The SaeR/S Gene Regulatory System Is Essential for Innate Immune Evasion by<i>Staphylococcus aureus</i>

Voyich, Jovanka M.; Vuong, Cuong; DeWald, Mark; Nygaard, Tyler K.; Kocianova, Stanislava; Griffith, Shannon; Jones, Jennifer M.; Iverson, Courtney; Sturdevant, Daniel E.; Braughton, Kevin R.; Whitney, Adeline R.; Otto, Michael; DeLeo, Frank R.

doi:10.1086/598967

Cited by 177 publications

(266 citation statements)

References 40 publications

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“…Diluted supernatants were added to plated PMNs, synchronized (400 × g, 8 min, 4°C), and then incubated statically at 37°C with 5% CO 2 . Membrane permeability and cytotoxicity caused by whole bacteria were evaluated as described using flow cytometry (11,47) or the CytoTox 96 Non-Radioactive Cytotoxicity assay (Promega) according to the manufacturer's instructions (31,33).…”

Section: Methodsmentioning

confidence: 99%

“…SaeRS regulates transcription of multiple toxins, including γ-toxin (hlgA, hlgB, hlgC), LukSF-PVL, and LukAB/LukGH, which have been shown to contribute to PMN lysis (26)(27)(28)(29)(30)(31). Additionally, transcription of the saePQRS operon and SaeR target genes are activated in response to PMN phagocytosis and PMN components (32)(33)(34).…”

Section: Mutagenesis Of the Predicted Extracellular Loop Of Saes Idenmentioning

confidence: 99%

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Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Flack

Zurek

Meishery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the histidine kinase SaeS recognizes specific host stimuli is unknown. After mutagenizing the predicted extracellular loop of SaeS, we discovered one methionine residue (M31) was essential for the ability of S. aureus to transcribe sae target genes, including hla, lukAB/lukGH, and hlgA. This single M31A mutation also significantly reduced cytotoxicity in human neutrophils to levels observed in cells following interaction with ΔsaeS. Another important discovery was that mutation of two aromatic anchor residues (W32A and F33A) disrupted the normal basal signaling of SaeS in the absence of inducing signals, yet both mutant kinases had appropriate activation of effector genes following exposure to neutrophils. Although the transcriptional profile of aromatic mutation W32A was consistent with that of WT in response to human α-defensin 1, mutant kinase F33A did not properly transcribe the γ-toxin genes in response to this stimulus. Taken together, our results provide molecular evidence for how SaeS recognizes host signals and triggers activation of select virulence factors to facilitate evasion of innate immunity. These findings have important implications for signal transduction in prokaryotes and eukaryotes due to conservation of aromatic anchor residues across both of these domains and the important role they play in sensor protein structure and function.host-pathogen interactions | membrane proteins

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Section: Methodsmentioning

confidence: 99%

Section: Mutagenesis Of the Predicted Extracellular Loop Of Saes Idenmentioning

confidence: 99%

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Flack

Zurek

Meishery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…4B). SaeRS is known to regulate virulence determinants, including surface proteins, toxins, and capsule biosynthesis components (30)(31)(32), and the saeR mutant shows high susceptibility to ␤-lactams in Staphylococcus epidermidis (33). This increased susceptibility to cell wall-acting antibiotics may be due to decreased teichoic acids in the cell wall.…”

Section: Teixobactin-induced Lysis Is Dependent On the Atl Autolysinmentioning

confidence: 99%

Dual Targeting of Cell Wall Precursors by Teixobactin Leads to Cell Lysis

Homma

Nuxoll

Gandt

et al. 2016

Antimicrob Agents Chemother

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Teixobactin represents the first member of a newly discovered class of antibiotics that act through inhibition of cell wall synthesis. Teixobactin binds multiple bactoprenol-coupled cell wall precursors, inhibiting both peptidoglycan and teichoic acid synthesis. Here, we show that the impressive bactericidal activity of teixobactin is due to the synergistic inhibition of both targets, resulting in cell wall damage, delocalization of autolysins, and subsequent cell lysis. We also find that teixobactin does not bind mature peptidoglycan, further increasing its activity at high cell densities and against vancomycin-intermediate Staphylococcus aureus (VISA) isolates with thickened peptidoglycan layers. These findings add to the attractiveness of teixobactin as a potential therapeutic agent for the treatment of infection caused by antibiotic-resistant Gram-positive pathogens.

