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.
Jason W. Rosch, Angela R. Boyd, Ernesto Hinojosa, Tamara Pestina, Yunming Hu, Derek A. Persons, Carlos J. Orihuela, Elaine I. Tuomanen
Title and authors | Publication | Year |
---|---|---|
Impact of oral simvastatin therapy on acute lung injury in mice during pneumococcal pneumonia
AR Boyd, CA Hinojosa, PJ Rodriguez, CJ Orihuela |
BMC Microbiology | 2012 |
Effect of pravastatin and fosinopril on recurrent urinary tract infections
KB Pouwels, ST Visser, E Hak |
Journal of Antimicrobial Chemotherapy | 2012 |
Statin therapy as prevention against development of acute respiratory distress syndrome: an observational study
EK Bajwa, CK Malhotra, BT Thompson, DC Christiani, MN Gong |
Critical Care Medicine | 2012 |