Role of a Borrelia burgdorferi fibronection-binding protein in Lyme Disease

描述（由申请人提供）：莱姆病是NIAID/NIH第1组优先新发和再发传染病，也是美国最常报告的节肢动物传播疾病。莱姆病螺旋体伯氏疏螺旋体可以持续感染人类多年。B。伯氏螺旋体通常存在于结缔组织中，并与细胞外基质（ECM）的组分如纤连蛋白相关。了解Borrellal粘附ECM成分背后的机制将允许开发破坏这些相互作用的策略。最近，我们发现，抗原外表面脂蛋白，RevA，结合到纤连蛋白。我们假设疏螺旋体-ECM相互作用，特别是由纤连蛋白结合蛋白介导的相互作用，对哺乳动物感染和在宿主中的持久性至关重要。拟进行以下研究：（1）通过RevA蛋白的定点诱变和纤连蛋白特异性结合片段的分析阐明RevA与纤连蛋白结合的机制;（2）表征在感染过程中，随着时间的推移以及在小鼠模型中的几种组织中，RevA表达如何受到调控。公共卫生相关性：导致莱姆病的细菌，伯氏疏螺旋体，可以感染人类和其他动物多年。疏螺旋体外表面的蛋白质在动物中建立感染中起重要作用。了解这些蛋白质是如何产生的，以及它们如何与宿主相互作用，将是了解这种病原体感染人类能力的重要一步。这些研究中获得的数据将指导开发用于治疗、预防和诊断莱姆病的改进工具。

DESCRIPTION (provided by applicant): Lyme disease is an NIAID/NIH Group 1 Priority Emerging and Re-emerging Infectious Disease, and the most frequently reported arthropod-borne disease in the United States. Borrelia burgdorferi, the Lyme disease spirochete, can persistently infect humans for years. B. burgdorferi is often found in the connective tissues and associates with components of the extracellular matrix (ECM) such as fibronectin. Understanding the mechanisms behind borrellal adhesion to ECM components will permit the development of strategies to disrupt these interactions. Recently, we discovered that an antigenic outer surface lipoprotein, RevA, binds to fibronectin. We hypothesize that borrelial-ECM interactions, especially those mediated by fibronectin-binding proteins, are crucial for mammalian infection and persistence In the host. Studies are proposed to (1) Elucidate the mechanisms of RevA binding to fibronectin through site-directed mutagenesis of the RevA protein and analyses of specifically-bound fragments of fibronectin and (2) Characterize how RevA expression is regulated during the infection process, over time and in several tissues in the mouse model. PUBLIC HEALTH RELEVANCE: The bacterium which causes Lyme disease, Borrelia burgdorferi, can infect humans and other animals for years. Proteins on the outer surface of Borrelia play important roles in establishing infection in animals. Appreciating how these proteins are made and how they interact with the host will be an important step towards understanding the ability of this pathogen to infect humans. Data obtained in these studies will direct development of improved tools for treatment, prevention, and diagnosis of Lyme disease.