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“…One reason for the observed strain-dependent PVL expression may be the activity of global virulence regulators. Several regulators like agr, sar and very recently sae have been identified as controlling luk-PV expression (Bronner et al, 2000;Voyich et al, 2009). Here we could confirm that the virulence regulator sae positively influences transcription: in the sae-knockout mutant ISP479c-sae, luk-PV-specific mRNA was no longer detectable.…”

Section: Influence Of Global Virulence Regulators On Luk-pv Transcripmentioning

confidence: 99%

“…The possible contribution of PVL to the virulence of S. aureus has been argued in studies using a variety of different animal models (Bubeck toxin A (ETA) (Sheehan et al, 1992). In a similar fashion, transcription of luk-PV was shown to depend on the activity of the regulators agr, sar and sae (Bronner et al, 2000;Voyich et al, 2009). Additionally, the composition of the growth medium (Bronner et al, 2000;Dumitrescu et al, 2007) and subinhibitory concentrations of different antibiotics exerted a strong effect on PVL expression (Dumitrescu et al, 2007;Stevens et al, 2007).…”

Section: Introductionmentioning

confidence: 96%

Transcription of the phage-encoded Panton–Valentine leukocidin of Staphylococcus aureus is dependent on the phage life-cycle and on the host background

et al. 2009

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Panton-Valentine leukocidin (PVL) is a pore-forming, bi-component toxin secreted by Staphylococcus aureus strains epidemiologically associated with diseases such as necrotizing pneumonia and skin and soft-tissue infections. Here we demonstrate that transcription of the phage-encoded PVL (encoded in the luk-PV operon) is dependent on two major determinants: the phage life-cycle and the host chromosomal background. Mitomycin C induction of PVLencoding prophages from different community-acquired MRSA strains led to an increase in the amount of luk-PV mRNA as a result of read-through transcription from latent phage promoters and an increase in phage copy numbers. Failing prophage excision was reflected in a constant expression of luk-PV as in the case of strain USA300, suggesting that wSa2USA300 is a replication-defective prophage. Additionally, we could show that luk-PV transcription is influenced by the S. aureus global virulence regulators agr and sae. We found a strong impact of the host background on prophage induction and replication when analysing PVL phages in different S. aureus strains. For example phage wSa2mw was greatly induced by mitomycin C in its native host MW2 and in strain Newman but to a considerably lesser extent in strains 8325-4, RN6390 and ISP479c. This discrepancy was not linked to the SOS response of the bacteria since recA transcription did not vary between the strains. These results suggest a fine tuning between certain phages and their host, with major impact on the expression of phage-encoded virulence genes. INTRODUCTIONStaphylococcus aureus causes a variety of local and systemic infections in humans and is one of the most important community-acquired and nosocomial pathogens. The versatility of this bacterium is due to its ability to produce a wide range of surface-exposed molecules which mediate interaction with the host cell, as well as several secreted virulence factors. S. aureus necrotizing pneumonia and skin and soft-tissue infections, which can also affect young, immunocompetent persons, is described as a threat associated with community-acquired (ca)MRSA and MSSA strains bearing the Panton-Valentine leukocidin (PVL) genes (Diederen & Kluytmans, 2006;Gillet et al., 2002;Vandenesch et al., 2003). The possible contribution of PVL to the virulence of S. aureus has been argued in studies using a variety of different animal models (Bubeck Wardenburg et al., 2008;Diep & Otto, 2008; LabandeiraRey et al., 2007;Montgomery et al., 2008;Voyich et al., 2006;Wang et al., 2007). PVL is a bi-component, poreforming cytotoxin that targets host defence cells such as human polymorphonuclear neutrophils, monocytes and macrophages (Genestier et al., 2005;Kaneko & Kamio, 2004;Prevost et al., 1995). The active form of PVL requires the assembly of two polypeptides, LukS-PV and LukF-PV, for which the corresponding genes (lukS-PV, lukF-PV) are carried by a prophage.Although tightly linked to the phage genome and dependent on it for horizontal transfer, most of the phage-encoded virulence factors are i...

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The SaeR/S Gene Regulatory System Is Essential for Innate Immune Evasion byStaphylococcus aureus

Cited by 177 publications

References 40 publications

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Dual Targeting of Cell Wall Precursors by Teixobactin Leads to Cell Lysis

Transcription of the phage-encoded Panton–Valentine leukocidin of Staphylococcus aureus is dependent on the phage life-cycle and on the host background

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