COMPLEMENT ACTIVATION BY MANNOSE-BINDING PROTEIN

长期目标是阐明甘露糖结合的作用。 蛋白质(MBP)在保护非免疫宿主免受压倒性感染中的作用 或者寄生虫的侵扰。总体目标是调查 新发现的MBP激活替代补体的能力 通过ACP途径增强血清杀菌活性。潜力 MBP、C-反应蛋白与血清淀粉样蛋白P的相互作用 (SAP)在控制补体激活中的作用将被研究。使用肠道 革兰氏阴性菌(主要是沙门氏菌) 内毒素中的甘露糖含量，敏感生物体的特征， MBP和补体，它们参与了这种免疫 将对机制进行研究。类似的研究将使用以下方法进行 大利什曼原虫，一种寄生虫，具有独特的富含甘露糖的 脂多糖在其感染阶段。MBP可能会 与C反应蛋白(CRP)或血清淀粉样蛋白P(SAP)相互作用 我们将探索补体激活的调节机制。为了实现这些目标， 将实现以下具体目标：一、确定结构 增加易感人群C3沉积所需的MBP要求 细菌通过研究MBP蛋白降解片段或杂交物的能力 增强C3与细菌的结合。 II.探讨MBP增强ACP活性的机制 检查其与ACP-C3的每个组成部分、B和D因子、 和备解素-以及调节蛋白-因子H和I-使用内毒素- 携载脂质体和细菌 通过比较内毒素与MBP的相互作用，确定与MBP相互作用的内毒素成分 与粗糙突变体和光滑野生型菌株的相互作用，通过尝试 用甘露糖、N-乙酰氨基葡萄糖或单抗阻断MBP活性 针对每种内毒素化学型，并通过检查最适内毒素长度 用于与MBP和补体的交互 IV.确定血清杀菌活性的机制 通过研究MBP对裂解末端补体的影响 C3酰胺键形成的组分和受体位置 五、确定MBP是否能促进主要补体的沉积 确定MBP激活补体是否受CRP或SAP的影响 这些似乎是关于MBP的极其重要的概念， 防止艾滋病毒侵入细胞的循环蛋白质，也是 参与对一种名为沙门氏菌的有机体的免疫反应 尤其是在艾滋病患者中难以根除。

The long term objectives are to elucidate the role of mannose-binding protein (MBP) in protecting non-immune hosts from overwhelming infections or parasitic infestations. The overall objective is to investigate the newly described capacity of MBP to activate the alternative complement pathway (ACP) and to enhance serum bactericidal activity. Potential interactions between MBP, C-reactive protein (CRP), and serum amyloid P (SAP) in control of complement activation will be studied. Using enteric gram negative bacteria (primarily Salmonella species) bearing various amounts of mannose in their LPS, characteristics of susceptible organisms, of MBP, and of complement which allow participation in this immune mechanism will be examined. similar studies will be performed using Leishmania major, a parasite with a distinct, mannose-rich lipophosphoglycan during its infective stage. The possibility that MBP may interact with C-reactive protein (CRP) or with serum amyloid P (SAP) to modulate complement activation will be explored. To achieve these goals, the following specific aims will be pursued: I. Determine structural requirements for MBP necessary to enhance C3 deposition on susceptible bacteria by studying the capacity of MBP proteolytic fragments or hybrids to enhance C3 binding to bacteria. II. Investigate the mechanism for enhanced ACP activation by MBP by examining its interaction with each component of the ACP -C3, Factors B&D, and properdin - and the regulatory proteins - Factors H&I - using LPS- bearing liposomes and bacteria III. Determine LPS components which interact with MBP by comparing its interaction with rough mutants and smooth wild type strains, by attempting to block MBP activity with mannose or N-acetylglucosamine or with MAb directed against each LPS chemotype, and by examining LPS lengths optimum for interactions with MBP and complement IV. Determine the mechanism for serum bactericidal activity mediated by MBP by investigating the effects MBP has on lytic terminal complement components and on the acceptor sites for C3 amide bond formation V. Determine if MBP enhances complement deposition on L. major VI. Determine if complement activation by MBP is affected by CRP or SAP These seem extremely important concepts to understand about MBP, a circulating protein which prevents invasion of cells by HIV, and also is involved in immune response to an organism, Salmonella, which is particularly difficult to eradicate in AIDS patients.