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.

项目摘要/摘要 引起发烧的载体传播的螺旋体被tick虫或人传递给人类 身体虱子。尽管确定了100年前复发发烧的病因学药物，但很少 有关其发病机理的信息。虽然发烧在发展中更为普遍 国家，tick骨复发发烧（TBRF）发生在美国地区的ixodes和ornithodoros物种 tick是TBRF螺旋体的向量，是地方性的。在自然的enzootic循环中，向量传播 螺旋体存在于节肢动物载体和脊椎动物中的两个不同的壁ni。很好 确定莱姆病螺旋体必须经历全球基因表达的重大变化，以允许 它们适应这两个不同的环境。循环二核苷酸第二使者（例如，C-DI-GMP和 C-di-amp）在Borrelia Burgdorferi的Enzootic循环中扮演关键角色，但它们的监管贡献 尚未研究TBRF螺旋体。我们将测试C-DI-AMP信号通路的作用 促进TBRF螺旋体适应细菌期间遇到的不同宿主环境 天然生命周期。因为在所有致病性疏螺旋体中都发现了C-DI-AMP信号通路，所以从此发现 工作还可以洞悉该系统在莱姆病渗流菌中的功能。在 特定的目标1，我们将使TBRF Spirochete中的单个组件C-DI-AMP信号系统灭活， 伯罗利亚（Borrelia turicatae），并定义了它们在信使分子生产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信号系统对全局调节，发病机理和载体的影响 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.曲霉的适应性在传播和感染过程中的适应性，并确定所需的毒力决定因素 通过细菌进行宿主 - 病原体和载体 - 病原体相互作用（S）。监管因子和毒力因素 该项目中确定的代表了未来治疗干预措施和/或 可以开发针对TBRF的诊断。 C-DI-AMP依赖性信号的分子表征 系统和C-DI-AMP调节的毒力决定因素将成为未来R01赠款建议的重点。