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，由于螺旋体伯氏伯氏菌（BB）感染，是美国最常见的媒介传播疾病。该疾病是分阶段发生的，很大程度上是由于宿主对螺旋体的免疫反应，因为它适应了持续存在于哺乳动物的宿主中。先天免疫是针对螺旋体侵袭的第一道防线，对于诱导保护性适应性免疫反应至关重要。模式识别分子的Toll样受体（TLR）家族的成员允许先天免疫细胞识别并响应BB成分。尽管对于宿主防御至关重要，但先天免疫也引起了与BB相关疾病的免疫病理学。 该提议是基于我们最近的发现，即缺乏TLR诱导的炎症所需的细胞内适配器分子，并不能消除BB感染的小鼠中的疾病，而是严重损害了尽管体液强烈的免疫力，但严重损害了宿主控制感染的能力。该提案的目标是1）确定在没有MYD88依赖性TLR信号的情况下，BB在体外激活先天免疫细胞的机制； 2）定义先天和/或自适应免疫反应的缺陷，从而导致MyD88缺陷小鼠的病原体扩张不受控制； 3）使用双基因敲除小鼠，确定抗体，FC受体和L补体在MyD88独立疾病表达中的贡献； 4）使用RNA干扰和条件突变小鼠，定义了MyD88依赖性TLR响应在BB感染持续阶段控制BB中的作用； 4）使用BB基因阵列，确定持续存在于抗体反应宿主中的螺旋体的基因表达。 这些研究的结果将为识别和反应BB和其他细胞外病原体所利用的途径提供新的见解。了解这些途径对炎症诱导的贡献可能表明治疗干预的新靶标或增强炎症性疾病的免疫力，无论是传染性和非感染而起源。对于莱姆病领域，定义由宿主适应的螺旋体表达的关键分子将使我们更近一步地了解这种病原体在免疫反应迅速的宿主中如何持续。