Simvastatin Inhibits<i>Staphylococcus aureus</i>Host Cell Invasion through Modulation of Isoprenoid Intermediates

Horn, Mary P.; Knecht, Sharmon M.; Rushing, Frances L.; Birdsong, Julie A.; Siddall, C. Parker; Johnson, Charron M.; Abraham, Terri N.; Brown, Amy; Volk, Catherine B.; Gammon, Kelly; Bishop, Derron L.; McKillip, John L.; McDowell, Susan A.

doi:10.1124/jpet.108.137927

Cited by 47 publications

(76 citation statements)

References 41 publications

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“…In the current study, infectioninduced increase in tissue factor concentration was also attenuated in the simvastatin-treated group. This may have been secondary to the inhibition of S. aureus invasion of endothelial cells and macrophages, as suggested by other reports [4,5,28,29]. Finally, tissue factor levels could have been attenuated by the enhancement of the protein C pathway, as this pathway down-regulates the pro-coagulant tendency induced by sepsis [25].…”

Section: Discussionmentioning

confidence: 60%

Simvastatin Is Protective During Staphylococcus Aureus Pneumonia

McDowell¹,

Ma²,

Akinbi³

2010

D53. Sepsis: Mechanisms and Implications for Management

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Epidemiologic studies suggest that the incidence and severity of sepsis are ameliorated in patients on statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) for cholesterol lowering indications. We sought to understand the mechanism underlying such protection and hypothesized that simvastatin would be protective in mice against acute infection with Staphylococcus aureus, the primary etiologic agent in sepsis. Mice were treated with simvastatin or buffer for two weeks and were subsequently challenged with S. aureus intratracheally or intravenously. Relative to buffer-treated mice, bacterial killing was enhanced 4-fold (p=0.02), systemic dissemination was reduced, and lethality was decreased (hazard ratio 8.8, 95% CI 2.5 to 31.3, p=0.001) in mice that were pretreated with simvastatin for two weeks. Systemic inflammatory response was abrogated and the local elaboration of inflammatory mediators was diminished. Serum concentrations of profibrinolytic protein C were elevated (p=0.034), while the concentration of pro-coagulant tissue factor in bronchoalveolar lavage fluids was attenuated (reduced 25%), p=0.001, in simvastatintreated mice. Taken together, these data indicate that extended treatment with simvastatin is protective during infection with S. aureus through enhanced bacterial clearance, antiinflammatory, and anti-coagulant activities. These studies provide insights into the mechanism by which statins confer protection in acute infection, support the notion that statins may be effective adjuncts in the treatment of sepsis, and provide a rationale for randomized control trials in patients that are at a high risk for infection and characterized by coagulopathy.

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Section: Discussionmentioning

confidence: 60%

Simvastatin Is Protective During Staphylococcus Aureus Pneumonia

McDowell¹,

Ma²,

Akinbi³

2010

D53. Sepsis: Mechanisms and Implications for Management

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“…Previous work had indicated that simvastatin inhibits endocytic uptake that is dependent on the precise localization of small-GTP-ases within cellular membranes [14,15,26,27]. Although incompletely understood, transfer of biomolecules to the acceptor cell relies in part on endocytic uptake [17].…”

Section: Resultsmentioning

confidence: 99%

“…For the majority of studies, the strain used was ATCC 29213 (American Type Culture Collection, Manassas, VA). This strain induces sepsis in vivo [13] and is invasive [14,15]. To investigate the role of invasion, minimally invasive ATCC 700699 also was examined.…”

Section: Methodsmentioning

confidence: 99%

Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesicles

DeWalt

Petkovich

Zahrt

et al. 2013

Biochemical and Biophysical Research Communications

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During severe sepsis, microvesicles that are positive for tissue factor (TF) are at increased levels within blood and in pulmonary lavage. These microvesicles potentially disperse TF, the major initiator of the coagulation cascade, throughout multiple organ systems, initiating fibrin deposition and resultant ischemia. The source of these microvesicles has remained incompletely defined. Although TF+ microvesicles are shed from cells that express nascent TF transcript in response to injury, recent findings revealed that circulating, full-length TF protein is detectable prior to these nascent transcripts. This finding suggested that the protein is released from constitutive sources as an acute response. We examined whether Staphylococcus aureus, the Gram-positive bacteria that is emerging as one of the most common etiologic agents in sepsis, is capable of stimulating the release of TF+ microvesicles from a pulmonary cell line that constitutively expresses TF protein. We found that host cell invasion stimulated an acute release of TF+ microvesicles and that these microvesicles mediated the transfer of the protein to TF-negative endothelial cells. We also found that transfer was inhibited by cholesterol-lowering simvastatin. Taken together, our findings reveal that S. aureus pathogenesis extends to the acute release of TF+ microvesicles and that inhibiting dispersal by this mechanism may provide a therapeutic target.

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“…At subinhibitory concentrations, statins reduce biofilm formation in P. aeruginosa , S. aureus and Staphylococcus epidermidis [89–91], and suppress production of S. aureus cytolysins alpha-toxin and Panton-Valentine leukocidin [90]. Statins may also block host epithelial or endothelial cell invasion by P. aeruginosa , S. aureus , or the neonatal pathogen group B Streptococcus [92–94]; the later study suggesting that mevastatin antagonism of Rho-family GTPases involved in endocytotic uptake might inhibit pathogen host cell entry.…”

Section: Statins: Repurposing a Leading Human Medication At The Host-mentioning

confidence: 99%

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

Munguia

Nizet

2017

Trends in Pharmacological Sciences

111

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The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies “outside-the-box” of current antibiotic paradigms.

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Simvastatin InhibitsStaphylococcus aureusHost Cell Invasion through Modulation of Isoprenoid Intermediates

Abstract: Patients on a statin regimen have a decreased risk of death due to bacterial sepsis. We have found that protection by simvastatin includes the inhibition of host cell invasion by Staphylococcus aureus, the most common etiologic agent of sepsis.

Cited by 47 publications

References 41 publications

Simvastatin Is Protective During Staphylococcus Aureus Pneumonia

Simvastatin Is Protective During Staphylococcus Aureus Pneumonia

Host cell invasion by Staphylococcus aureus stimulates the shedding of microvesicles

Pharmacological Targeting of the Host–Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

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