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组优先出现和再次出现的传染病，也是美国最常见的节肢动物传播疾病。伯氏疏螺旋体是一种莱姆病螺旋体，可以持续感染人类多年。伯氏杆菌常见于结缔组织中，与纤维连接蛋白等细胞外基质成分有关。了解钻井液与ECM组件粘合的机制将有助于制定破坏这些相互作用的策略。最近，我们发现了一种抗原性外表面脂蛋白，Reva，它与纤维连接蛋白结合。我们推测，硼-ECM的相互作用，特别是那些由纤维连接蛋白结合蛋白介导的相互作用，对哺乳动物的感染和在宿主中的持久性至关重要。研究的目的是(1)通过Reva蛋白的定点突变和分析纤维连接蛋白的特异结合片段，阐明Reva与纤维连接蛋白结合的机制；(2)研究Reva在感染过程中、随着时间的推移以及在小鼠模型中几个组织中的表达是如何调节的。与公共卫生相关：引起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。疏螺旋体外表面蛋白在动物感染中起着重要作用。了解这些蛋白质是如何合成的，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改进的莱姆病治疗、预防和诊断工具的开发。

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.