Borrelia gene products critical for natural infection cycle

项目摘要/摘要 莱姆疏螺旋体病，也被称为莱姆病，在中国许多地区仍然是一种流行的壁虱传播感染。 世界。仅在美国，每年就有超过30万例新病例发生。感染是 由伯氏疏螺旋体引起，它是一组非典型的胞外细菌病原体， 通过复杂的地方性感染循环在自然界中生存，涉及属于肩部硬蜱的扁虱 复杂和一系列脊椎动物宿主，最常见的是野生啮齿动物。尽管做出了认真的努力来控制 在过去的几十年里，这种感染持续存在，主要是由于缺乏有效的控制 防治扁虱感染的措施、缺乏人类疫苗、早期感染的诊断困难以及临床 与使用目前可用的抗菌剂治疗相关的并发症。具体地说，几个月 在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性或复发 症状，称为慢性莱姆病或治疗后莱姆病综合征，对其进一步 治疗方案仍然不可用。因此，疫苗和新药的发展是高度 被授权与莱姆病作斗争。这个项目追求一个长期的目标，以了解生物 一组关键的微生物毒力决定因素的意义和获得必要的知识 开发干预莱姆型疏螺旋体病的新治疗策略。重点是蛋白质- 对于病原体感染和宿主中的持久性至关重要的蛋白质相互作用，其目标是提供 定义三种螺旋体生物学意义的全面结构和功能信息 标记为BB0323、BB0238和BB0104(BbHtrA)的蛋白质，它们中的每一个独立或作为 复合体对于感染是必不可少的。上一个项目周期表明，定向删除或 蛋白质配对或短结合表位的改变会影响蛋白质的稳定性并使病原体 在哺乳动物宿主中不具传染性。目前提案的总体目标是进一步侧重于 BB0323及其相关蛋白质：1)确定蛋白质成熟的特定事件；2) 确定蛋白质之间的相互作用，以及3)有助于确定它们的结构以 更好地了解它们在哺乳动物螺旋体感染和扁虱传播中的作用。 这些研究将启发我们对螺旋体非典型生物学的基本知识，并将促进 设计非传统抗感染战略以抗击莱姆疏螺旋体病，包括制定 疫苗、小分子药物和生物制品。

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.