Analysis of the DksA regulon in the Lyme disease spirochete

莱姆病螺旋体中 DksA 调节子的分析

基本信息

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
项目类别：
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

项目摘要

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.

抽象的严格的反应是细菌使用的一种生理机制来适应营养剥夺，许多其他压力。在Borrelia burgdorferi（BB），莱姆病的病因学药物中，介导了严格的反应由Alarmone核苷酸（P）PPGPP和RNA聚合酶结合蛋白DKSA均通过。最近，我们发现 DKSA在调节BB的毒力中起着至关重要的作用。首先，DKSA在感染动物中高度表达 BB需要感染哺乳动物宿主。其次，DKSA对于BB的最佳增长至关重要。第三， BB要求DKSA应对代谢应激。最后，除了充当严格的响应之外调节剂DKSA促进了有助于BB在宿主中生存的基因的转录和/或翻译。这些组合数据引起了我们的假设，即DKSA是管理BB的毒力基因的主调节器表达。该假设将以两个具体目标解决。在本提案的目标1中，我们将确定 DKSA对BB在壁虱中的生存和持久性的贡献。在AIM 2中，我们将确定由 DKSA在各种体外和体内条件下。这些合并的研究将（i）定义整个DKSA调节；（ii）对DKSA和法规的体内重要性提供了一种变革性的理解。结果调查结果可能导致开发预防和/或治疗莱姆病的新策略。