Dataset Information


Staphylococcus aureus coordinates leukocidins expression and pathogenesis by sensing metabolic fluxes via RpiRC

ABSTRACT: Staphylococcus aureus (S. aureus) is a formidable human pathogen that uses secreted cytolytic factors such as hemolysins, leukocidins and cytolytic peptides to injure immune cells and promote infection of its host. Of these secreted molecules, the bicomponent family of pore-forming leukocidins are a potent class of cytolytic proteins with critical contributions to 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 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, in addition to altering metabolic fluxes in the TCA cycle, glycolysis and amino acid metabolism. Using mutational analyses, we confirmed that RpiRc signals through the accessory gene regulatory quorum-sensing system (Agr) in USA300. Specifically, in wildtype USA300, RpiRc represses the rnaIII promoter resulting in increased production of the repressor of toxins –Rot, which in turn represses leukocidin expression. In fact, deletion of rpiRc phenocopied deletion of rot. We show that RpiRc-mediated regulation of virulence factors is critical for killing of primary human polymorphonuclear leukocytes and for 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 thereby promoting invasive disease. Overall design: wild-type AH LAC versus AH LAC carrying the bursa aurealis transposon in the rpiRC gene

INSTRUMENT(S): Ion Torrent PGM (Staphylococcus aureus)

SUBMITTER: Andy Weiss 

PROVIDER: GSE77301 | GEO | 2017-01-26



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