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Abstract
The GraS/GraR two-component system has been shown to control cationic antimicrobial peptide (CAMP) resistance in the major human pathogen Staphylococcus aureus. We demonstrated that graX, also involved in CAMP resistance and cotranscribed with graRS, encodes a regulatory cofactor of the GraSR signaling pathway, effectively constituting a three-component system. We identified a highly conserved ten base pair palindromic sequence (5′ ACAAA TTTGT 3′) located upstream from GraR-regulated genes (mprF and the dlt and vraFG operons), which we show to be essential for transcriptional regulation by GraR and induction in response to CAMPs, suggesting it is the likely GraR binding site. Genome-based predictions and transcriptome analysis revealed several novel GraR target genes. We also found that the GraSR TCS is required for growth of S. aureus at high temperatures and resistance to oxidative stress. The GraSR system has previously been shown to play a role in S. aureus pathogenesis and we have uncovered previously unsuspected links with the AgrCA peptide quorum-sensing system controlling virulence gene expression. We also show that the GraSR TCS controls stress reponse and cell wall metabolism signal transduction pathways, sharing an extensive overlap with the WalKR regulon. This is the first report showing a role for the GraSR TCS in high temperature and oxidative stress survival and linking this system to stress response, cell wall and pathogenesis control pathways.
Highlights
The opportunistic pathogen Staphylococcus aureus is both a commensal and a major Gram-positive pathogen, causing a variety of infections ranging from superficial skin abscesses to more serious diseases such as pneumonia, meningitis, endocarditis, septicemia and toxic shock syndrome [1]
We analyzed graR expression in the DgraX mutant by quantitative RT-PCR, showing that graR expression is increased approximately 2-fold compared to the parental strain. This is likely through stabilization of the graRS transcript due to increased proximity with the operon promoter in the DgraX mutant, suggesting that cationic antimicrobial peptide (CAMP) sensitivity of the DgraX mutant may be underestimated
Part of the success of some major human pathogens such as Staphylococcus aureus can be attributed to efficient CAMP resistance
Summary
The opportunistic pathogen Staphylococcus aureus is both a commensal and a major Gram-positive pathogen, causing a variety of infections ranging from superficial skin abscesses to more serious diseases such as pneumonia, meningitis, endocarditis, septicemia and toxic shock syndrome [1]. The ubiquitous nature of this pathogen stems mostly from its capacity to survive a large variety of environmental conditions as well as an impressive ability to resist host innate immune defense mechanisms and produce systemic infections, often in healthy humans [2,3]. This unique adaptive potential has made S. aureus one of the major causes of nosocomial infections today, compounded by the rapid emergence of multiple antibiotic-resistant strains over the past few decades [4], methicillin and vancomycin-intermediate resistant strains (MRSA and VISA). Recent work has shown that several CAMPs, including indolicidin and colistin, can kill by inhibiting intracellular processes such as protein and DNA synthesis as well as septum formation and division [9]
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