Complement evasion by Borrelia burgdorferi

伯氏疏螺旋体的补体逃避

• 批准号: 7048802
• 负责人: DARRIN R. AKINS
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048802
• 关键词: Borrelia; Lyme disease; bacteria infection mechanism; bacterial genetics; bacterial proteins; binding proteins; complement; complement inhibitors; gene expression; genetic strain; histopathology; host organism interaction; joints; laboratory mouse; membrane proteins; species difference; virulence

DESCRIPTION (provided by applicant): Pathogenic spirochetes most often associated with human Lyme disease have been grouped into three genospecies, B. burgdorferi, B. afzelii, and B. garinii. Interestingly, all three genospecies seem to populate different niches during persistent infection, which ultimately results in different clinical manifestations. For example, B. burgdorferi and B. afzelii are commonly associated with disease involving the joints and skin, respectively, while B. garinii typically causes central nervous system abnormalities. The underlying mechanism that results in the different tissue tropisms and disease manifestations between genospecies is not clear. However, it was recently shown that both B. burgdorferi and B. afzelii bind host serum complement inhibitor factor H on their cell surface, which confers complement resistance. By contrast, B. garinii does not bind factor H and is complement sensitive, which has led to the hypothesis that B. garinii organisms persistently infect the central nervous system because it is an environment limited in cytotoxic complement. Recently, several B. burgdorferi outer surface lipoproteins (Osp) were identified by us and others that can bind factor H in vitro. The factor H binding proteins identified include several lipoproteins related to OspE as well as a borrelial protein designated BbA68. To further these prior studies, and more directly examine the actual role that factor H-binding proteins play in complement resistance, we inactivated the bbA68 gene in an avirulent strain of B. burgdorferi. While the wild type parental strain is fully complement resistant, the mutant that lacked expression of BbA68 was found to be highly complement sensitive, suggesting that this protein may be the major molecule that imparts complement resistance to B. burgdorferi. To further examine the contribution of BbA68 in complement resistance of Borrelia spp. during an actual infection (i.e., in vivo), we propose to (i) inactivate the bbA68 gene in a virulent strain of B. burgdorferi and (ii) over express BbA68 in a virulent, complement sensitive B. garinii isolate. The mutant strains generated will then be examined for changes in virulence and/or disease pathogenesis using the mouse model of Lyme disease. The combined studies outlined in this R21 application focus on providing the necessary foundation and preliminary data for a future R01 application that will examine the functional role of BbA68 in spirochete tissue tropism and Lyme disease pathogenesis.

描述（由申请人提供）：最常与人类莱姆病有关的致病螺旋体已分为三个基因种类，即B. Burgdorferi，B。Afzelii和B. Garinii。有趣的是，在持续感染期间，这三个基因种类似乎都占不同的壁ni，最终导致了不同的临床表现。例如，伯格多菲尔（B. burgdorferi）和afzelii通常与涉及关节和皮肤的疾病相关，而b. garinii通常会引起中枢神经系统异常。导致基因种之间的不同组织往流和疾病表现的潜在机制尚不清楚。然而，最近表明，B。brgdorferi和B. afzelii均在其细胞表面结合了宿主血清补体抑制剂h，这赋予了补体耐药性。相比之下，B. garinii不结合因子H，并且是补体敏感的，这导致了以下假设：B. garinii有机体持续感染中枢神经系统，因为它是一种受细胞毒性补体的环境。最近，美国和其他可以在体外结合H的爆发芽孢杆菌外表面脂蛋白（OSP）。鉴定出的因子H结合蛋白包括几种与OSPE以及指定BBA68的杂质蛋白有关的脂蛋白。为了进一步进行这些先前的研究，并更直接地研究了H结合蛋白在补体耐药性中起作用的实际作用，我们在B. burgdorferi的无毒菌株中灭活了BBA68基因。虽然野生型亲本菌株完全补体耐药性，但发现缺乏BBA68表达的突变体具有高度补体敏感性，这表明该蛋白可能是赋予B. burgdorferi抗性的主要分子。进一步研究BBA68在疏螺旋体spp的补体耐药性中的贡献。在实际感染（即体内）期间，我们提议（i）在bba68基因中灭活bba68基因在b. b. b. b. b. b. b. b. b. b. bba68中，在具有毒性的敏感敏感的B. garinii孤立株中。然后，将使用莱姆病小鼠模型检查产生的突变菌株的毒力和/或疾病发病机理的变化。此R21应用中概述的合并研究重点是为未来的R01应用提供必要的基础和初步数据，该应用将检查BBA68在螺旋藻组织的热带主义和莱姆病发病机理中的功能作用。