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）：最常与人类莱姆病相关的致病螺旋体已分为三个基因种：伯氏疏螺旋体、阿夫泽勒疏螺旋体和加里尼疏螺旋体。有趣的是，所有三个基因种在持续感染期间似乎占据不同的生态位，最终导致不同的临床表现。例如，伯氏疏螺旋体和阿氏疏螺旋体通常分别与涉及关节和皮肤的疾病相关，而加里尼疏螺旋体通常导致中枢神经系统异常。导致基因种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，伯氏疏螺旋体和阿夫泽勒疏螺旋体都在其细胞表面结合宿主血清补体抑制剂 H 因子，从而产生补体抗性。相比之下，B. garinii 不结合 H 因子并且对补体敏感，这导致了这样的假设：B. garinii 生物体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，我们和其他人鉴定出了几种可以在体外结合 H 因子的伯氏疏螺旋体外表面脂蛋白 (Osp)。鉴定出的 H 因子结合蛋白包括几种与 OspE 相关的脂蛋白以及称为 BbA68 的疏螺旋体蛋白。为了进一步推进这些先前的研究，并更直接地检验 H 因子结合蛋白在补体抗性中发挥的实际作用，我们灭活了伯氏疏螺旋体无毒菌株中的 bbA68 基因。虽然野生型亲本菌株完全具有补体抗性，但缺乏 BbA68 表达的突变体被发现具有高度补体敏感性，表明该蛋白可能是赋予伯氏疏螺旋体补体抗性的主要分子。为了进一步研究 BbA68 在伯氏疏螺旋体 (Borrelia spp) 补体抗性中的贡献。在实际感染期间（即体内），我们建议（i）灭活伯氏疏螺旋体强毒株中的 bbA68 基因，以及（ii）在强毒、补体敏感的加氏疏螺旋体分离株中过度表达 BbA68。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 申请中概述的综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，该应用将检查 BbA68 在螺旋体组织向性和莱姆病发病机制中的功能作用。