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
• 负责人: Renee M Tsolis
• 金额: $ 23.31万
• 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: 2014-06-17 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8718850
• 关键词: Agonist; Animal Model; Animals; Area; Bacterial Typing; Brucella; Brucella abortus; Brucella melitensis; Brucellosis; Cells; Consumption; Cytosol; Dairy Products; Data; Detection; Disease; Disease Outcome; Endoplasmic Reticulum; Fever; Goals; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injection of therapeutic agent; Insulin-Dependent Diabetes Mellitus; Link; Microbe; Modeling; Molecular; Molecular Chaperones; Mus; NF-kappa B; Natural Immunity; Outcome; Pathogen detection; Pathogenesis; Pathway interactions; Pattern; Pattern Recognition; Pattern recognition receptor; Process; Proteins; Research; Role; Signal Pathway; Signaling Molecule; Structure; Testing; Tissues; Type IV Secretion System Pathway; Viral Pathogenesis; Virulence Factors; Virus Diseases; Work; Zoonotic Infection; base; in vivo; innovation; microbial; pathogen; public health relevance; response

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. The objective of this application is to study how translocation of the T4SS substrate VceC into host cells induces pro-inflammatory responses and alters the disease outcome. Our central hypothesis is that translocation of the T4SS substrate VceC activates the unfolded protein response (UPR) with consequent induction of NF-kB- dependent inflammatory responses, thereby contributing to B. abortus-induced inflammation in vivo. We will test our hypothesis by identifying the innate immune signaling molecules downstream of the UPR that activate inflammatory responses and by testing the role of these pathways 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 viral pathogenesis, innate immunity and the pathogenesis of certain inflammatory disorders involving the UPR, 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））检测组织中微生物的存在。然而，PAMP可以存在于所有微生物中，而不管它们的致病潜力如何。为了区分病原体与其他致病潜力较低的微生物，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，例如宿主细胞胞质溶胶中微生物产物的存在。鉴定参与检测病原体诱导的过程的信号通路通常是困难的，因为病原体表达的PAMP可以并行激活许多模式识别受体。流产布鲁氏菌是一种隐蔽的病原体，表达修饰的PAMP，不再作为模式识别受体的激动剂。因此，在B.流产感染完全依赖于检测毒力因子IV型分泌系统（T4 SS）作为病原体诱导过程的部署。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，该信号通路参与感知T4 SS依赖性蛋白质注入宿主细胞胞质溶胶作为病原体诱导的过程。本申请的目的是研究T4 SS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。我们的中心假设是T4 SS底物VceC的易位激活未折叠蛋白反应（UPR），随后诱导NF-κ B依赖性炎症反应，从而促成B。流产引起的体内炎症。我们将通过识别激活炎症反应的UPR下游的先天免疫信号分子并通过测试这些途径在体内的作用来验证我们的假设。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来推动该领域的发展，该系统检测靶向ER的微生物蛋白作为病原体诱导的过程。这一新概念不仅对细菌的致病机理，而且对病毒的致病机理、先天性免疫 以及某些涉及UPR的炎性疾病如1型糖尿病和炎性肠病的发病机制。