes PeptidoglycanN-Deacetylase andO-Acetylase Result in Enhanced Lysozyme Sensitivity, Bacteriolysis, and Hyperinduction of Innate Immune PathwaysInfection and Immunity, 2011
- c-di-AMP Secreted by Intracellular Listeria monocytogenes Activates a Host Type I Interferon ResponseScience, 2010
- Disulfide Bond Formation and Cysteine Exclusion in Gram-positive Bacteria*Online Journal of Public Health Informatics, 2010
- YybT Is a Signaling Protein That Contains a Cyclic Dinucleotide Phosphodiesterase Domain and a GGDEF Domain with ATPase ActivityOnline Journal of Public Health Informatics, 2010
- Listeria monocytogenes — from saprophyte to intracellular pathogenNature Reviews Microbiology, 2009
- Life on the inside: the intracellular lifestyle of cytosolic bacteriaNature Reviews Microbiology, 2009
- Functional impact of mutational activation on the Listeria monocytogenes central virulence regulator PrfAMicrobiology, 2008
- Cancer immunotherapy using Listeria monocytogenes and listerial virulence factorsImmunologic Research, 2008
- Age-related changes in glutathione and glutathione-related enzymes in rat brainBrain Research, 2006
- Role of hemolysin for the intracellular growth of Listeria monocytogenes.The Journal of Experimental Medicine, 1988