Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease
Jason W. Rosch, … , Carlos J. Orihuela, Elaine I. Tuomanen
Jason W. Rosch, … , Carlos J. Orihuela, Elaine I. Tuomanen
Published January 19, 2010
Citation Information: J Clin Invest. 2010;120(2):627-635. https://doi.org/10.1172/JCI39843.
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Research Article Microbiology

Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease

Abstract

Sickle cell disease (SCD) is characterized by intravascular hemolysis and inflammation coupled to a 400-fold greater incidence of invasive pneumococcal infection resulting in fulminant, lethal pneumococcal sepsis. Mechanistically, invasive infection is facilitated by a proinflammatory state that enhances receptor-mediated endocytosis of pneumococci into epithelial and endothelial cells. As statins reduce chronic inflammation, in addition to their serum cholesterol-lowering effects, we hypothesized that statin therapy might improve the outcome of pneumococcal infection in SCD. In this study, we tested this hypothesis in an experimental SCD mouse model and found that statin therapy prolonged survival following pneumococcal challenge. The protective effect resulted in part from decreased platelet-activating factor receptor expression on endothelia and epithelia, which led to reduced bacterial invasion. An additional protective effect resulted from inhibition of host cell lysis by pneumococcal cholesterol-dependent cytotoxins (CDCs), including pneumolysin. We conclude therefore that statins may be of prophylactic benefit against invasive pneumococcal disease in patients with SCD and, more broadly, in settings of bacterial pathogenesis driven by receptor-mediated endocytosis and the CDC class of toxins produced by Gram-positive invasive bacteria.

Authors

Jason W. Rosch, Angela R. Boyd, Ernesto Hinojosa, Tamara Pestina, Yunming Hu, Derek A. Persons, Carlos J. Orihuela, Elaine I. Tuomanen

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Figure 5

Effect of simvastatin on cytolysin-mediated endothelial cell death.

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Effect of simvastatin on cytolysin-mediated endothelial cell death. (A) ...
(A) PI staining of HBMECs following exposure to pneumolysin. Cells were treated with increasing concentrations of simvastatin overnight (0.1, 1.0, and 10 μM, respectively) or with simvastatin (1 μM) supplemented with mevalonate. For each condition, 20,000 cells were analyzed by FACS for PI-positive staining. Percentages of PI-positive cells in controls were: mock, 1.5%; simvastatin, 0.1%; mevalonate, 0.2%; simvastatin plus mevalonate, 0.1%. Data represent the mean ± SD from 2 independent experiments. *P < 0.01 versus mock. (B) Western blot of pneumolysin (arrowhead) in HBMEC membranes with or without simvastatin and/or mevalonate pretreatment (molecular weight markers indicated). (C and D) Release of LDH as a measure of HBMEC lysis after 1 hour of exposure to living bacteria (C) or cholesterol-dependent toxins pneumolysin (C), tetanolysin (D), or streptolysin O (D). Pretreatment with simvastatin and reversal by mevalonate as indicated. LDH released from HBMEC monolayer completely lysed by 1% Triton X-100 was assigned a value of 100%. *P < 0.01 versus mock. Error bars represent SD. (E) SCD and WT mice with or without simvastatin treatment were challenged intratracheally with 500 ng recombinant pneumolysin in 0.5% glycerol. Lung histology was assessed at 5 hours. Effects of pneumolysin toxoid and 0.5% glycerol alone are shown as negative controls. Data are representative images from at least 3 mice per group. Scale bar: 100 μM.