Genesis & Conrol of Lyme Disease by Innate Immunity

创世纪

• 批准号: 7023910
• 负责人: Linda K. Bockenstedt
• 金额: $ 39.91万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023910
• 关键词: Borrelia; Lyme disease; RNA interference; antibacterial antibody; antibody receptor; bacteria infection mechanism; bacterial genetics; bacterial proteins; bactericidal immunity; biological signal transduction; complement; cytokine; dendritic cells; gene expression; genetic regulation; genetically modified animals; host organism interaction; laboratory mouse; macrophage; microarray technology; toll like receptor

DESCRIPTION (provided by applicant): Lyme disease, due to infection with the spirochete Borrelia burgdorferi (Bb), is the most common vector-borne disease in the United States. The disease occurs in stages and is largely due to the host immune response to the spirochete as it adapts to persist in the mammalian host. Innate immunity is provides the first line of defense against spirochete invasion and is critical for the induction of protective adaptive immune responses. Members of the Toll-like receptor (TLR) family of pattern recognition molecules allow innate immune cells to recognize and respond to Bb components. Although essential for host defense, innate immunity also gives rise to the immunopathology of Bb-associated disease. This proposal is based on our recent findings that absence of MyD88, an intracellular adaptor molecule required for TLR-induced inflammation, does not eliminate disease in Bb-infected mice, but severely impairs the ability of the host to control infection despite strong humoral immunity. The objectives of this proposal are to 1) determine the mechanisms through which Bb activates innate immune cells in vitro in the absence of MyD88-dependent TLR signaling; 2) define the defect in innate and/or adaptive immune response that leads to uncontrolled pathogen expansion in MyD88-deficient mice; 3) using double knock-out mice, determine the contribution of antibody, Fc receptors and l complement in MyD88-independent disease expression; 4) using RNA interference and conditional mutant mice, define the role of MyD88-dependent TLR responses in the control of Bb in the persistent phase of Bb infection; and 4) using Bb gene arrays, determine gene expression of spirochetes that persist in the antibody-responsive host. The results of these studies will provide new insight into the pathways utilized by innate immunity to recognize and respond to Bb and other extracellular pathogens. Understanding the contribution of these pathways to induction of inflammation may suggest new targets for therapeutic intervention or for enhancing immunity in inflammatory disorders, both infectious and non-infectious in origin. For the field of Lyme disease, defining the key molecules expressed by host-adapted spirochetes will move us one step closer toward understanding how this pathogen persists in an immunologically responsive host.

描述（由申请人提供）：莱姆病是由伯氏疏螺旋体（Bb）感染引起的，是美国最常见的媒介传播疾病。该病分阶段发生，主要是由于宿主对螺旋体的免疫反应，因为它适应在哺乳动物宿主中持续存在。先天免疫是抵御螺旋体入侵的第一道防线，对诱导保护性适应性免疫反应至关重要。toll样受体（TLR）家族的模式识别分子允许先天免疫细胞识别Bb成分并作出反应。先天免疫虽然对宿主防御至关重要，但也会引起bb相关疾病的免疫病理。