Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease.
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.
Rosch
Jason W
JW
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
Boyd
Angela R
AR
Hinojosa
Ernesto
E
Pestina
Tamara
T
Hu
Yunming
Y
Persons
Derek A
DA
Orihuela
Carlos J
CJ
Tuomanen
Elaine I
EI
D000755:Anemia, Sickle Cell / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000627:therapeutic use; D003603:Cytotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D011008:Pneumococcal Infections / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000502:physiology; D013301:Streptolysins / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D001426:Bacterial Proteins; D003603:Cytotoxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; C039351:platelet activating factor receptor