Structure-Function Relationships of C-Reactive Protein

描述(由申请人提供)：C反应蛋白(CRP)是天然免疫的一种成分，在炎症状态下，包括细菌感染时，其血清水平会上升。在体外，CRP与肺炎链球菌的细胞壁C-多糖(PNC)结合，随后激活血清中的补体系统。CRP还与补体因子H结合，这种蛋白也与肺炎球菌结合并用于逃避补体介导的杀伤。在小鼠感染模型中，人的CRP对肺炎链球菌的致死性感染具有保护作用。我们的长期目标是确定CRP预防小鼠肺炎球菌感染的机制。C反应蛋白是如何直接或间接作用于细菌表面以杀死它们的？我们的假设是，CRP的保护作用机制涉及到补体系统的激活。据推测，CRP是通过与PNC结合，通过经典的级联反应激活补体，然后通过补体依赖的吞噬作用减少菌血症的途径发挥保护作用的。两个观察表明，这条途径是不够的。C反应蛋白的保护机制比以前所认识的要复杂得多。首先，人的C反应蛋白不能结合小鼠的C1q，因此不能激活经典的补体级联。其次，不能与PNC结合的CRP突变体仍然对小鼠的肺炎球菌感染具有保护作用。这两个耐人寻味的观察将分别在以下两个具体目标中进行。1.验证一种假设，即在CRP与肺炎球菌结合后，肺炎球菌表面补体成分的激活和募集参与了CRP介导的小鼠免受肺炎球菌感染的保护作用。2.验证C反应蛋白与H因子包被肺炎球菌上的补体H结合参与保护小鼠免受感染的假设。 公共卫生相关性我们的目标是了解C-反应蛋白(CRP)的体外结合和功能能力与其体内炎症功能相关的机制。阐明CRP保护小鼠免受肺炎链球菌感染的机制将有助于实现我们的目标。此外，对C反应蛋白-补体因子H相互作用的研究也可能对其他临床医学领域有意义，如老年性黄斑变性。

DESCRIPTION (provided by applicant): C-reactive protein (CRP) is a component of innate immunity and whose serum level rises during inflammatory states including bacterial infections. In vitro, CRP binds to cell wall C-polysaccharide (PnC) on Streptococcus pneumoniae and subsequently activates the complement system in serum. CRP also binds to complement factor H, the protein that pneumococci also bind to and use to escape complement-mediated killing. In murine models of infection, human CRP is protective against lethal infection with S. pneumoniae. Our long-term goal is to define the mechanisms by which CRP protects against pneumococcal infection in mice. How does CRP, directly or indirectly, act on the bacterial surfaces to kill them? Our hypothesis is that the mechanism of protective action of CRP involves the activation of the complement system. It was assumed that CRP was protective through a pathway in which CRP binds to PnC, activates complement through the classical cascade, and then bacteremia is reduced through complement-dependent phagocytosis. Two observations suggest that this pathway is not sufficient. The mechanism of CRP protection is much more sophisticated than previously appreciated. First, human CRP cannot bind murine C1q and therefore cannot activate the classical complement cascade. Second, a CRP mutant incapable of binding to PnC is still protective against pneumococcal infection in mice. Each of these two intriguing observations will be separately pursued in the following two specific aims. 1. To test the hypothesis that the activation and recruitment of the complement components on the pneumococcal surface, subsequent to the binding of CRP to pneumococci, participate in CRP-mediated protection of mice from pneumococcal infection. 2. To test the hypothesis that the binding of CRP to complement factor H on factor H-coated pneumococci participates in the protection of mice from infection. PUBLIC HEALTH RELEVANCE Our goal is to understand the mechanisms by which the in vitro binding and functional capabilities of C-reactive protein (CRP) relate to its in vivo functions in inflammation. Elucidation of the mechanisms by which CRP protects mice from Streptococcus pneumoniae infections would help achieve our goal. In addition, the investigation of CRP-complement factor H interactions may also have implications in other areas of clinical medicine such as age-related macular degeneration.