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

Flack, Caralyn E.; Zurek, Oliwia W.; Meishery, Delisha D.; Pallister, Kyler B.; Malone, Cheryl L.; Horswill, Alexander R.; Voyich, Jovanka M.

doi:10.1073/pnas.1322125111

Cited by 61 publications

(75 citation statements)

References 48 publications

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“…5). As expected based on previous studies (12,(15)(16)(17)25), we observed a dose-dependent transcriptional response in the wild-type strain in the presence of 0, 0.5, 2.5, or 5.0 g ml Ϫ1 HNP-1. The coa promoter activity in the vfrB mutant in the presence of low HNP-1 concentrations (0.5 g ml Ϫ1 ) had a similar reduction (4.7-fold) as when no HNP-1 was added.…”

Section: Resultssupporting

confidence: 91%

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

2017

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In previous studies, we identified the fatty acid kinase virulence factor regulator B (VfrB) as a potent regulator of ␣-hemolysin and other virulence factors in Staphylococcus aureus. In this study, we demonstrated that VfrB is a positive activator of the SaeRS two-component regulatory system. Analysis of vfrB, saeR, and saeS mutant strains revealed that VfrB functions in the same pathway as SaeRS. At the transcriptional level, the promoter activities of SaeRS class I (coa) and class II (hla) target genes were downregulated during the exponential growth phase in the vfrB mutant, compared to the wild-type strain. In addition, saePQRS expression was decreased in the vfrB mutant strain, demonstrating a need for this protein in the autoregulation of SaeRS. The requirement for VfrB-mediated activation was circumvented when SaeS was constitutively active due to an SaeS (L18P) substitution. Furthermore, activation of SaeS via human neutrophil peptide 1 (HNP-1) overcame the dependence on VfrB for transcription from class I Sae promoters. Consistent with the role of VfrB in fatty acid metabolism, hla expression was decreased in the vfrB mutant with the addition of exogenous myristic acid. Lastly, we determined that aspartic acid residues D38 and D40, which are predicted to be key to VfrB enzymatic activity, were required for VfrB-mediated ␣-hemolysin production. Collectively, this study implicates VfrB as a novel accessory protein needed for the activation of SaeRS in S. aureus.IMPORTANCE The SaeRS two-component system is a key regulator of virulence determinant production in Staphylococcus aureus. Although the regulon of this twocomponent system is well characterized, the activation mechanisms, including the specific signaling molecules, remain elusive. Elucidating the complex regulatory circuit of SaeRS regulation is important for understanding how the system contributes to disease causation by this pathogen. To this end, we have identified the fatty acid kinase VfrB as a positive regulatory modulator of SaeRS-mediated transcription of virulence factors in S. aureus. In addition to describing a new regulatory aspect of SaeRS, this study establishes a link between fatty acid kinase activity and virulence factor regulation.

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Section: Resultssupporting

confidence: 91%

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

2017

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“…Consistent with these findings, virulence of the mutant strain is reduced significantly in mouse models of S. aureus infection [14,36]. SaeRS induces expression of genes encoding molecules involved in virulence, such as hla , LukAB / LukGH , and hlgA [37 ▪ ], and those encoding Ssls protein and staphylococcal nuclease [38 ▪ ,39]. Collectively, these data support the idea that SaeRS is important for the ability of S. aureus to circumvent killing by neutrophils and thereby cause disease.…”

Section: Regulation Of Virulencementioning

confidence: 73%

How methicillin-resistant Staphylococcus aureus evade neutrophil killing

Greenlee‐Wacker

DeLeo

Nauseef

2015

Current Opinion in Hematology

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Purpose of review Methicillin-resistant strains of the important human pathogen Staphylococcus aureus pose a significant public health threat in the community, as they are easily transmitted, especially prone to cause invasive disease, and infect otherwise healthy individuals. The mechanistic basis for the ability of these organisms to evade the innate immune responses remains incompletely defined. Recent findings The success of pathogens such as S. aureus rests, in part, on their capacity to overcome neutrophil-mediated host defense to establish infection and cause human disease. S. aureus has the potential to thwart effective neutrophil chemotaxis, and phagocytosis, and succeeds in evading killing by neutrophils. Furthermore, S. aureus surviving within neutrophils promotes neutrophil cytolysis, with release of host-derived molecules that promote local inflammation. Here, we provide a brief overview of our understanding of the mechanisms by which S. aureus – including methicillin-resistant S. aureus – avoids neutrophil-mediated host defense and causes disease. Summary Understanding the molecular mechanisms by which S. aureus avoids neutrophil-mediated responses and initiates signaling cascades that culminate in neutrophil lysis will provide insights prerequisite to the development of novel targets for treating staphylococcal infections.

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“…agr is an important regulator of virulence and is also a TCS consisting of the response regulator AgrA and the kinase AgrC. The SaeR/S TCS in essential to the evasion of the innate immune system by reducing reactive oxygen species, aiding survival in the face of host defense peptides, reducing expression of IL-8, and increasing the expression of leukocidins [32, 40, 42, 189, 190]. SaeRS can also regulate the expression of virulence genes including hla [191].…”

Section: Two-component Systemsmentioning

confidence: 99%

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

Kane

Carothers

Lee

2018

CDT

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Background Staphylococcus aureus is a major bacterial pathogen capable of causing a range of infections in humans from gastrointestinal disease, skin and soft tissue infections, to severe outcomes such as sepsis. Staphylococcal infections in humans can be frequent and recurring, with treatments becoming less effective due to the growing persistence of antibiotic resistant S. aureus strains. Due to the prevalence of antibiotic resistance, and the current limitations on antibiotic development, an active and highly promising avenue of research has been to develop strategies to specifically inhibit the activity of virulence factors produced S. aureus as an alternative means to treat disease. Objective In this review we specifically highlight several major virulence factors produced by S. aureus for which recent advances in antivirulence approaches may hold promise as an alternative means to treating diseases caused by this pathogen. Strategies to inhibit virulence factors can range from small molecule inhibitors, to antibodies, to mutant and toxoid forms of the virulence proteins. Conclusion The major prevalence of antibiotic resistant strains of S. aureus combined with the lack of new antibiotic discoveries highlight the need for vigorous research into alternative strategies to combat diseases caused by this highly successful pathogen. Current efforts to develop specific antivirulence strategies, vaccine approaches, and alternative therapies for treating severe disease caused by S. aureus have the potential to stem the tide against the limitations that we face in the post-antibiotic era.

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

Cited by 61 publications

References 48 publications

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

How methicillin-resistant Staphylococcus aureus evade neutrophil killing

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

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