Cyclic di-AMP-dependent signaling in tickborne relapsing fever Borrelia

项目摘要/摘要 引起回归热的媒介传播的螺旋体通过扁虱或人类传播给人类。 体虱。尽管100多年前发现了复发发烧的病原体，但很少有 关于它们的发病机制，目前已有相关信息。尽管复发热在发展中更常见 在美国，壁虱传播的复发热(TBRF)发生在美国的一些地区，那里有硬蜱和鸟形目物种 扁虱是TBRF螺旋体的媒介，是地方性的。在它们自然的地方病循环中，媒介传播的 螺旋体存在于节肢动物媒介和脊椎动物的两个不同的生态位中。这很好 确定莱姆病螺旋体必须经历全球基因表达的显著变化才能 让他们适应这两个不同的环境。环二核苷酸第二信使(例如，c-di-GMP和 C-di-AMP)在伯氏疏螺旋体流行循环中起着关键作用，但它们在 TBRF螺旋体还没有被调查过。我们将测试c-di-AMP信号通路在 促进TBRF螺旋体对细菌过程中遇到的不同宿主环境的适应 自然生命周期。由于c-di-AMP信号通路在所有致病的疏螺旋体中都被发现，因此 这项工作也有可能深入了解该系统在莱姆病疏螺旋体中的功能。在……里面 具体目标1，我们将灭活TBRF螺旋体中的单个组件c-di-AMP信号系统， 并确定了它们在信使分子生产和一般螺旋体生理中的作用。 我们还将研究单个途径组件和c-di-AMP合成的调节。具体目标2 和3将阐明c-di-amp信号系统对全球调控、发病机制和载体的影响。 殖民/传播。这些目标将提供有关监管网络的关键知识， 控制斑疹伤寒杆菌在传播和感染期间的适应并确定所需的毒力决定因素 由细菌进行宿主-病原体和病媒-病原体的相互作用(S)。调节器和毒力因子 本项目中确定的潜在目标是未来的治疗干预和/或 可以开发针对TBRF的诊断方法。C-di-AMP依赖信号转导的分子特征 系统和c-di-AMP调节的毒力决定因素将是未来R01拨款提案的重点。

PROJECT SUMMARY/ABSTRACT The vector-borne spirochetes that cause relapsing fever are transmitted to humans by either ticks or human body lice. Despite identification of the etiological agents of relapsing fever over 100 years ago, very little information exists regarding their pathogenesis. Although relapsing fever is more common in developing countries, tickborne relapsing fever (TBRF) occurs in areas of the U.S. where Ixodes and Ornithodoros species of ticks, the vectors for TBRF spirochetes, are endemic. During their natural enzootic cycle, vector-borne spirochetes exist in two distinct niches found within the arthropod vector and the vertebrate. It is well established that Lyme disease spirochetes must undergo significant changes in global gene expression to allow them to adapt to these two diverse environments. Cyclic dinucleotide second messengers (e.g., c-di-GMP and c-di-AMP) play key roles during the enzootic cycle of Borrelia burgdorferi, but their regulatory contributions in TBRF spirochetes have not been investigated. We will test the role of the c-di-AMP signaling pathway in promoting adaptation of TBRF spirochetes to the different host environments encountered during the bacterial natural lifecycle. Because the c-di-AMP signaling pathway is found in all pathogenic Borrelia, findings from this work also has the potential to provide insight into the function of this system in Lyme disease Borrelia. In Specific Aim 1, we will inactivate individual components c-di-AMP signaling system in the TBRF spirochete, Borrelia turicatae, and define their roles in messenger molecule production and general spirochetal physiology. We will also study the regulation of individual pathway components and c-di-AMP synthesis. Specific Aims 2 and 3 will elucidate the impact of the c-di-AMP signaling system on global regulation, pathogenesis, and vector colonization/transmission. These aims will provide critical knowledge regarding the regulatory networks that control B. turicatae adaptation during transmission and infection and identify virulence determinants required by the bacteria for host-pathogen and vector-pathogen interaction(s). Regulators and virulence factors identified in this project represent potential targets against which future therapeutic interventions and/or diagnostics for TBRF could be developed. Molecular characterization of the c-di-AMP-dependent signaling system and c-di-AMP-regulated virulence determinants will be the focus of future R01 grant proposals.