ANTIGEN SPECIFIC RESPONSES TO BORRELIA

对疏螺旋体的抗原特异性反应

• 批准号: 6170005
• 负责人: Jorge L. Benach
• 金额: $ 25.46万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170005
• 关键词: Borrelia; antibacterial antibody; antigen antibody reaction; bacterial antigens; bacterial proteins; bactericidal immunity; borreliosis; enzyme activity; genetically modified animals; laboratory mouse; lipase; membrane proteins; microorganism culture; monoclonal antibody; nonhuman therapy evaluation; passive immunization

DESCRIPTION (Adapted from the applicant's abstract): The main and long term goal of this application is to understand the mechanism of action of bactericidal antibodies in Borrelia infections. A number of monoclonal antibodies have been discovered that can kill Borrelia burgdorferi without the assistance of complement, and the Fab fragments of the antibodies have the same bactericidal activity. Earlier studies showed that these antibodies function by lysis of the outer membrane in a Ca++ dependent medium process. This application is based on the hypothesis that complement independent bactericidal antibodies represent a novel and fundamental mechanism of host resistance in infections with Borrelia, and possibly in infections with other bacteria. The Research Plan is based on three underlying hypotheses that support the main goal of this application to characterize the mechanisms by which bactericidal antibodies can destroy Borrelia spp. The first approach will be to examine the antibodies themselves for possible catalytic properties which could result in a breakdown of the antigen leading to changes in the physical association of the antigen with other outer membrane molecules. The possibility that the antibodies could induce unique conformational changes in their antigens, which in turn could affect the topology and integrity of the outer membrane will also be evaluated. The second approach will be to test the hypothesis that the antibody-antigen complex induces the activation of lytic enzymes through an outer membrane signal transduction mechanism. Specifically, the identification and role of lipases and phospholipases in Borrelia will be evaluated. Such enzymes exist in these organisms and should be involved in the lysis of the outer membrane. If this mechanism of killing Borrelia is found to occur, it will represent a novel, and overlooked form of host defense. The third approach will be to test the possibility that bactericidal antibodies are a major form of host defense in Borrelia infections. Passive immunization studies will be conducted with the bactericidal antibodies in complement deficient (transgenic) mice to determine their role in preventing infection in a complement independent manner. Other studies will be involved in raising targeted bactericidal antibodies to antigens expressed in vivo. The possibility that the bactericidal antibodies may select more invasive phenotypes will also be evaluated.

描述（根据申请人的摘要改编）：主要和长期 该应用的目标是了解行动机理 伯氏感染中的杀菌性抗体。 许多单克隆 已经发现可以杀死无需杀死Borrelia Burgdorferi的抗体 补充的帮助，抗体的晶圆厂碎片具有 相同的杀菌活性。 较早的研究表明这些 抗体通过Ca ++的外膜裂解作用 中等过程。 该应用程序基于以下假设 独立的杀菌抗体代表一种新颖而基本的抗体 伯氏感染中宿主抗性的机制，可能在 其他细菌感染。 该研究计划基于支持支持的三个基本假设 该应用的主要目标是表征其机制 杀菌抗体会破坏疏螺旋体属。 第一种方法将 要检查抗体本身是否可能催化特性 这可能会导致抗原破裂，从而导致变化 抗原与其他外膜分子的物理关联。 抗体可能诱导独特构象的可能性 其抗原的变化反过来可能影响拓扑和 外膜的完整性也将进行评估。 第二种方法 将测试抗体 - 抗原复合物诱导的假设 通过外膜信号转导激活裂解酶 机制。 具体而言，脂肪酶的识别和作用和 将评估疏螺旋酶的磷脂酶。 这些酶存在于其中 生物体应参与外膜的裂解。 如果 发现这种杀死疏杠的机制发生了，它将代表 新颖，被忽视的主机防御形式。 第三种方法是 测试杀菌抗体是宿主的主要形式的可能性 疏波雷利亚感染中的防御。 被动免疫研究将是 用杀菌抗体进行补体的抗体进行 （转基因）小鼠确定它们在防止感染中的作用 补充独立的方式。 其他研究将参与提高 对体内表达的抗原的靶向杀菌抗体。 这 杀菌抗体可能选择更多侵入性的可能性 还将评估表型。