Borrelia gene products critical for natural infection cycle

项目概要/摘要 莱姆疏螺旋体病，也称为莱姆病，在许多地区仍然是一种流行的蜱传感染 世界。仅在美国，每年就有超过 30 万例新病例发生。感染是 由伯氏疏螺旋体 (Borrelia burgdorferi sensu lato) 引起，这是一组非典型细胞外细菌病原体， 通过复杂的地方性动物感染周期在自然界中生存，其中包括属于肩胛硬蜱的蜱虫 复杂的和一系列脊椎动物宿主，最常见的是野生啮齿动物。尽管做出了认真的努力来控制 过去几十年来，感染持续存在，很大程度上是由于缺乏有效的控制 蜱虫感染的防治措施、缺乏人类疫苗、早期感染诊断困难以及临床 与使用现有抗菌药物治疗相关的并发症。具体来说，几个月 标准护理抗生素治疗后，一部分患者可能会经历一系列持续或复发的症状 症状，称为慢性莱姆病或治疗后莱姆病综合症，进一步 治疗方案仍然不可用。因此，疫苗和新药的研发受到高度重视。 可以对抗莱姆病。该项目追求的长期目标是了解生物 一组关键微生物毒力决定因素的重要性并获得必要的知识 开发新的治疗策略来干预莱姆疏螺旋体病。重点是蛋白质—— 蛋白质相互作用对于病原体感染和在宿主体内的持续存在至关重要，目标是提供 全面的结构和功能信息，定义了三种螺旋体的生物学意义 注释为 BB0323、BB0238 和 BB0104 (BbHtrA) 的蛋白质，其中每一个都独立或作为 复合体是感染所必需的。之前的项目周期表明，有针对性的删除或 蛋白质伴侣或短结合表位的改变会影响蛋白质稳定性并导致病原体 在哺乳动物宿主中不具有传染性。当前提案的总体目标是进一步关注 BB0323 和相关蛋白质，以便：1) 定义蛋白质成熟的特定事件，2) 确定蛋白质-蛋白质相互作用，3) 有助于确定其结构 更好地了解它们在决定哺乳动物螺旋体感染和蜱传播中的作用。 这些研究将启发我们对螺旋体非典型生物学的基础知识，并将促进 设计非传统抗感染策略来对抗莱姆疏螺旋体病，包括开发 疫苗、小分子药物和生物制剂。

PROJECT SUMMARY/ABSTRACT Lyme borreliosis, also known as Lyme disease, remains a prevalent tick-borne infection in many parts of the world. In the United States alone, there are over 300,000 new cases occurring each year. The infection is caused by Borrelia burgdorferi sensu lato, which is a group of atypical extracellular bacterial pathogens that survive in nature through a complex enzootic infection cycle, involving ticks belonging to the Ixodes scapularis complex and an array of vertebrate hosts, most commonly wild rodents. Despite serious efforts to control the infection over the past several decades, the infection persists, largely due to the absence of effective control measures against tick infestation, lack of human vaccines, difficulties in diagnosis of early infection, and clinical complications associated with treatment using currently-available antimicrobials. Specifically, several months after standard-care antibiotic therapy, a subset of patients can experience a series of persistent or relapsing symptoms, known as chronic Lyme disease or post-treatment Lyme disease syndrome, for which further treatment options remain unavailable. Therefore, the development of vaccines and new drugs is highly warranted to combat Lyme disease. This project pursues a long-term goal to understand the biological significance of a critical set of microbial virulence determinants and gain knowledge necessary for the development of new therapeutic strategies to intervene with Lyme borreliosis. The emphasis is on protein- protein interactions essential for pathogen infection and persistence in the host, and the goal is to provide comprehensive structural and functional information that defines the biological significance of three spirochete proteins annotated as BB0323, BB0238, and BB0104 (BbHtrA), each of which either independently or as a complex are essential for infection. The previous project cycle demonstrated that the targeted deletion or alteration of either protein partners or short binding epitopes impact protein stability and render the pathogen non-infectious in a mammalian host. The overall objective of the current proposal is to further focus on BB0323 and associated proteins in order to: 1) define the specific events of protein maturation, 2) determine protein-protein interactions, and 3) contribute to the determination of their structures to better understand their roles in dictating spirochete infection in mammals and transmission from ticks. These studies will enlighten our fundamental knowledge of the atypical biology of spirochetes and will facilitate the design of non-traditional anti-infective strategies to combat Lyme borreliosis, including the development of vaccines, small molecule drugs, and biologics.