Complement-mediated anti-pneumococcal functions of C-reactive protein

C反应蛋白补体介导的抗肺炎球菌功能

• 批准号: 10543464
• 负责人: ALOK AGRAWAL
• 金额: $ 37万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-05 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543464
• 关键词: Acute-Phase Proteins; Age related macular degeneration; Animal Model; Area; Bacteremia; Binding; Binding Proteins; Blood; C-reactive protein; Cell Wall; Classical Complement Pathway; Clinical Medicine; Complement; Complement 1q; Complement 2; Complement Activation; Complement Factor H; Complement Inactivators; Complex; Development; Gene Proteins; Goals; Human; Immobilization; In Vitro; Infection; Inflammation; Inflammatory Response; Investigation; Knock-out; Knockout Mice; Ligand Binding; Ligands; Mediating; Modeling; Mus; Names; Natural Immunity; Pathway interactions; Patients; Phosphorylcholine; Plasma Proteins; Pneumococcal Infections; Polysaccharides; Property; Proteins; Retina; Role; Serum; Streptococcus pneumoniae; Structure; Surface; Testing; Time; Work; antimicrobial; complement system; in vivo; insight; mouse model; mutant; protective effect; protein function; recruit; treatment strategy

Project Summary / Abstract C-reactive protein (CRP) was discovered in the blood obtained from patients infected with Streptococcus pneumoniae and was found to be a component of innate immunity and inflammatory response. In murine models of infection, human CRP is protective against lethal infection with S. pneumoniae. The mechanisms of anti-pneumococcal action of CRP are not defined yet. Interestingly, CRP was protective only during the early stages of infection, i.e., when CRP was injected into mice within 6 h of administering pneumococci. CRP was not protective during the late stages of infection, i.e., CRP was not protective when injected into mice after 6 h of administering pneumococci. In vitro, CRP binds to phosphocholine groups present in the cell wall C- polysaccharide of pneumococci and subsequently activates the complement system. Accordingly, it is hypothesized that CRP is protective because ligand-bound CRP activates the complement system on the pneumococcal surface leading to the reduction of bacteremia. This hypothesis explains the protective effects of CRP during the early stages of infection, but this does not explain why CRP loses its protective effect during the late stages of infection. We hypothesize that CRP works through two mechanisms: one mechanism based on the binding of CRP to phosphocholine and subsequent complement activation and one mechanism based on the binding of CRP to complement inhibitor factor H. This hypothesis will be tested in the following three specific aims. In aim 1, the hypothesis that “the activation of the complement system on the pneumococcal surface, subsequent to the binding of CRP to pneumococci, participate in CRP-mediated protection” will be tested. In aim 2, two hypotheses that “pneumococci recruit complement inhibitory protein factor H on their surface and evade complement attack during late stage infection” and that “structurally altered CRP capable of binding to factor H can protect mice against infection during the late stages also” will be tested. In aim 3, the hypothesis that “the binding of CRP to phosphocholine groups is critical for complement activation and killing of pneumococci” will be tested. These hypotheses will be tested by using mutants of CRP incapable of activating murine complement, capable of binding to factor H, and incapable of binding to phosphocholine and by employing both wild-type and CRP knockout mice. Successful completion of this project will provide insight into the mechanisms of anti-pneumococcal functions of CRP which may lead to the development of a CRP-based strategy to treat late stage pneumococcal infection.

项目总结/摘要 在链球菌感染患者的血液中发现了C反应蛋白（CRP 肺炎，并且被发现是先天免疫和炎症反应的组分。小鼠 感染模型中，人CRP对S.肺炎。的机制 CRP的抗肺炎球菌作用尚未确定。有趣的是，CRP仅在早期 感染阶段，即，当CRP在给予肺炎球菌后6小时内注射到小鼠体内时。CRP为 在感染的晚期阶段没有保护性，即，CRP在6 h后注射到小鼠体内时没有保护作用 使用肺炎双球菌。在体外，CRP与存在于细胞壁中的磷酸胆碱基团结合。 肺炎球菌的多糖，并随后激活补体系统。因此，它 假设CRP是保护性的，因为配体结合的CRP激活补体系统， 肺炎球菌表面导致菌血症减少。这一假说解释了 CRP在感染的早期阶段，但这并不能解释为什么CRP失去其保护作用， 感染的晚期阶段。我们假设CRP通过两种机制起作用：一种机制基于 对CRP与磷酸胆碱的结合以及随后的补体激活的影响， CRP与补体抑制因子H的结合。这一假设将在以下三个方面得到检验： 明确的目标。在目的1中，假设“补体系统对肺炎球菌的激活， 在CRP与肺炎球菌结合后，表面参与CRP介导的保护作用”将是 测试.在目的2中，两种假说“肺炎球菌招募补体抑制蛋白因子H， 在晚期感染期间表面和逃避补体攻击”和“结构改变CRP能够 与H因子结合可以保护小鼠在晚期阶段免受感染。在目标3中， 假设“CRP与磷酸胆碱基团的结合对于补体激活和杀伤 肺炎球菌”进行检测。这些假设将通过使用不能激活 鼠补体，能结合H因子，不能结合磷酸胆碱， 使用野生型和CRP敲除小鼠。该项目的成功完成将提供深入了解 CRP的抗肺炎球菌功能的机制，这可能会导致CRP为基础的发展， 治疗晚期肺炎球菌感染策略。