Mechanisms of Inflammasome Defense against Cytosol-invasive Bacteria

炎症小体防御细胞质侵入细菌的机制

基本信息

批准号：
9754764
负责人：
Youssef Aachoui
金额：
$ 10.8万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-02 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754764
关键词：
Bacteria Bacterial Infections Biochemistry Burkholderia Burkholderia pseudomallei CASP1 gene Caspase Cell Death Cells Cleaved cell Cytosol Data Detection Disease Dose Epithelial Flagellin Fostering Future Gram-Negative Bacteria Hour Immune In Vitro Infection Inflammasome Inflammation Inflammatory Innate Immune Response Innate Immune System Interferon Type II Interferons Interleukin-1 Interleukin-1 beta Interleukin-18 Lead Life Style Ligands Link Lymphoid Cell Lytic Maintenance Mediating Minor Modeling Morphology Mus N-terminal Outcome Pathway interactions Phenotype Play Predisposition Process Publishing Resistance Role Signal Transduction Source Surveys System Therapeutic Tissues Type III Secretion System Pathway cell type cytokine experimental study in vivo infectious disease treatment insight macrophage microbial neutrophil pathogen preference prevent programs response therapeutic target tool

项目摘要

Abstract Inflammasomes survey the cytosol for signs of perturbation or bacterial contamination and initiate inflammation during microbial defense or inflammatory diseases. The NLRC4 inflammasome detects the activity of bacterial type III secretion systems (T3SS) as well as flagellin, and then activates caspase-1, which processes IL-1β and IL-18 to their mature forms, and initiates a form of programmed lytic cell death called pyroptosis to prevent the establishment of an intracellular replication niche. Caspase-11, the non-canonical inflammasome, detects LPS in the cytosol and triggers pyroptosis, but cannot process pro-IL-1β or IL-18 alone. Using Burkholderia thailandensis, a model for the cytosol invasive select agent Burkholderia pseudomallei, I found that B. thailandensis is primarily cleared via caspase-11, while caspase-1 plays a minor role in defense. Specifically, I found that caspase-1 activation by the T3SS provides a priming signal, IL-18-induced IFN-γ, upstream of caspase-11 expression during defense against B. thailandensis, leading to clearance in 24 hours. By contrast, in the absence of caspase-1-driven IL-18, bacterial burdens persist for several days, eventually triggering other signals that induce IFN-γ and downstream caspase-11 expression. In this proposal, I will investigate why caspase-1 and -11 dependent pyroptosis are not equivalent, and what is the cellular source of IFN-γ that prime caspase-11 to protect against B.thailandensis. These studies will provide new insights into the mechanisms behind inflammasome-mediated defense against infection, and thus aid future treatments aimed at therapeutic manipulation of the host innate immune system.

抽象的炎症小体调查细胞质中是否存在扰动或细菌污染的迹象，并启动 NLRC4 炎症小体可检测微生物防御或炎症性疾病期间的炎症。细菌 III 型分泌系统 (T3SS) 以及鞭毛蛋白的活性，然后激活 caspase-1，从而将 IL-1β 和 IL-18 加工成成熟形式，并启动一种称为程序性裂解细胞死亡的形式焦亡以阻止细胞内复制生态位的建立，Caspase-11是非经典的。炎症小体，检测细胞质中的 LPS 并引发细胞焦亡，但不能单独处理 IL-1β 前体或 IL-18。使用泰国伯克霍尔德氏菌（Burkholderia thailandensis），一种细胞质侵入选择剂假鼻疽伯克霍尔德氏菌的模型，I 发现 B. thailandensis 主要通过 caspase-11 清除，而 caspase-1 在防御中发挥次要作用。具体来说，我发现 T3SS 激活 caspase-1 提供启动信号，即 IL-18 诱导的 IFN-γ，在针对 B. thailandensis 的防御过程中 caspase-11 表达的上游，导致 24 小时内清除。相比之下，在缺乏 caspase-1 驱动的 IL-18 的情况下，细菌负担会持续数天，最终触发诱导 IFN-γ 和下游 caspase-11 表达的其他信号。研究为什么 caspase-1 和 -11 依赖性焦亡不等价，以及其细胞来源是什么 IFN-γ 启动 caspase-11 以预防泰国芽孢杆菌。这些研究将为了解泰国芽孢杆菌提供新的见解。炎症小体介导的感染防御背后的机制，从而有助于未来的治疗在宿主先天免疫系统的治疗操作中。