Cyclic di-GMP Second Messenger Signaling in the Tickborne Relapsing Fever Spirochete, Borrelia turicatae

蜱传回归热螺旋体、Borrelia turicatae 中的环状 di-GMP 第二信使信号传导

• 批准号: 10378138
• 负责人: Jon Scott Blevins
• 金额: $ 22.43万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-25 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378138
• 关键词: Address; Antimicrobial Resistance; Applications Grants; Area; Argasidae; Arthropod Vectors; Arthropods; Bacteria; Biology; Borrelia; Borrelia burgdorferi; Borrelia turicatae; Cell physiology; Chemotaxis; Defect; Developing Countries; Diagnostic; Digestion; Dinucleoside Phosphates; Environment; Etiology; Future; Gel; Gel Chromatography; Gene Expression; Gene Proteins; Global Change; Guanosine Monophosphate; Heavy Metals; High-Throughput Nucleotide Sequencing; Human; Human body; Individual; Infection; Ixodes; Knowledge; Lead; Liquid Chromatography; Lyme Disease; Measures; Mediating; Microbial Biofilms; Modeling; Molecular; Mus; Order Spirochaetales; Ornithodoros; Pathogenesis; Pathogenicity; Pattern; Pediculus humanus humanus; Periodicity; Phenotype; Photosynthesis; Play; Process; Production; Proteome; Regulation; Regulon; Relapsing Fever; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Spirochaetales Infections; System; Testing; Therapeutic Intervention; Tick-Borne Relapsing Fever; Ticks; Virulence; Virulence Factors; Virulent; Work; bacterial metabolism; cDNA Library; cell motility; defined contribution; dimer; environmental adaptation; enzootic; insight; mutant; neglect; pathogen; protein expression; relapsing fever borrelia; small molecule; tandem mass spectrometry; transcriptome; transcriptome sequencing; transmission process; vector; vector-borne

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 of these bacteria. Relapsing fever is more common in developing countries, but tickborne relapsing fever (TBRF) also 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 dimeric guanosine monophosphate (c-di-GMP) is an important second messenger molecule that plays a key role during the enzootic cycle of Borrelia burgdorferi, but its regulatory contribution in TBRF spirochetes has not been investigated. In this proposal, we will test the role of the c-di-GMP signaling pathway in promoting adaptation of TBRF spirochetes to the different host environments encountered during the bacterial natural lifecycle. While we expect c-di-GMP-dependent signaling to be important for the enzootic cycle of TBRF spirochetes, there are also significant differences between the pathogenesis and vector biology of Lyme disease Borrelia and TBRF Borrelia that lead us to anticipate that the relative contribution of c-di-GMP during TBRF spirochete infection and vector colonization could be unique. To being addressing this, we have inactivated individual components in the c-di-GMP regulatory system in a low-passage, virulent isolate of B. turicatae. In Specific Aim 1, the phenotypes of these mutants will be evaluated using the experimental B. turicatae-O. turicata transmission/infection model to define the importance of the c-di-GMP signaling pathway during the enzootic cycle of B. turicatae. In Specific Aim 2, we will use these mutants to determine the influence of the c-di-GMP signaling system on B. turicatae global gene expression and protein production. These aims will provide critical knowledge regarding the regulatory networks that control B. turicatae adaptation during transmission and infection. Molecular characterization of the individual c-di-GMP signaling components, their specific roles in virulence regulation, and potential virulence determinants will be the focus of future R01 grant proposals. Regulators and virulence factors identified in this project represent potential targets against which future therapeutic interventions and/or diagnostics for TBRF could be developed.

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 有关于这些细菌的致病机制的信息。复发热在发展中更常见 在美国，硬蜱和鸟形目的地区也会发生硬蜱复发热(TBRF)。 作为TBRF螺旋体的传播媒介，扁虱是当地特有的。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。环状二聚鸟苷一磷酸(c-di-GMP)是一种 在伯氏疏螺旋体流行循环中起关键作用的重要第二信使分子， 但其在TBRF螺旋体中的调节作用尚未被研究。在本提案中，我们将测试 C-di-GMP信号通路在促进TBRF螺旋体适应不同宿主中的作用 在细菌自然生命周期中遇到的环境。虽然我们预计c-di-GMP依赖 信号对于TBRF螺旋体的流行循环是重要的，也有显著的差异 莱姆病、疏螺旋体和TBRF疏螺旋体致病机理与媒介生物学的关系 预计c-di-GMP在TBRF螺旋体感染和媒介定植过程中的相对贡献 可能是独一无二的。为了解决这个问题，我们已经停用了c-di-gmp中的单个组件。 枯草杆菌低传代强毒力分离株的调控系统。在具体目标1中，这些表型 突变体将使用实验性的图拉氏菌-O进行评估。斑疹伤寒传播/感染模型定义 C-di-GMP信号通路在斑疹伤寒杆菌流行循环中的重要性。在具体目标2中， 我们将利用这些突变体来确定c-di-GMP信号系统对全球斑疹杆菌的影响。 基因表达和蛋白质生产。这些目标将提供有关监管的关键知识 控制斑疹杆菌在传播和感染过程中适应的网络。分子生物学特性的研究 单独的c-di-GMP信号成分，它们在毒力调节中的特定作用，以及潜在的 毒力决定因素将是未来R01拨款提案的重点。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。