Mechanistic elucidation of inflammasome assembly and regulation. Supplement: Testing drugs that curtail inflammasome activation to suppress SARS-CoV-2 pathogenesis

炎症小体组装和调节的机制阐明。

基本信息

批准号：
10159600
负责人：
Judy Lieberman
金额：
$ 26.5万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159600
关键词：
3-Dimensional Apoptosis Autoimmune Diseases Biological CASP1 gene COVID-19 COVID-19 pandemic Caspase Caspase Inhibitor Cell Death Cell Line Cells Characteristics Clinical Clinical Trials Complex Coronavirus Data Deterioration Disease Disease Progression Disulfiram Epithelial Cells Exhibits FDA approved HDAC6 gene Health Host Defense Immune response Immunology Infection Infiltration Inflammasome Inflammatory Interleukin-18 Interruption Link Lung Lung Inflammation Lymphocyte Lymphopenia Mediating Microtubules Middle East Respiratory Syndrome Coronavirus Molecular Natural Immunity Nature Pathogenesis Pathway interactions Patients Peptide Hydrolases Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Physiological Pneumonia Proteins Regulation Reporting Research Personnel Role SARS coronavirus Science Sepsis Severe Acute Respiratory Syndrome Signal Transduction Structure Testing Therapeutic VDAC1 gene Viral Virus Replication Work autoinflammatory base chemokine cytokine cytokine release syndrome drug testing human disease in vitro Model inhibitor/antagonist interleukin-1beta-converting enzyme inhibitor marenostrin microbial monocyte particle pathogen recruit response sensor tool

项目摘要

Abstract Inflammasomes are supramolecular signaling complexes that activate a subset of caspases known as inflammatory caspases such as caspase-1. Upon stimulation by microbial and damage-associated signals, inflammasomes assemble to elicit the first line of host defense by proteolytic maturation of cytokines IL-1b and IL-18, and by induction of pyroptotic cell death. Assembly of an inflammasome requires activation of an upstream sensor, a downstream effector, and in most cases an adaptor molecule such as apoptosis-associate speck-like protein containing a caspase recruitment domain (ASC). Depending on whether ASC is required, inflammasomes can be categorized into ASC-dependent and ASC-independent inflammasomes. Despite the biological importance of inflammasomes in innate immunity, no structural and mechanistic information is available. This proposal seeks to link SARS-CoV-2 infection to inflammasomes and to test whether inflammasome inhibitors alleviate SARS-CoV-2 pathogenesis. Inflammasome activation, in particular through the NLRP3 inflammasome and the pore forming protein GSDMD, underlies the serious, and often fatal cytokine storm, lung inflammation and sepsis that are associated with SARS-CoV-2 clinical deterioration. It may even contribute to lymphopenia, an important characteristic of severe COVID-19 cases. These data from SARS-CoV-2 and from related coronaviruses, SARS-CoV and MERS-CoV, led us to propose the following hypothesis: the severe acute respiratory syndrome (SARS) pneumonia induced by SARS-CoV-2 is caused by massive inflammatory cell infiltration and elevated proinflammatory cytokine/chemokine responses that depend on GSDMD and/or NLRP3 activation.

抽象的炎症小体是激活半胱天冬酶子集的超分子信号复合物称为炎症性半胱天冬酶，例如 caspase-1。在微生物的刺激下损伤相关信号，炎症小体聚集以引发宿主防御的第一道防线细胞因子 IL-1b 和 IL-18 的蛋白水解成熟，以及诱导焦亡细胞死亡。炎症小体的组装需要激活上游传感器、下游传感器效应子，并且在大多数情况下是衔接分子，例如凋亡相关斑点样蛋白含有半胱天冬酶招募结构域 (ASC)。根据是否需要 ASC，炎症小体可分为ASC依赖性和ASC非依赖性炎症小体。尽管炎症小体在先天免疫中具有重要的生物学意义，但没有可获得结构和机械信息。该提案旨在将 SARS-CoV-2 感染与炎症小体联系起来，并测试是否炎性体抑制剂可减轻 SARS-CoV-2 的发病机制。炎症小体激活，在特别是通过 NLRP3 炎性体和孔形成蛋白 GSDMD，与之相关的严重且往往致命的细胞因子风暴、肺部炎症和败血症 SARS-CoV-2 临床恶化。它甚至可能导致淋巴细胞减少，这是一个重要的严重 COVID-19 病例的特征。这些数据来自 SARS-CoV-2 和相关冠状病毒、SARS-CoV 和 MERS-CoV 使我们提出以下假设： SARS-CoV-2 引起的严重急性呼吸综合征 (SARS) 肺炎是由大量炎症细胞浸润和促炎细胞因子/趋化因子升高依赖于 GSDMD 和/或 NLRP3 激活的反应。