Role of Borrelia burgdorferi Rev fibronectin binding proteins in Lyme disease

描述（由申请人提供）：莱姆病病原体伯氏疏螺旋体是一种细胞外病原体，必须适应其蜱虫载体和脊椎动物宿主。B。伯氏菌引起的持续感染可持续宿主的一生。B的发病机制。伯氏菌依赖于与细胞、细胞外基质和宿主免疫系统组分相互作用的外表面蛋白。我最近在B中发现了两种新的纤连蛋白结合蛋白。burgdorferi命名为RevA和RevB。这两种细菌表面蛋白在哺乳动物感染期间表达，但在载体蜱的定殖期间被抑制。我假设这些独特的纤连蛋白结合蛋白通过帮助B而对自然感染周期至关重要。伯氏菌与宿主组织相互作用。本文提出了三个具体的目的：（1）分析RevA和RevB在B过程中的作用。（2）明确RevA和RevB与纤连蛋白结合的机制;（3）详细阐述B. burgdorferi控制RevA和RevB的生产。从这些研究中获得的知识将形成R 01的基础，旨在了解纤连蛋白结合蛋白如何对B起作用。本发明的目的在于提供莱姆病的新的治疗性和预防性治疗，从而指导莱姆病的新的治疗性和预防性治疗的开发。 公共卫生相关性：莱姆病病原体伯氏疏螺旋体可以长时间感染人类，并且经常与宿主结缔组织相关，我发现了两种新的B。结合宿主纤连蛋白（宿主细胞外基质（ECM）的主要组分）的伯氏螺旋体蛋白。我假设纤连蛋白结合蛋白帮助B。伯氏菌与宿主组织相互作用，并且对于哺乳动物感染是至关重要的。拟议的研究将通过检查纤连蛋白结合蛋白在B中的作用来严格检验这一假设。莱姆病螺旋体感染的过程，定义的机制，疏螺旋体蛋白结合到他们的主机配体，并检查如何莱姆病螺旋体控制这些粘附素的表达。

DESCRIPTION (provided by applicant): Borrelia burgdorferi, the Lyme disease agent, is an extracellular pathogen that must adapt to both its tick vector and its vertebrate hosts. B. burgdorferi causes persistent infection that can last for the hosts' lifetime. The pathogenesis of B. burgdorferi depends on outer surface proteins that interact with the cells, extracellular matrix, and components of the hosts' immune system. I recently identified two novel fibronectin-binding proteins in B. burgdorferi named RevA and RevB. Both of these bacterial surface proteins are expressed during mammalian infection, yet repressed during colonization of vector ticks. I hypothesize that these unique fibronectin binding proteins are critical to the natural infectious cycle by helping B. burgdorferi interact with host tissues. I propose three Specific Aims: (1) analyze the roles of RevA and RevB during the B. burgdorferi infectious cycle; (2) define the mechanisms involved in RevA and RevB binding to fibronectin; (3) detail the mechanisms by which B. burgdorferi controls production of RevA and RevB. Knowledge gained from these studies will form the foundation for an R01 aimed at understanding how fibronectin-binding proteins contribute to B. burgdorferi virulence, thereby directing the development of novel therapeutic and preventative treatments for Lyme disease. Public Health Relevance: The Lyme disease agent, Borrelia burgdorferi, can infect humans for long periods of time and is frequently found associated with host connective tissues, and I identified two novel B. burgdorferi proteins that bind host fibronectin, a major component of host extracellular matrix (ECM). I hypothesize that fibronectin-binding proteins help B. burgdorferi interact with host tissues and are crucial for mammalian infection. The proposed studies will critically test this hypothesis, by examining the role(s) of fibronectin-binding proteins in B. burgdorferi infection processes, defining the mechanisms by which the borrelial proteins bind to their host ligand, and examining how the Lyme disease spirochete controls expression of these adhesins.