The SaeR/S Gene Regulatory System Induces a Pro-Inflammatory Cytokine Response during Staphylococcus aureus Infection

Watkins, Robert L.; Pallister, Kyler B.; Voyich, Jovanka M.

doi:10.1371/journal.pone.0019939

Cited by 34 publications

(36 citation statements)

References 50 publications

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“…The Sae TCS is primarily known for its requirement for the expression of cytotoxin-encoding genes (22,24,42,46,56). Consistent with this, the Sae TCS plays a critical role in S. aureus pathogenesis in several animal models of infection (25,36,42,56,57). In addition, the Sae TCS plays an essential role in S. aureus survival in human whole blood and in the avoidance of human neutrophil-mediated killing (56).…”

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confidence: 74%

Rot and SaeRS Cooperate To Activate Expression of the Staphylococcal Superantigen-Like Exoproteins

et al. 2012

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Staphylococcus aureus is a significant human pathogen that is capable of infecting a wide range of host tissues. This bacterium is able to evade the host immune response by utilizing a repertoire of virulence factors. These factors are tightly regulated by various two-component systems (TCS) and transcription factors. Previous studies have suggested that transcriptional regulation of a subset of immunomodulators, known as the staphylococcal superantigen-like proteins (Ssls), is mediated by the master regulators accessory gene regulator (Agr) TCS, S. aureus exoprotein expression (Sae) TCS, and Rot. Here we demonstrate that Rot and SaeR, the response regulator of the Sae TCS, synergize to coordinate the activation of the ssl promoters. We have determined that both transcription factors are required, but that neither is sufficient, for promoter activation. This regulatory scheme is mediated by direct binding of both transcription factors to the ssl promoters. We also demonstrate that clinically relevant methicillinresistant S. aureus (MRSA) strains respond to neutrophils via the Sae TCS to upregulate the expression of ssls. Until now, Rot and the Sae TCS have been proposed to work in opposition of one another on their target genes. This is the first example of these two regulators working in concert to activate promoters.

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confidence: 74%

Rot and SaeRS Cooperate To Activate Expression of the Staphylococcal Superantigen-Like Exoproteins

et al. 2012

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“…10), which is required in turn for virulence (41), innate immune response evasion (64), and proinflammatory cytokine production during S. aureus infections (65). However, WalR c -dependent early triggering of the host inflammatory response is independent from its effect on SaeSR and instead due to its role in controlling autolytic enzyme production.…”

Section: Discussionmentioning

confidence: 99%

The WalKR System Controls Major Staphylococcal Virulence Genes and Is Involved in Triggering the Host Inflammatory Response

et al. 2012

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ABSTRACTThe WalKR two-component system is essential for the viability ofStaphylococcus aureus, playing a central role in controlling cell wall metabolism. We produced a constitutively active form of WalR inS. aureusthrough a phosphomimetic amino acid replacement (WalRc, D55E). The strain displayed significantly increased biofilm formation and alpha-hemolytic activity. Transcriptome analysis was used to determine the full extent of the WalKR regulon, revealing positive regulation of major virulence genes involved in host matrix interactions (efb,emp,fnbA, andfnbB), cytolysis (hlgACB,hla, andhlb), and innate immune defense evasion (scn,chp, andsbi), through activation of the SaeSR two-component system. The impact on pathogenesis of varying cell envelope dynamics was studied using a murine infection model, showing that strains producing constitutively active WalRcare strongly diminished in their virulence due to early triggering of the host inflammatory response associated with higher levels of released peptidoglycan fragments. Indeed, neutrophil recruitment and proinflammatory cytokine production were significantly increased when the constitutively activewalRcallele was expressed, leading to enhanced bacterial clearance. Taken together, our results indicate that WalKR play an important role in virulence and eliciting the host inflammatory response by controlling autolytic activity.

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“…In mouse models, it is known that a number of T h 1 and T h 17 cytokines are associated with protection against fatal S. aureus infection (46)(47)(48). This is especially true for the T h 17 response, which is associated with neutrophil recruitment and protection against extracellular bacteria (49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections

et al. 2013

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bStaphylococcus aureus is one of the most common etiological agents of community-acquired skin and soft tissue infection (SSTI). Although the majority of S. aureus community-acquired SSTIs are uncomplicated and self-clearing in nature, some percentage of these cases progress into life-threatening invasive infections. Current animal models of S. aureus SSTI suffer from two drawbacks: these models are a better representation of hospital-acquired SSTI than community-acquired SSTI, and they involve methods that are difficult to replicate. For these reasons, we sought to develop a murine model of community-acquired methicillin-resistant S. aureus SSTI (CA-MRSA SSTI) that can be consistently reproduced with a high degree of precision. We utilized this model to begin to characterize the host immune response to this type of infection. We infected mice via epicutaneous challenge of the skin on the outer ear pinna using Morrow-Brown allergy test needles coated in S. aureus USA300. When mice were challenged in this model, they developed small, purulent, self-clearing lesions with predictable areas of inflammation that mimicked a human infection. CFU in the ear pinna peaked at day 7 before dropping by day 14. The T h 1 and T h 17 cytokines gamma interferon (IFN-␥), interleukin-12 (IL-12) p70, tumor necrosis factor alpha (TNF-␣), IL-17A, IL-6, and IL-21 were all significantly increased in the draining lymph node of infected mice, and there was neutrophil recruitment to the infection site. In vivo neutrophil depletion demonstrated that neutrophils play a protective role in preventing bacterial dissemination and fatal invasive infection.

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The SaeR/S Gene Regulatory System Induces a Pro-Inflammatory Cytokine Response during Staphylococcus aureus Infection

Cited by 34 publications

References 50 publications

Rot and SaeRS Cooperate To Activate Expression of the Staphylococcal Superantigen-Like Exoproteins

Rot and SaeRS Cooperate To Activate Expression of the Staphylococcal Superantigen-Like Exoproteins

The WalKR System Controls Major Staphylococcal Virulence Genes and Is Involved in Triggering the Host Inflammatory Response

Epicutaneous Model of Community-Acquired Staphylococcus aureus Skin Infections

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