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中文摘要
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 描述(由申请人提供):结核分枝杆菌(Mtb)的一个定义特征是其表现为可持续多年的潜伏感染的能力。潜伏性结核病影响近20亿人,在世界大部分地区,Mtb的重新激活是绝大多数活动性结核病(TB)的原因。以这种方式,潜伏和再活化形成Mtb发病机制和传播,并且是TB控制的主要障碍。细菌的信号机制和效应器驱动潜伏期和再激活之间的转换(潜伏期转换)几乎完全未知。在其他细菌中支持这种类型转换的信号转导通过磷酸化途径传播。使用一个高度可重复的,定义在体外缺氧模型,然后再充气模型潜伏期和再激活结核分枝杆菌,我们现在表明,丝氨酸/苏氨酸蛋白激酶PknB和它的同源磷酸酶,PstP,是复制的主要调节器,在响应氧气,并显示PknB是由一个新的结核分枝杆菌翻译后修饰,蛋白酪氨酸磷酸化。基于这些数据,我们假设Ser/Thr和Tyr磷酸化信号传导控制Mtb潜伏期开关。通过定义一个磷酸化信号系统- PknB和PstP-,控制Mtb的生理反应,转变氧张力,我们提供了一个机会,以确定相关的下游底物和效应器,执行缺氧适应。这些发现将揭示控制潜伏期和再激活的信号通路和效应器。
英文摘要
 DESCRIPTION (provided by applicant): A defining feature of Mycobacterium tuberculosis (Mtb) is its ability to manifest as a latent infection that can last for many years. Latent tuberculosis affects nearly 2 billion people, and in much of the world, reactivating Mtb is responsible for the vast majority of active tuberculosis (TB). In this way, latency and reactivatio shape Mtb pathogenesis and transmission and are major impediments to TB control. The bacterial signaling mechanisms and effectors driving the switch between latency and reactivation (the latency switch) are almost entirely unknown. The signal transduction that underpins transitions of this type in other bacteria propagates through phosphorylation pathways. Using a highly reproducible, defined in vitro model of hypoxia followed by reaeration to model latency and reactivation in Mtb, we now show that the Ser/Thr protein kinase PknB and its cognate phosphatase, PstP, are major regulators of replication in response to oxygen and show that PknB is regulated by a new Mtb posttranslational modification, protein Tyr phosphorylation. Based on these data, we hypothesize that Ser/Thr and Tyr phosphosignaling control the Mtb latency switch. By defining a phosphosignaling system- PknB and PstP- that controls the physiologic response of Mtb to shifting oxygen tension, we provide an opportunity to identify the relevant downstream substrates and effectors that execute hypoxia adaptations. These findings will uncover signaling pathways and effectors that control latency and reactivation.
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Functional exploration of a deep Mycobacterium tuberculosis phosphoproteome
  • 批准号:
    10656957
  • 项目类别:
  • 资助金额:
    $61.73万
  • 财政年份:
    2023
  • 负责人:
    Christoph Grundner
  • 依托单位:
Calcium signaling in Mycobacterium tuberculosis
  • 批准号:
    10726978
  • 项目类别:
  • 资助金额:
    $30.92万
  • 财政年份:
    2023
  • 负责人:
    Christoph Grundner
  • 依托单位:
Direct activation of TGFbeta by an Mtb virulence factor to suppress CD4 T-cell responses
  • 批准号:
    10374127
  • 项目类别:
  • 资助金额:
    $23.56万
  • 财政年份:
    2021
  • 负责人:
    Christoph Grundner
  • 依托单位:
Direct activation of TGFbeta by an Mtb virulence factor to suppress CD4 T-cell responses
  • 批准号:
    10191677
  • 项目类别:
  • 资助金额:
    $28.28万
  • 财政年份:
    2021
  • 负责人:
    Christoph Grundner
  • 依托单位:
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