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。

• 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
• 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

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 结构和机械信息是可用的。 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 重症 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。