Genesis & Conrol of Lyme Disease by Innate Immunity

描述（由申请人提供）：莱姆病，由于感染螺旋体伯氏疏螺旋体（Bb），是美国最常见的病媒传播疾病。这种疾病分阶段发生，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。天然免疫是抵抗螺旋体入侵的第一道防线，对于诱导保护性适应性免疫应答至关重要。Toll样受体（TLR）家族的模式识别分子的成员允许先天免疫细胞识别和响应Bb组分。尽管先天免疫对于宿主防御是必不可少的，但它也引起了B b相关疾病的免疫病理学。 这一建议是基于我们最近的发现，即缺乏MyD 88，TLR诱导的炎症所需的细胞内衔接分子，并不能消除B b感染小鼠的疾病，但严重损害宿主控制感染的能力，尽管有很强的体液免疫。该提议的目的是1）确定Bb在缺乏MyD 88依赖性TLR信号传导的情况下体外激活先天免疫细胞的机制; 2）定义导致MyD 88缺陷小鼠中不受控制的病原体扩增的先天和/或适应性免疫应答的缺陷; 3）使用双敲除小鼠，确定抗体、Fc受体和补体在MyD 88非依赖性疾病表达中的贡献; 4）使用RNA干扰和条件突变小鼠，确定MyD 88依赖性TLR应答在Bb感染的持续阶段中控制Bb的作用;和4）使用Bb基因阵列，确定在抗体应答宿主中持续存在的螺旋体的基因表达。 这些研究的结果将为先天免疫识别和响应Bb和其他细胞外病原体的途径提供新的见解。了解这些途径对诱导炎症的贡献可能为治疗干预或增强炎症性疾病（感染性和非感染性）的免疫力提供新的靶点。对于莱姆病领域，定义宿主适应性螺旋体表达的关键分子将使我们更接近理解这种病原体如何在免疫应答宿主中持续存在。

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.