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 存在关于这些细菌的发病机制的信息。回归热在发展中国家更为常见 国家，但蜱传回归热 (TBRF) 也发生在美国硬蜱和钝蜱存在的地区 蜱虫是 TBRF 螺旋体的载体，是地方性的。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。环状二聚鸟苷单磷酸 (c-di-GMP) 是一种 重要的第二信使分子，在伯氏疏螺旋体的地方性动物流行周期中发挥关键作用， 但其对 TBRF 螺旋体的调节作用尚未得到研究。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 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 信号传导对于 TBRF 螺旋体的地方性流行循环很重要，但也存在显着差异 莱姆病伯氏疏螺旋体和 TBRF 伯氏疏螺旋体的发病机制和媒介生物学之间的关系使我们能够 预测 TBRF 螺旋体感染和载体定植期间 c-di-GMP 的相对贡献 可能是独一无二的。为了解决这个问题，我们灭活了 c-di-GMP 中的各个成分 B. turicatae 的低传代、强毒分离株中的调控系统。在具体目标 1 中，这些的表型 将使用实验 B. turicatae-O 来评估突变体。定义turicata传播/感染模型 c-di-GMP 信号通路在 B. turicatae 地方性动物流行周期中的重要性。在具体目标 2 中， 我们将使用这些突变体来确定 c-di-GMP 信号系统对 B. turicatae 全球的影响 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 B. turicatae 在传播和感染过程中适应的网络。分子表征 各个 c-di-GMP 信号传导成分、它们在毒力调节中的具体作用以及潜在的 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。