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: 10503309
• 负责人: Jon Scott Blevins
• 金额: $ 61.26万
• 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/10503309
• 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; Gene Proteins; 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; Lyme Disease; Mass Spectrum Analysis; Measures; Mediating; Modeling; Molecular; Morphology; Mus; Mutagenesis; Mutation; Nutrient; Order Spirochaetales; Ornithodoros; Pathogenesis; Pathogenicity; Pathway interactions; Pediculus humanus humanus; Periodicity; Phenotype; Physiological; Physiology; Play; Poison; Post-Transcriptional Regulation; Production; 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; protein expression; relapsing fever borrelia; response; small molecule; transcriptome; transcriptome sequencing; transmission process; vector; 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.

项目总结/摘要 引起回归热的媒介传播的螺旋体通过蜱或人类传播给人类。 体虱尽管100多年前就确定了回归热的病原体， 关于其发病机理的信息存在。虽然回归热在发展中国家更常见， 在一些国家，蜱传回归热（TBRF）发生在美国的一些地区， 蜱是结核分枝杆菌出血热螺旋体的媒介，是地方性的。在自然的地方性流行周期中， 螺旋体存在于节肢动物媒介和脊椎动物中发现的两个不同的小生境中。公 莱姆病螺旋体必须经历全局基因表达的显著变化， 以适应这两种不同的环境。环状二核苷酸第二信使（例如，c-d1-GMP和 c-di-AMP）在伯氏疏螺旋体的地方性流行周期中起关键作用，但它们在 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螺旋体适应细菌感染期间遇到的不同宿主环境， 自然生命周期。因为c-di-AMP信号通路在所有致病性疏螺旋体中都有发现， 这项工作也有可能提供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，我们将研究TBRF螺旋体中c-di-AMP信号系统的单个组分， 疏螺旋体，并确定其在信使分子的生产和一般螺旋体生理学的作用。 我们还将研究单个通路组分和c-di-AMP合成的调节。具体目标2 和3将阐明c-di-AMP信号系统对全局调节、发病机制和载体的影响， 殖民化/传播。这些目标将提供有关监管网络的关键知识， 对照B。在传播和感染过程中的毒力适应，并确定所需的毒力决定因素 宿主-病原体和病媒-病原体相互作用的细菌。调节因子和毒力因子 本项目中确定的潜在靶点代表了未来治疗干预和/或 可以开发TBRF的诊断方法。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R 01资助提案的重点。