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 炎症是超分子信号传导复合物，激活了胱天蛋白酶的子集 称为炎症性胱天蛋白酶，例如caspase-1。通过微生物刺激和 与损害相关的信号，炎症组合组装，以引起第一线宿主防御 细胞因子IL-1B和IL-18的蛋白水解成熟，并通过诱导凋亡细胞死亡。 炎性体的组装需要激活上游传感器，下游 效应器，在大多数情况下 包含caspase募集域（ASC）。取决于是否需要ASC 炎症体可以归类为ASC依赖性和ASC独立 炎症。尽管炎症体在先天免疫中具有生物学重要性，但 可以提供结构和机械信息。 该提案旨在将SARS-COV-2感染与炎性症联系起来，并测试是否是否 炎性抑制剂减轻了SARS-COV-2发病机理。炎症体激活，IN 特别是通过NLRP3炎性体和形成蛋白质GSDMD的孔，底部 相关的严重且经常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症，这是一个重要的 严重的Covid-19病例的特征。这些数据来自SARS-COV-2和相关的 冠状病毒，SARS-COV和MERS-COV，使我们提出了以下假设： 由SARS-COV-2诱导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性细胞因子/趋化因子升高 取决于GSDMD和/或NLRP3激活的响应。