<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc

ABSTRACT Staphylococcus aureus is a formidable human pathogen that uses secreted cytolytic factors to injure immune cells and promote infection of its host. Of these proteins, the bicomponent family of pore-forming leukocidins play critical roles in S. aureus pathogenesis. The regulatory mechanisms...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Divya Balasubramanian, Elizabeth A. Ohneck, Jessica Chapman, Andy Weiss, Min Kyung Kim, Tamara Reyes-Robles, Judy Zhong, Lindsey N. Shaw, Desmond S. Lun, Beatrix Ueberheide, Bo Shopsin, Victor J. Torres
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/5580eb7c97fb46ef8e5c10e18d612681
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5580eb7c97fb46ef8e5c10e18d612681
record_format	dspace
spelling	oai:doaj.org-article:5580eb7c97fb46ef8e5c10e18d6126812021-11-15T15:50:15Z<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc10.1128/mBio.00818-162150-7511https://doaj.org/article/5580eb7c97fb46ef8e5c10e18d6126812016-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00818-16https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is a formidable human pathogen that uses secreted cytolytic factors to injure immune cells and promote infection of its host. Of these proteins, the bicomponent family of pore-forming leukocidins play critical roles in S. aureus pathogenesis. The regulatory mechanisms governing the expression of these toxins are incompletely defined. In this work, we performed a screen to identify transcriptional regulators involved in leukocidin expression in S. aureus strain USA300. We discovered that a metabolic sensor-regulator, RpiRc, is a potent and selective repressor of two leukocidins, LukED and LukSF-PV. Whole-genome transcriptomics, S. aureus exoprotein proteomics, and metabolomic analyses revealed that RpiRc influences the expression and production of disparate virulence factors. Additionally, RpiRc altered metabolic fluxes in the tricarboxylic acid cycle, glycolysis, and amino acid metabolism. Using mutational analyses, we confirmed and extended the observation that RpiRc signals through the accessory gene regulatory (Agr) quorum-sensing system in USA300. Specifically, RpiRc represses the rnaIII promoter, resulting in increased repressor of toxins (Rot) levels, which in turn negatively affect leukocidin expression. Inactivation of rpiRc phenocopied rot deletion and increased S. aureus killing of primary human polymorphonuclear leukocytes and the pathogenesis of bloodstream infection in vivo. Collectively, our results suggest that S. aureus senses metabolic shifts by RpiRc to differentially regulate the expression of leukocidins and to promote invasive disease. IMPORTANCE The bicomponent pore-forming leukocidins play pivotal roles in the ability of S. aureus to kill multiple host immune cells, thus enabling this pathogen to have diverse tissue- and species-tropic effects. While the mechanisms of leukocidin-host receptor interactions have been studied in detail, the regulatory aspects of leukocidin expression are less well characterized. Moreover, the expression of the leukocidins is highly modular in vitro, suggesting the presence of regulators other than the known Agr, Rot, and S. aureus exoprotein pathways. Here, we describe how RpiRc, a metabolite-sensing transcription factor, mediates the repression of two specific leukocidin genes, lukED and pvl, which in turn has complex effects on the pathogenesis of S. aureus. Our findings highlight the intricacies of leukocidin regulation by S. aureus and demonstrate the involvement of factors beyond traditional virulence factor regulators.Divya BalasubramanianElizabeth A. OhneckJessica ChapmanAndy WeissMin Kyung KimTamara Reyes-RoblesJudy ZhongLindsey N. ShawDesmond S. LunBeatrix UeberheideBo ShopsinVictor J. TorresAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 3 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Divya Balasubramanian Elizabeth A. Ohneck Jessica Chapman Andy Weiss Min Kyung Kim Tamara Reyes-Robles Judy Zhong Lindsey N. Shaw Desmond S. Lun Beatrix Ueberheide Bo Shopsin Victor J. Torres <named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc
description	ABSTRACT Staphylococcus aureus is a formidable human pathogen that uses secreted cytolytic factors to injure immune cells and promote infection of its host. Of these proteins, the bicomponent family of pore-forming leukocidins play critical roles in S. aureus pathogenesis. The regulatory mechanisms governing the expression of these toxins are incompletely defined. In this work, we performed a screen to identify transcriptional regulators involved in leukocidin expression in S. aureus strain USA300. We discovered that a metabolic sensor-regulator, RpiRc, is a potent and selective repressor of two leukocidins, LukED and LukSF-PV. Whole-genome transcriptomics, S. aureus exoprotein proteomics, and metabolomic analyses revealed that RpiRc influences the expression and production of disparate virulence factors. Additionally, RpiRc altered metabolic fluxes in the tricarboxylic acid cycle, glycolysis, and amino acid metabolism. Using mutational analyses, we confirmed and extended the observation that RpiRc signals through the accessory gene regulatory (Agr) quorum-sensing system in USA300. Specifically, RpiRc represses the rnaIII promoter, resulting in increased repressor of toxins (Rot) levels, which in turn negatively affect leukocidin expression. Inactivation of rpiRc phenocopied rot deletion and increased S. aureus killing of primary human polymorphonuclear leukocytes and the pathogenesis of bloodstream infection in vivo. Collectively, our results suggest that S. aureus senses metabolic shifts by RpiRc to differentially regulate the expression of leukocidins and to promote invasive disease. IMPORTANCE The bicomponent pore-forming leukocidins play pivotal roles in the ability of S. aureus to kill multiple host immune cells, thus enabling this pathogen to have diverse tissue- and species-tropic effects. While the mechanisms of leukocidin-host receptor interactions have been studied in detail, the regulatory aspects of leukocidin expression are less well characterized. Moreover, the expression of the leukocidins is highly modular in vitro, suggesting the presence of regulators other than the known Agr, Rot, and S. aureus exoprotein pathways. Here, we describe how RpiRc, a metabolite-sensing transcription factor, mediates the repression of two specific leukocidin genes, lukED and pvl, which in turn has complex effects on the pathogenesis of S. aureus. Our findings highlight the intricacies of leukocidin regulation by S. aureus and demonstrate the involvement of factors beyond traditional virulence factor regulators.
format	article
author	Divya Balasubramanian Elizabeth A. Ohneck Jessica Chapman Andy Weiss Min Kyung Kim Tamara Reyes-Robles Judy Zhong Lindsey N. Shaw Desmond S. Lun Beatrix Ueberheide Bo Shopsin Victor J. Torres
author_facet	Divya Balasubramanian Elizabeth A. Ohneck Jessica Chapman Andy Weiss Min Kyung Kim Tamara Reyes-Robles Judy Zhong Lindsey N. Shaw Desmond S. Lun Beatrix Ueberheide Bo Shopsin Victor J. Torres
author_sort	Divya Balasubramanian
title	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc
title_short	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc
title_full	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc
title_fullStr	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc
title_full_unstemmed	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc
title_sort	<named-content content-type="genus-species">staphylococcus aureus</named-content> coordinates leukocidin expression and pathogenesis by sensing metabolic fluxes via rpirc
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/5580eb7c97fb46ef8e5c10e18d612681
work_keys_str_mv	AT divyabalasubramanian namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT elizabethaohneck namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT jessicachapman namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT andyweiss namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT minkyungkim namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT tamarareyesrobles namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT judyzhong namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT lindseynshaw namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT desmondslun namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT beatrixueberheide namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT boshopsin namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc AT victorjtorres namedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentcoordinatesleukocidinexpressionandpathogenesisbysensingmetabolicfluxesviarpirc
_version_	1718427458262269952

<named-content content-type="genus-species">Staphylococcus aureus</named-content> Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc

Ejemplares similares