The SaeR/S two-component system induces interferon-gamma production in neutrophils during invasive Staphylococcus aureus infection

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

doi:10.1016/j.micinf.2013.05.004

Cited by 10 publications

(15 citation statements)

References 24 publications

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“…concurrent infiltration of activated neutrophils in this CAUTI model are consistent with other models of S. aureus infection, as the recruitment and activation of immune cell infiltrates, including neutrophils, are a hallmark of human blood infection, skin and soft tissue infection, and systemic disease (53,59,62,63). These data suggest that while MRSA and E. faecalis both exploit the host's inflammatory response to cause CAUTI, they pursue fundamentally different mechanisms to resist the immune system and establish persistent disease.…”

Section: Discussionsupporting

confidence: 86%

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Walker

Flores-Mireles

Pinkner

et al. 2017

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

127

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Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging cause of catheter-associated urinary tract infection (CAUTI), which frequently progresses to more serious invasive infections. We adapted a mouse model of CAUTI to investigate how catheterization increases an individual's susceptibility to MRSA UTI. This analysis revealed that catheterization was required for MRSA to achieve high-level, persistent infection in the bladder. As shown previously, catheter placement induced an inflammatory response resulting in the release of the host protein fibrinogen (Fg), which coated the bladder and implant. Following infection, we showed that MRSA attached to the urothelium and implant in patterns that colocalized with deposited Fg. Furthermore, MRSA exacerbated the host inflammatory response to stimulate the additional release and accumulation of Fg in the urinary tract, which facilitated MRSA colonization. Consistent with this model, analysis of catheters from patients with S. aureus-positive cultures revealed colocalization of Fg, which was deposited on the catheter, with S. aureus. Clumping Factors A and B (ClfA and ClfB) have been shown to contribute to MRSA-Fg interactions in other models of disease. We found that mutants in clfA had significantly greater Fg-binding defects than mutants in clfB in several in vitro assays. Paradoxically, only the ClfB − strain was significantly attenuated in the CAUTI model. Together, these data suggest that catheterization alters the urinary tract environment to promote MRSA CAUTI pathogenesis by inducing the release of Fg, which the pathogen enhances to persist in the urinary tract despite the host's robust immune response.host-pathogen interactions | MRSA CAUTI | ClfB-fibrinogen interactions

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Section: Discussionsupporting

confidence: 86%

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Walker

Flores-Mireles

Pinkner

et al. 2017

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

127

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“…Since the compound was not overtly toxic, we tested its ability to reduce bacterial burden in vivo using a mouse model of invasive staphylococcal disease [16], [17]. Mice were treated with 100 µM THAM-3ФG either at the same time or one hour after an i.p .…”

Section: Resultsmentioning

confidence: 99%

“…injection with 5×10 7 MRSA in 100 µl sterile PBS [16], [17]. The first treatment group was injected i.p.…”

Section: Methodsmentioning

confidence: 99%

Antibacterial Activity of THAM Trisphenylguanide against Methicillin-Resistant Staphylococcus aureus

et al. 2014

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This study investigated the potential antibacterial activity of three series of compounds synthesized from 12 linear and branched polyamines with 2–8 amino groups, which were substituted to produce the corresponding guanides, biguanides, or phenylguanides, against Acinetobacter baumannii, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Antibacterial activity was measured for each compound by determining the minimum inhibitory concentration against the bacteria, and the toxicity towards mammalian cells was determined. The most effective compound, THAM trisphenylguanide, was studied in time-to-kill and cytoplasmic leakage assays against methicillin-resistant Staphylococcus aureus (MRSA, USA300) in comparison to chlorhexidine. Preliminary toxicity and MRSA challenge studies in mice were also conducted on this compound. THAM trisphenylguanide showed significant antibacterial activity (MIC ∼1 mg/L) and selectivity against MRSA relative to all the other bacteria examined. In time-to-kill assays it showed increased antimicrobial activity against MRSA versus chlorhexidine. It induced leakage of cytoplasmic content at concentrations that did not reduce cell viability, suggesting the mechanism of action may involve membrane disruption. Using an intraperitoneal mouse model of invasive MRSA disease, THAM trisphenylguanide reduced bacterial burden locally and in deeper tissues. This study has identified a novel guanide compound with selective microbicidal activity against Staphylococcus aureus, including a methicillin-resistant (MRSA) strain.

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“…These studies suggest that the response of PBMCs and resident cells to S. aureus may strongly impact the outcome of neutrophil- S. aureus interactions. Supporting this idea are studies demonstrating that S. aureus promotes production of IFN-γ and this production has been linked to poorer outcome of infection in mouse models (Watkins et al, 2011, 2013). IFN-γ impacts neutrophil function in many ways, including priming of oxidative burst and degranulation mechanisms (Ellis and Beaman, 2004).…”

Section: Neutrophil Priming: a Potential Target Of S Aureus?mentioning

confidence: 96%

“…Using a murine wound model of S. aureus infection, IFN-γ-mediated CXC chemokine production by T cells promoted a robust recruitment of neutrophils that resulted in elevated S. aureus burdens at the infectious foci (McLoughlin et al, 2008). Subsequent studies using a mouse peritonitis model also demonstrated IFN-γ was associated with higher bacterial burdens but that the source of IFN-γ was neutrophils (Watkins et al, 2013). Potentially, priming by IFN-γ causes overactivation and inflammation in neutrophils making them less effective at clearing S. aureus .…”

Section: Neutrophil Priming: a Potential Target Of S Aureus?mentioning

confidence: 99%

Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus

Guerra

Borgogna

Patel

et al. 2017

Front. Cell. Infect. Microbiol.

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118

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Neutrophils are the most abundant leukocytes in human blood and the first line of defense after bacteria have breached the epithelial barriers. After migration to a site of infection, neutrophils engage and expose invading microorganisms to antimicrobial peptides and proteins, as well as reactive oxygen species, as part of their bactericidal arsenal. Ideally, neutrophils ingest bacteria to prevent damage to surrounding cells and tissues, kill invading microorganisms with antimicrobial mechanisms, undergo programmed cell death to minimize inflammation, and are cleared away by macrophages. Staphylococcus aureus (S. aureus) is a prevalent Gram-positive bacterium that is a common commensal and causes a wide range of diseases from skin infections to endocarditis. Since its discovery, S. aureus has been a formidable neutrophil foe that has challenged the efficacy of this professional assassin. Indeed, proper clearance of S. aureus by neutrophils is essential to positive infection outcome, and S. aureus has developed mechanisms to evade neutrophil killing. Herein, we will review mechanisms used by S. aureus to modulate and evade neutrophil bactericidal mechanisms including priming, activation, chemotaxis, production of reactive oxygen species, and resolution of infection. We will also highlight how S. aureus uses sensory/regulatory systems to tailor production of virulence factors specifically to the triggering signal, e.g., neutrophils and defensins. To conclude, we will provide an overview of therapeutic approaches that may potentially enhance neutrophil antimicrobial functions.

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The SaeR/S two-component system induces interferon-gamma production in neutrophils during invasive Staphylococcus aureus infection

Cited by 10 publications

References 24 publications

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Catheterization alters bladder ecology to potentiate Staphylococcus aureus infection of the urinary tract

Antibacterial Activity of THAM Trisphenylguanide against Methicillin-Resistant Staphylococcus aureus

Epic Immune Battles of History: Neutrophils vs. Staphylococcus aureus

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