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

摘要 炎性小体是激活caspase子集的超分子信号复合体。 称为炎症性caspase，如caspase-1。在微生物的刺激下， 损伤相关信号，炎性小体聚集在一起，通过以下方式诱导宿主防御的第一道防线 细胞因子IL-1b和IL-18的蛋白水解性成熟，以及通过诱导嗜热细胞死亡。 组装炎症体需要激活上游传感器、下游传感器 效应器，在大多数情况下是接头分子，如凋亡相关的斑点样蛋白 包含半胱氨酸天冬氨酸酶招募结构域(ASC)。根据是否需要ASC， 炎性小体可分为ASC依赖型和ASC非依赖型 炎症性小体。尽管炎性小体在先天性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。 这项提案试图将SARS-CoV-2感染与炎症体联系起来，并测试 炎症体抑制剂可减轻SARS-CoV-2的致病作用。炎性小体激活，输入 特别是通过NLRP3炎症体和孔道形成蛋白GSDMD， 严重的、往往是致命的细胞因子风暴、肺部炎症和败血症 随着SARS-CoV-2临床病情的恶化。它甚至可能导致淋巴细胞减少，这是一种重要的 以严重的新冠肺炎病例为特征。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引起的严重急性呼吸综合征(SARS)肺炎是由 大量炎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。

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.