Analysis of the DksA regulon in the Lyme disease spirochete

莱姆病螺旋体中 DksA 调节子的分析

• 批准号: 10189812
• 负责人: Zhiming Ouyang
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-19 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189812
• 关键词: Address; Animals; Bacteria; Binding; Binding Proteins; Borrelia burgdorferi; Complement; Complex; DNA-Directed RNA Polymerase; Data; Development; Disease; Environment; Etiology; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; In Vitro; Infection; Interruption; Intervention; Ixodes; Knowledge; Lead; Life Cycle Stages; Lyme Disease; Mammals; Mediating; Metabolic stress; Modality; Molecular; Mus; Nature; Nucleotides; Pathogenicity; Phase; Physiological; Play; Proteome; Regulation; Regulon; Role; Stress; Ticks; Translations; United States; Vector-transmitted infectious disease; Virulence; Work; arthropod-borne; bacterial fitness; disorder prevention; environmental adaptation; enzootic; expectation; genetic approach; genetic regulatory protein; human disease; in vivo; innovation; insight; metabolome; mutant; novel; nutrient deprivation; prevent; response; transcriptome; transmission process; vector tick

ABSTRACT Stringent response is a physiological mechanism utilized by bacteria to adapt to nutrient deprivation and many other stresses. In Borrelia burgdorferi (Bb), the etiological agent of Lyme disease, stringent response is mediated by both the alarmone nucleotides (p)ppGpp and the RNA polymerase-binding protein DksA. Recently, we found that DksA plays an essential role in regulating Bb's virulence. First, dksA is highly expressed in infected animals and is required by Bb to infect the mammalian hosts. Second, DksA is critical for Bb's optimal growth. Third, DksA is required by Bb to cope with metabolic stress. Finally, in addition to function as a stringent response regulator, DksA promotes the transcription and/or translation of genes contributing to Bb's survival in the host. These combined data give rise to our hypothesis that DksA is a master regulator governing Bb's virulence gene expression. This hypothesis will be addressed in two Specific Aims. In Aim 1 of this proposal, we will determine the contribution of DksA to Bb's survival and persistence in ticks. In Aim 2, we will identify genes regulated by DksA under various in vitro and in vivo conditions. These combined studies will (i) define the entire DksA regulon; and (ii) provide a transformative understanding of the in vivo importance of DksA and the regulon. Resultant findings could lead to the development of new strategies to prevent and/or treat Lyme disease.

抽象的 严格反应是细菌利用的一种生理机制，以适应营养缺乏和许多 其他压力。在莱姆病的病原体伯氏疏螺旋体 (Bb) 中，介导严格反应 由报警素核苷酸 (p)ppGpp 和 RNA 聚合酶结合蛋白 DksA 共同作用。最近，我们发现 DksA 在调节 Bb 毒力方面发挥着重要作用。首先，dksA在感染动物中高表达 Bb 需要它来感染哺乳动物宿主。其次，DksA 对于 Bb 的最佳生长至关重要。第三， Bb 需要 DksA 来应对代谢应激。最后，除了作为严格的应对措施之外 作为调节因子，DksA 促进有助于 Bb 在宿主中生存的基因的转录和/或翻译。 这些综合数据得出我们的假设，即 DksA 是控制 Bb 毒力基因的主调节因子 表达。这一假设将在两个具体目标中得到解决。在本提案的目标 1 中，我们将确定 DksA 对 Bb 在蜱中的存活和持久性的贡献。在目标 2 中，我们将鉴定受以下因素调控的基因： 各种体外和体内条件下的 DksA。这些综合研究将 (i) 定义整个 DksA 调节子； (ii) 提供对 DksA 和调节子的体内重要性的变革性理解。结果 研究结果可能会导致制定预防和/或治疗莱姆病的新策略。