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

• 批准号: 8920474
• 负责人: Renee M Tsolis
• 金额: $ 38.37万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8920474
• 关键词: Agonist; Animal Model; Animals; Brucella; Brucella abortus; Brucella melitensis; Brucellosis; Cells; Consumption; Cytosol; Dairy Products; Data; Detection; Disease; Disease Outcome; Endoplasmic Reticulum; Fever; Genes; Goals; Health; Immune; Immune response; Immune system; Induced Abortion; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Lead; Link; Microbe; Molecular; Molecular Chaperones; NF-kappa B; Natural Immunity; Outcome; Pathogen detection; Pathogenesis; Pathway interactions; Pattern; Pattern Recognition; Pattern recognition receptor; Process; Proteins; Signal Pathway; Structure; Testing; Tissues; Type IV Secretion System Pathway; Virulence Factors; Virus Diseases; Work; Zoonotic Infection; abortion; base; in vivo; innovation; microbial; pathogen; response; transmission process; unpasteurized; virus host interaction

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（称为病原体相关分子模式（PAMP））来检测组织中微生物的存在，但是 PAMP 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致病潜力较低的微生物区分开来，先天免疫系统可以通过以下机制检测病原体诱导的过程，例如宿主细胞胞质中是否存在微生物产物。鉴定参与病原体诱导过程检测的信号通路通常很困难，因为病原体表达的 PAMP 可以同时激活许多模式识别受体，流产布鲁氏菌是一种表达修饰的 PAMP 的隐秘病原体，而这些受体不再发挥作用。因此，流产布鲁氏菌感染期间产生的宿主反应完全依赖于检测作为病原体诱导的毒力因子，即 IV 型分泌系统 (T4SS) 的部署。在这里，我们建议使用这种模型生物来定义一个新的信号通路，该通路参与感知 T4SS 依赖性蛋白质注射到宿主细胞胞质中作为病原体诱导的过程。我们的长期目标是确定其机制和后果。本申请的目的是研究 T4SS 底物 VceC 转位到宿主细胞中如何诱导促炎症反应并改变疾病结果。激活未折叠蛋白反应 (UPR)，随后诱导 NF-κB 依赖性炎症反应，从而导致流产巴氏杆菌引起的流产。我们将测试我们假设的关键方面，并通过追求两个特定目标来实现本申请的目标。 ：（1）阐明检测VceC靶向内质网的信号通路；（2）表征UPR激活体内炎症反应的机制。通过将 UPR 建立为先天免疫系统的一个组成部分，该系统可检测针对 ER 的微生物蛋白作为病原体诱导的过程，从而推动该领域向前发展。这一新概念不仅对细菌发病机制，而且对宿主与病毒的相互作用也具有重要影响。先天免疫和某些炎症性疾病的发病机制，例如 1 型糖尿病和炎症性肠病。