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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 February 1, 2010; First published January 19, 2010
Citation Information: J Clin Invest. 2010;120(2):627-635. https://doi.org/10.1172/JCI39843.
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Categories: Research Article Microbiology

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

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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 1

Impact of statin therapy on survival of pneumococcal infection in SCD mice.

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Impact of statin therapy on survival of pneumococcal infection in SCD mi...
(A) Survival of WT versus SCD mice receiving mock treatment (n = 26 and n = 24, respectively) or simvastatin (n = 27 and n = 32, respectively) following intranasal challenge with pneumococci; *P = 0.023 versus SCD, **P = 0.0001 versus SCD. (B) Blood and lung bacterial titers at 24 hours after challenge of SCD mice receiving mock or simvastatin treatment. (C) Blood and lung bacterial titers at 24 hours after challenge of WT mice receiving mock or simvastatin treatment. Each symbol represents an individual mouse; horizontal lines indicate the mean; dashed lines indicate limit of detection. *P < 0.01, mock versus simvastatin; Mann-Whitney U test.
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