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Of these proteins, the bicomponent family of pore-forming leukocidins play critical roles in\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            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\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            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,\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            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\n            <jats:italic>rnaIII<\/jats:italic>\n            promoter, resulting in increased repressor of toxins (Rot) levels, which in turn negatively affect leukocidin expression. Inactivation of\n            <jats:italic>rpiRc<\/jats:italic>\n            phenocopied\n            <jats:italic>rot<\/jats:italic>\n            deletion and increased\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            killing of primary human polymorphonuclear leukocytes and the pathogenesis of bloodstream infection\n            <jats:italic>in vivo.<\/jats:italic>\n            Collectively, our results suggest that\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            senses metabolic shifts by RpiRc to differentially regulate the expression of leukocidins and to promote invasive disease.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            The bicomponent pore-forming leukocidins play pivotal roles in the ability of\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            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\n            <jats:italic>in vitro<\/jats:italic>\n            , suggesting the presence of regulators other than the known Agr, Rot, and\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            exoprotein pathways. Here, we describe how RpiRc, a metabolite-sensing transcription factor, mediates the repression of two specific leukocidin genes,\n            <jats:italic>lukED<\/jats:italic>\n            and\n            <jats:italic>pvl<\/jats:italic>\n            , which in turn has complex effects on the pathogenesis of\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            . Our findings highlight the intricacies of leukocidin regulation by\n            <jats:named-content content-type=\"genus-species\">S. aureus<\/jats:named-content>\n            and demonstrate the involvement of factors beyond traditional virulence factor regulators.\n          <\/jats:p>","DOI":"10.1128\/mbio.00818-16","type":"journal-article","created":{"date-parts":[[2016,6,23]],"date-time":"2016-06-23T17:13:59Z","timestamp":1466702039000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":62,"title":["Staphylococcus aureus Coordinates Leukocidin Expression and Pathogenesis by Sensing Metabolic Fluxes via RpiRc"],"prefix":"10.1128","volume":"7","author":[{"given":"Divya","family":"Balasubramanian","sequence":"first","affiliation":[{"name":"Department of Microbiology, New York University School of Medicine, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth 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