(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection

ABSTRACT In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp and codY mutant strains of Enterococcus faecalis in a catheter-associated urinary tract...

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Autores principales:	C. Colomer-Winter, A. L. Flores-Mireles, S. Kundra, S. J. Hultgren, J. A. Lemos
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	(p)ppGpp CAUTI CodY Enterococcus stringent response Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d766f30005b3461db9db62df55f53248
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spelling	oai:doaj.org-article:d766f30005b3461db9db62df55f532482021-11-15T15:22:27Z(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection10.1128/mSphere.00392-192379-5042https://doaj.org/article/d766f30005b3461db9db62df55f532482019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00392-19https://doaj.org/toc/2379-5042ABSTRACT In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp and codY mutant strains of Enterococcus faecalis in a catheter-associated urinary tract infection (CAUTI) mouse model and used global transcriptional analysis to investigate the relationship of (p)ppGpp and CodY. The absence of (p)ppGpp or single inactivation of codY led to lower bacterial loads in catheterized bladders and diminished biofilm formation on fibrinogen-coated surfaces under in vitro and in vivo conditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolase rel did not affect virulence, supporting previous evidence that the association of (p)ppGpp with enterococcal virulence is not dependent on the activation of the stringent response. Inactivation of codY in the (p)ppGpp0 strain restored E. faecalis virulence in the CAUTI model as well as the ability to form biofilms in vitro. Transcriptome analysis revealed that inactivation of codY restores, for the most part, the dysregulated metabolism of (p)ppGpp0 cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicates that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may play a role in enterococcal CAUTI. Collectively, data from this study identify the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and support that basal (p)ppGpp pools and CodY promote virulence through maintenance of a balanced metabolism under adverse conditions. IMPORTANCE Catheter-associated urinary tract infections (CAUTIs) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently causes complicated CAUTI is the bacterium Enterococcus faecalis, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by which E. faecalis causes CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability of E. faecalis to infect the catheterized bladder of mice.C. Colomer-WinterA. L. Flores-MirelesS. KundraS. J. HultgrenJ. A. LemosAmerican Society for Microbiologyarticle(p)ppGppCAUTICodYEnterococcusstringent responseMicrobiologyQR1-502ENmSphere, Vol 4, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	(p)ppGpp CAUTI CodY Enterococcus stringent response Microbiology QR1-502
spellingShingle	(p)ppGpp CAUTI CodY Enterococcus stringent response Microbiology QR1-502 C. Colomer-Winter A. L. Flores-Mireles S. Kundra S. J. Hultgren J. A. Lemos (p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
description	ABSTRACT In Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp and codY mutant strains of Enterococcus faecalis in a catheter-associated urinary tract infection (CAUTI) mouse model and used global transcriptional analysis to investigate the relationship of (p)ppGpp and CodY. The absence of (p)ppGpp or single inactivation of codY led to lower bacterial loads in catheterized bladders and diminished biofilm formation on fibrinogen-coated surfaces under in vitro and in vivo conditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolase rel did not affect virulence, supporting previous evidence that the association of (p)ppGpp with enterococcal virulence is not dependent on the activation of the stringent response. Inactivation of codY in the (p)ppGpp0 strain restored E. faecalis virulence in the CAUTI model as well as the ability to form biofilms in vitro. Transcriptome analysis revealed that inactivation of codY restores, for the most part, the dysregulated metabolism of (p)ppGpp0 cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicates that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may play a role in enterococcal CAUTI. Collectively, data from this study identify the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and support that basal (p)ppGpp pools and CodY promote virulence through maintenance of a balanced metabolism under adverse conditions. IMPORTANCE Catheter-associated urinary tract infections (CAUTIs) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently causes complicated CAUTI is the bacterium Enterococcus faecalis, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by which E. faecalis causes CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability of E. faecalis to infect the catheterized bladder of mice.
format	article
author	C. Colomer-Winter A. L. Flores-Mireles S. Kundra S. J. Hultgren J. A. Lemos
author_facet	C. Colomer-Winter A. L. Flores-Mireles S. Kundra S. J. Hultgren J. A. Lemos
author_sort	C. Colomer-Winter
title	(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
title_short	(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
title_full	(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
title_fullStr	(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
title_full_unstemmed	(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection
title_sort	(p)ppgpp and cody promote <named-content content-type="genus-species">enterococcus faecalis</named-content> virulence in a murine model of catheter-associated urinary tract infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d766f30005b3461db9db62df55f53248
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(p)ppGpp and CodY Promote <named-content content-type="genus-species">Enterococcus faecalis</named-content> Virulence in a Murine Model of Catheter-Associated Urinary Tract Infection

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