Genesis & Conrol of Lyme Disease by Innate Immunity

描述(申请人提供)：莱姆病，由于感染伯氏疏螺旋体(BB)，是美国最常见的媒介传播疾病。这种疾病是分阶段发生的，主要是由于宿主对螺旋体的免疫反应，因为它适应了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)模式识别分子家族的成员允许先天免疫细胞识别BB成分并对其做出反应。尽管先天免疫对宿主防御是必不可少的，但它也会引起BB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MyD88，TLR诱导的炎症所需的细胞内适配器分子，并不能消除BB感染小鼠的疾病，而是严重损害宿主控制感染的能力，尽管有很强的体液免疫。本研究的目的是：1)确定在缺乏依赖MYD88的TLR信号的情况下，BB体外激活天然免疫细胞的机制；2)确定导致MYD88缺陷小鼠病原体失控扩张的先天和/或获得性免疫反应的缺陷；3)利用双基因敲除小鼠，确定抗体、Fc受体和L补体在MYD88非依赖疾病表达中的作用；4)利用RNA干扰和条件突变小鼠，确定依赖MYD88的TLR反应在控制BB感染持续期的作用；以及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天然免疫识别和响应BB和其他细胞外病原体的途径提供新的见解。了解这些途径在诱导炎症中的作用可能会为治疗干预或提高炎症性疾病的免疫力提供新的靶点，无论是感染性的还是非传染性的。对于莱姆病领域，定义宿主适应的螺旋体表达的关键分子将使我们更接近了解这种病原体如何在免疫应答的宿主中持续存在。

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.