Induction of the Unfolded Protein Response by Brucella abortus VceC

流产布鲁氏菌 VceC 诱导未折叠蛋白反应

基本信息

  • 批准号:
    9115043
  • 负责人:
  • 金额:
    $ 38.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-01 至 2018-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The innate immune system detects the presence of microbes in tissue by pattern recognition of conserved microbial structures, known as pathogen-associated molecular patterns (PAMPs). However PAMPs can be present in all microbes regardless of their pathogenic potential. To distinguish pathogens from other microbes with lower disease-causing potential the innate immune system can detect pathogen-induced processes, such as the presence of microbial products in the host cell cytosol, through mechanisms that are not fully resolved. Identification of signaling pathways involved in the detection of pathogen-induced processes is often difficult because PAMPs expressed by a pathogen can activate many pattern recognition receptors in parallel. Brucella abortus is a stealthy pathogen expressing modified PAMPs that no longer serve as agonists for pattern recognition receptors. As a result, host responses generated during B. abortus infection are entirely dependent on detecting the deployment of a virulence factor, the type IV secretion system (T4SS), as a pathogen-induced process. Here we propose to use this model organism to define a new signaling pathway involved in sensing the T4SS-dependent injection of proteins into the host cell cytosol as a pathogen-induced process. Our long-range goal is to determine the mechanisms and consequences of inducing inflammatory host responses during B. abortus infection. The objectives of this application are to study how translocation of the T4SS substrate VceC into host cells induces pro-inflammatory responses and alters the disease outcome. We hypothesize that translocation of the T4SS substrate VceC activates the unfolded protein response (UPR) with consequent induction of NF-κB-dependent inflammatory responses, thereby contributing to B. abortus- induced abortion. We will test key aspects of our hypothesis and accomplish the objectives of this application by pursuing two specific aims: (1) Elucidate the signaling pathway that detects targeting of VceC to the endoplasmic reticulum; and (2) Characterize the mechanism by which the UPR activates inflammatory responses in vivo. Successful completion of this work will move the field forward by establishing the UPR as a component of the innate immune system that detects microbial proteins targeting the ER as a pathogen- induced process. This new concept has important ramifications not only for bacterial pathogenesis, but also for host-virus interactions, innate immunity and the pathogenesis of certain inflammatory disorders, such as type 1 diabetes and inflammatory bowel disease.
描述(由申请人提供):先天免疫系统通过保守微生物结构的模式识别来检测组织中微生物的存在,称为病原体相关分子模式(PAMPs)。然而,PAMPs可以存在于所有微生物中,无论其致病潜力如何。为了将病原体与其他具有较低致病潜力的微生物区分开来,先天免疫系统可以通过尚未完全解决的机制检测病原体诱导的过程,例如宿主细胞质中微生物产物的存在。由于病原体表达的PAMPs可以平行激活许多模式识别受体,因此识别涉及病原体诱导过程检测的信号通路通常是困难的。流产布鲁氏菌是一种隐形病原体,表达修饰的PAMPs,不再作为模式识别受体的激动剂。因此,在B. abortus感染期间产生的宿主反应完全依赖于检测一种毒力因子的部署,即IV型分泌系统(T4SS),作为病原体诱导的过程。在这里,我们建议使用这种模式生物来定义一种新的信号通路,该信号通路涉及感知t4ss依赖性蛋白注射到宿主细胞质中作为病原体诱导的过程。我们的长期目标是确定在B. abortus感染期间诱导炎症宿主反应的机制和后果。本应用程序的目的是研究T4SS底物VceC易位到宿主细胞中如何诱导促炎反应并改变疾病结果。我们假设T4SS底物VceC的易位激活未折叠蛋白反应(UPR),从而诱导NF-κ b依赖性炎症反应,从而导致B. abortus诱导流产。我们将测试我们假设的关键方面,并通过追求两个具体目标来实现本应用的目标:(1)阐明检测VceC靶向内质网的信号通路;(2)描述UPR在体内激活炎症反应的机制。这项工作的成功完成将通过建立UPR作为先天免疫系统的一个组成部分,作为病原体诱导的过程来检测靶向内质网的微生物蛋白,从而推动该领域的发展。这一新概念不仅对细菌发病机制,而且对宿主-病毒相互作用、先天免疫和某些炎症性疾病(如1型糖尿病和炎症性肠病)的发病机制具有重要影响。

项目成果

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Renee M Tsolis其他文献

Renee M Tsolis的其他文献

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{{ truncateString('Renee M Tsolis', 18)}}的其他基金

2023 Salmonella Biology and Pathogenesis Gordon Research Conference and Seminar
2023年沙门氏菌生物学与发病机制戈登研究会议暨研讨会
  • 批准号:
    10683617
  • 财政年份:
    2023
  • 资助金额:
    $ 38.39万
  • 项目类别:
Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection
SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用
  • 批准号:
    10468025
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection
SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用
  • 批准号:
    10224776
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection
SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用
  • 批准号:
    10022095
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
2019 Microbial Adhesion and Signal Transduction GRC/GRS
2019微生物粘附与信号转导GRC/GRS
  • 批准号:
    9752745
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection
SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用
  • 批准号:
    10683118
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection
SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用
  • 批准号:
    10772361
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
Neutrophil-intrinsic role of SLC11A1/NRAMP1 in control of bacterial infection
SLC11A1/NRAMP1 在控制细菌感染中的中性粒细胞内在作用
  • 批准号:
    10755395
  • 财政年份:
    2019
  • 资助金额:
    $ 38.39万
  • 项目类别:
Systemic infections with non-typhoidal Salmonella
非伤寒沙门氏菌全身感染
  • 批准号:
    9238432
  • 财政年份:
    2016
  • 资助金额:
    $ 38.39万
  • 项目类别:
Detection of bacterial Type IV secretion by the unfolded protein response
通过未折叠蛋白反应检测细菌 IV 型分泌物
  • 批准号:
    8718850
  • 财政年份:
    2014
  • 资助金额:
    $ 38.39万
  • 项目类别:

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