Structure-Function Relationships of C-Reactive Protein

描述（由申请人提供）：c -反应蛋白（CRP）是先天免疫的一个组成部分，在包括细菌感染在内的炎症状态下其血清水平升高。在体外，CRP与肺炎链球菌细胞壁c -多糖（PnC）结合，随后激活血清中的补体系统。CRP也与补体因子H结合，肺炎球菌也与补体因子H结合并利用这种蛋白质来逃避补体介导的杀伤。在小鼠感染模型中，人类CRP对肺炎链球菌的致命感染具有保护作用。我们的长期目标是确定CRP保护小鼠免受肺炎球菌感染的机制。CRP是如何直接或间接作用于细菌表面杀死它们的？我们的假设是，CRP的保护作用机制涉及补体系统的激活。假设CRP通过与PnC结合，通过经典级联激活补体，然后通过补体依赖性吞噬减少菌血症的途径发挥保护作用。两项观察表明，这种途径是不够的。CRP的保护机制比以前认识到的要复杂得多。首先，人类CRP不能结合小鼠C1q，因此不能激活经典的补体级联反应。其次，不能与PnC结合的CRP突变体在小鼠中仍然对肺炎球菌感染具有保护作用。这两个有趣的观察结果将分别在以下两个具体目标中加以探讨。1. 为了验证以下假设：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介导的小鼠肺炎球菌感染保护。2. 验证c反应蛋白与补体因子H结合在因子H包被肺炎球菌上参与保护小鼠免受感染的假设。

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.