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)：与人类莱姆病最常见的致病螺旋体已被归类为三个基因种，伯氏杆菌、阿菲氏杆菌和加里尼氏杆菌。有趣的是，在持续感染期间，这三个基因种似乎都存在于不同的生态位，最终导致不同的临床表现。例如，伯氏杆菌和阿氏杆菌通常分别与涉及关节和皮肤的疾病有关，而加里尼氏杆菌通常会导致中枢神经系统异常。导致不同基因种之间组织趋向性和疾病表现不同的潜在机制尚不清楚。然而，最近发现伯氏杆菌和阿氏杆菌都能与宿主血清补体抑制因子H结合在细胞表面，从而产生补体抵抗。相比之下，加里尼芽胞杆菌不结合H因子，对补体敏感，这导致了这样的假设，即加里尼芽孢杆菌生物体持续感染中枢神经系统，因为它是一个受限于细胞毒补体的环境。最近，我们等人在体外发现了几种能与因子H结合的伯氏杆菌外表面脂蛋白(OSP)。已鉴定的H因子结合蛋白包括几种与OSPE相关的脂蛋白以及一种命名为BbA68的脆性蛋白。为了进一步这些先前的研究，并更直接地检验因子H结合蛋白在补体抵抗中所起的实际作用，我们在伯氏杆菌无毒株中灭活了bbA68基因。野生型亲本菌株是完全补体抗性的，而缺乏BbA68表达的突变体对补体高度敏感，这表明该蛋白可能是赋予伯氏杆菌补体抗性的主要分子。进一步探讨BbA68在疏螺旋体补体抗性中的作用。在实际感染期间(即在体内)，我们建议(I)在伯氏杆菌强毒株中灭活bbA68基因，(Ii)在强毒力、补体敏感的加里尼氏杆菌分离株中过表达BbA68。然后将使用莱姆病的小鼠模型来检查产生的突变菌株的毒力和/或疾病发病机制的变化。本R21应用中概述的联合研究重点是为未来的R01应用提供必要的基础和初步数据，该应用将研究BbA68在螺旋体组织趋向性和莱姆病发病机制中的功能作用。