Complement evasion by Borrelia burgdorferi

伯氏疏螺旋体的补体逃避

• 批准号: 7230023
• 负责人: DARRIN R. AKINS
• 金额: $ 17.78万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230023
• 关键词: Binding; Binding Proteins; Borrelia; Borrelia burgdorferi; Borrelia burgdorferi OspE protein; Cell surface; Chromosomes; Clinical; Complement; Complement Factor H; Complement Inactivators; Complement component C5; Congenital neurologic anomalies; Data; Disease; Environment; Foundations; Future; Genes; Human; In Vitro; Infection; Joints; Lipoproteins; Location; Lyme Disease; Neuraxis; Order Spirochaetales; Organism; Pathogenesis; Play; Proteins; Resistance; Role; Serum; Skin; Suggestion; Thinking; Virulence; Virulent; cytotoxic; in vivo; mouse model; mutant; outer surface lipoprotein; tissue tropism

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）：与人类莱姆病最相关的致病性螺旋体被分为三个基因种，伯氏螺旋体、阿夫泽利螺旋体和加里尼螺旋体。有趣的是，在持续感染期间，所有三种基因种似乎都分布在不同的生态位，最终导致不同的临床表现。例如，B. burgdorferi和B. afzelii通常分别与涉及关节和皮肤的疾病相关，而B. garinii通常导致中枢神经系统异常。导致不同基因种的组织趋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，B. burgdorferi和B. afzelii都能在其细胞表面结合宿主血清补体抑制因子H，从而产生补体抗性。相比之下，B. garinii不结合因子H，对补体敏感，这导致了B. garinii生物持续感染中枢神经系统的假设，因为它是一个限制细胞毒性补体的环境。近年来，我们等人在体外鉴定了几种能结合H因子的伯氏疏螺旋体外表面脂蛋白（Osp）。已鉴定的因子H结合蛋白包括几种与OspE相关的脂蛋白以及一种名为BbA68的螺旋体蛋白。为了进一步深化这些先前的研究，并更直接地研究因子h结合蛋白在补体耐药中的实际作用，我们在一株无毒的伯氏疏螺旋体中灭活了bbA68基因。野生型亲本菌株完全具有补体抗性，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B. burgdorferi补体抗性的主要分子。为了进一步研究BbA68对伯氏疏螺旋体在实际感染（即体内）中补体抗性的贡献，我们建议(i)灭活伯氏疏螺旋体毒力菌株中的BbA68基因，（ii）在对补体敏感的伯氏疏螺旋体毒力菌株中过表达BbA68。然后将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。本R21申请中概述的联合研究重点是为未来的R01申请提供必要的基础和初步数据，以研究BbA68在螺旋体组织趋向性和莱姆病发病机制中的功能作用。