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）：最常与人类莱姆病相关的致病性螺旋体分为三个基因种，B。burgdorferi，B. afzelii和B. garinii。有趣的是，所有三个基因种似乎在持续感染期间占据不同的小生境，这最终导致不同的临床表现。例如，B。burgdorferi和B.阿氏杆菌通常分别与涉及关节和皮肤的疾病相关，而B.伽氏病通常引起中枢神经系统异常。导致基因种之间不同组织向性和疾病表现的潜在机制尚不清楚。然而，最近的研究表明，这两个B。burgdorferi和B. Afzelii在其细胞表面上结合宿主血清补体抑制因子H，这赋予补体抗性。相比之下，B. Garinii不结合因子H，并且是补体敏感的，这导致了B.加里尼氏微生物持续感染中枢神经系统，因为它是一个细胞毒性补体有限的环境。最近，几家B. Burgdorferi外表面脂蛋白（Osp）被我们和其他人鉴定为可以在体外结合因子H。所鉴定的H因子结合蛋白包括与OspE相关的几种脂蛋白以及命名为BbA 68的疏螺旋体蛋白。为了进一步这些先前的研究，并更直接地检查因子H结合蛋白在补体抗性中发挥的实际作用，我们灭活了B的无毒菌株中的bbA 68基因。burgdorferi。虽然野生型亲本菌株是完全补体抗性的，但发现缺乏BbA 68表达的突变体是高度补体敏感的，表明该蛋白质可能是赋予B补体抗性的主要分子。burgdorferi。为了进一步研究BbA 68在疏螺旋体属的补体抗性中的贡献。在实际感染期间（即，in vivo），我们提出（i）在B的强毒株中克隆bbA 68基因。burgdorferi和（ii）在毒性补体敏感性B中过表达BbA 68。加里尼分离株。然后使用莱姆病小鼠模型检查产生的突变株的毒力和/或疾病发病机制的变化。R21申请中概述的联合研究重点是为未来的R 01申请提供必要的基础和初步数据，该申请将研究BbA 68在螺旋体组织嗜性和莱姆病发病机制中的功能作用。