Unraveling the link between serine/threonine protein kinase and two-component system regulation of environment-mediated Mycobacterium tuberculosis growth arrest

揭示丝氨酸/苏氨酸蛋白激酶与环境介导的结核分枝杆菌生长停滞的双组分系统调节之间的联系

基本信息

  • 批准号:
    10693160
  • 负责人:
  • 金额:
    $ 20.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT A marked feature of Mycobacterium tuberculosis (Mtb) infection is heterogeneity that encompasses several aspects, including in bacterial replication status and in the local microenvironment. This heterogeneity exists not just temporally, but also spatially even within a single lesion, as revealed at the single bacterium level by an integrated imaging system that combines the use of fluorescent reporter Mtb strains, a murine infection model that recapitulates hallmark caseous necrotic lesions, and confocal imaging. While environmental signals such as nitric oxide (NO) are known to be able to drive Mtb into growth arrest, how Mtb coordinates its replication with environmental cue response remains largely unknown. Further, the interplay between the two key systems that play central roles in Mtb signal transduction, namely serine/threonine protein kinases (STPKs) and two- component systems (TCSs), is also poorly understood. To this end, we recently uncovered the essential transcription factor PrrA, part of the PrrAB TCS, as (i) a regulator of Mtb response to multiple environmental cues, including NO, and (ii) a TCS whose function is significantly modulated by STPK phosphorylation, with consequent effects on Mtb replication status in response to NO. Aim 1 of this proposal thus seeks to elucidate the global transcriptional impact of STPK regulation of PrrA on the adaptive entry of Mtb into a non-replicating state upon extended NO exposure, utilizing a PrrA STPK phosphoablative mutant. A bacterial-two-hybrid approach will further be undertaken to uncover the STPKs responsible for phosphorylation of PrrA. Aim 2 focuses on understanding the functional consequences of STPK regulation of PrrA on Mtb replication status during infection in vivo, with single bacterium resolution. This will exploit the use of a replication reporter- expressing STPK phosphoablative PrrA mutant with our integrated imaging system, to delineate how STPK regulation of PrrA may differentially influence Mtb growth in disparate lesion sublocations, and reveal its relation to local NO conditions. This project is conceptually innovative in its focus on the connection between STPKs and TCSs in Mtb, and between Mtb environmental response and replication regulation. By laying the groundwork for revealing key connecting nodes in these understudied concepts, these studies will provide insight into facets of Mtb infection biology critical for bacterial colonization success, and open new avenues of study targeted at understanding and exploiting these vital aspects for therapeutic purposes.
项目总结/文摘

项目成果

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Shumin Tan其他文献

Shumin Tan的其他文献

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{{ truncateString('Shumin Tan', 18)}}的其他基金

Elucidating the link between Mycobacterium tuberculosis potassium homeostasis and its lipid metabolism and growth in vivo
阐明结核分枝杆菌钾稳态与其脂质代谢和体内生长之间的联系
  • 批准号:
    10628034
  • 财政年份:
    2022
  • 资助金额:
    $ 20.43万
  • 项目类别:
Unraveling the link between serine/threonine protein kinase and two-component system regulation of environment-mediated Mycobacterium tuberculosis growth arrest
揭示丝氨酸/苏氨酸蛋白激酶与环境介导的结核分枝杆菌生长停滞的双组分系统调节之间的联系
  • 批准号:
    10428709
  • 财政年份:
    2022
  • 资助金额:
    $ 20.43万
  • 项目类别:
Elucidating the link between Mycobacterium tuberculosis potassium homeostasis and its lipid metabolism and growth in vivo
阐明结核分枝杆菌钾稳态与其脂质代谢和体内生长之间的联系
  • 批准号:
    10509286
  • 财政年份:
    2022
  • 资助金额:
    $ 20.43万
  • 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
  • 批准号:
    10468026
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
  • 批准号:
    10684689
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
  • 批准号:
    10020314
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
Mycobacterium tuberculosis environmental signal integration: single cell in vivo understanding of its influence on infection heterogeneity and treatment efficacy
结核分枝杆菌环境信号整合:单细胞体内了解其对感染异质性和治疗效果的影响
  • 批准号:
    10225474
  • 财政年份:
    2019
  • 资助金额:
    $ 20.43万
  • 项目类别:
Bacterial Sensing and Response to Chloride as a Novel Tuberculosis Drug Target
细菌对氯化物作为新型结核病药物靶点的感知和反应
  • 批准号:
    9304978
  • 财政年份:
    2016
  • 资助金额:
    $ 20.43万
  • 项目类别:
Bacterial Sensing and Response to Chloride as a Novel Tuberculosis Drug Target
细菌对氯化物作为新型结核病药物靶点的感知和反应
  • 批准号:
    8966959
  • 财政年份:
    2015
  • 资助金额:
    $ 20.43万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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