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，仍然是一种流行的蜱传感染，在许多地区， 世界仅在美国，每年就有30多万新病例发生。所述感染是 由广义伯氏疏螺旋体（Borrelia burgdorferi sensu lato）引起，其是一组非典型细胞外细菌病原体， 在自然界中通过复杂的地方性感染循环生存，涉及属于肩突硬蜱的蜱 复杂和一系列脊椎动物宿主，最常见的是野生啮齿动物。尽管作出了认真的努力， 在过去几十年中，感染持续存在，主要是由于缺乏有效的控制 预防蜱虫感染的措施，缺乏人用疫苗，早期感染诊断困难， 与使用当前可用的抗菌剂治疗相关的并发症。具体来说，几个月 在标准抗生素治疗后，一部分患者可能会经历一系列持续性或复发性 症状，称为慢性莱姆病或治疗后莱姆病综合征，对于其进一步 治疗方案仍然不可用。因此，疫苗和新药的开发是非常重要的。 来对抗莱姆病该项目追求一个长期目标，以了解生物 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病。重点是蛋白质- 蛋白质相互作用的病原体感染和持久性在宿主中是必不可少的，目标是提供 定义三种螺旋体生物学意义的全面结构和功能信息 注释为BB 0323、BB 0238和BB 0104（BbHtrA）的蛋白质，其中每一个独立地或作为 是感染的关键上一个项目周期表明，有针对性的删除或 蛋白质伴侣或短结合表位的改变影响蛋白质稳定性并使病原体 在哺乳动物宿主中无感染性。本提案的总体目标是进一步侧重于 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本知识， 设计非传统的抗感染策略来对抗莱姆病，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.