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

蜱传回归热伯氏疏螺旋体中的环状双 AMP 依赖性信号传导

• 批准号: 10679004
• 负责人: Jon Scott Blevins
• 金额: $ 58.77万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-08 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679004
• 关键词: Affinity; Applications Grants; Area; Argasidae; Arthropod Vectors; Arthropods; Bacteria; Binding Proteins; Biological Assay; Bite; Borrelia; Borrelia burgdorferi; Borrelia turicatae; Cell physiology; Data; Defect; Developing Countries; Diagnostic; Dinucleoside Phosphates; Disease; Elements; Environment; Environmental Impact; Enzymes; Etiology; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Global Change; Gram-Positive Bacteria; Growth; Heat-Shock Response; High-Throughput Nucleotide Sequencing; Human; Human body; Hydrolysis; In Vitro; Individual; Infection; Ixodes; Knowledge; Life Cycle Stages; Lyme Disease; Mass Spectrum Analysis; Measures; Mediating; Modeling; Molecular; Morphology; Mus; Mutagenesis; Mutation; Nutrient; Nutrient availability; Order Spirochaetales; Ornithodoros; Osmosis; Pathogenesis; Pathogenicity; Pathway interactions; Pediculus humanus humanus; Periodicity; Phenotype; Physiological; Physiology; Play; Poison; Post-Transcriptional Regulation; Production; Proteins; Proteome; Reactive Oxygen Species; Regulation; Regulon; Relapsing Fever; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stress; Suppressor Mutations; System; Testing; Therapeutic Intervention; Tick-Borne Relapsing Fever; Ticks; Virulence; Virulence Factors; Work; beta-Lactams; cDNA Library; environmental stressor; enzootic; genome sequencing; insight; mutant; neglect; pathogen; promoter; relapsing fever borrelia; response; small molecule; transcriptome; transcriptome sequencing; transmission process; vector; vector tick; vector-borne; whole genome

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.

项目概要/摘要 引起回归热的媒介传播螺旋体通过蜱或人类传播给人类 体虱。尽管 100 多年前就已经确定了回归热的病因，但很少 存在有关其发病机制的信息。尽管回归热在发展中国家更为常见 国家中，蜱传回归热 (TBRF) 发生在美国地区，蜱传蜱虫和钝蜱属 蜱虫是 TBRF 螺旋体的传播媒介，是地方性流行病。在其自然地方性流行周期中，媒介传播的 螺旋体存在于节肢动物载体和脊椎动物中发现的两个不同的生态位中。很好 确定莱姆病螺旋体必须经历整体基因表达的显着变化才能允许 他们适应这两种不同的环境。环状二核苷酸第二信使（例如，c-di-GMP 和 c-di-AMP）在伯氏疏螺旋体的地方性动物流行周期中发挥着关键作用，但它们的调节作用 尚未对 TBRF 螺旋体进行研究。我们将测试 c-di-AMP 信号通路在 促进 TBRF 螺旋体适应细菌过程中遇到的不同宿主环境 自然生命周期。由于 c-di-AMP 信号通路存在于所有致病性疏螺旋体中，因此本研究的发现 这项工作还有可能深入了解该系统在莱姆病疏螺旋体中的功能。在 具体目标1，我们将灭活TBRF螺旋体中c-di-AMP信号系统的各个成分， Borrelia turicatae，并定义了它们在信使分子产生和一般螺旋体生理学中的作用。 我们还将研究各个途径成分和 c-di-AMP 合成的调节。具体目标2 3 将阐明 c-di-AMP 信号系统对整体调控、发病机制和载体的影响 定植/传播。这些目标将提供有关监管网络的关键知识， 控制 B. turicatae 在传播和感染过程中的适应并确定所需的毒力决定因素 由细菌进行宿主-病原体和载体-病原体相互作用。调节因子和毒力因子 该项目中确定的代表了未来治疗干预和/或的潜在目标 可以开发 TBRF 诊断方法。 c-di-AMP 依赖性信号传导的分子表征 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。