Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-3678, USA.
J Clin Invest. 2010 Feb;120(2):627-35. doi: 10.1172/JCI39843. Epub 2010 Jan 19.
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.
镰状细胞病（SCD）的特征是血管内溶血和炎症，伴有 400 倍以上侵袭性肺炎球菌感染的发生率，导致暴发性、致命性肺炎球菌败血症。从机制上讲，侵袭性感染是由增强肺炎球菌受体介导内吞作用进入上皮细胞和内皮细胞的促炎状态所促进的。由于他汀类药物除了降低血清胆固醇外，还能减轻慢性炎症，我们假设他汀类药物治疗可能改善 SCD 患者肺炎球菌感染的预后。在这项研究中，我们在实验性 SCD 小鼠模型中检验了这一假设，发现他汀类药物治疗可延长肺炎球菌感染后的生存时间。保护作用部分归因于内皮细胞和上皮细胞上血小板激活因子受体表达的减少，这导致细菌入侵减少。另一个保护作用来自抑制肺炎球菌胆固醇依赖性细胞毒素（CDCs），包括肺炎球菌溶血素，导致宿主细胞裂解。因此，我们得出结论，他汀类药物可能对 SCD 患者的侵袭性肺炎球菌病具有预防作用，更广泛地说，在由受体介导的内吞作用和革兰氏阳性侵袭性细菌产生的 CDC 类毒素驱动的细菌发病机制中具有预防作用。
