Role and Mitigation of Inflammasomes and Inflammation During COVID-19

摘要 由 SARS-CoV-2 引起的 COVID-19 大流行已造成迅速且灾难性的损失 影响全球人类生活。急性呼吸窘迫综合征（ARDS）是最常见的疾病之一 COVID-19 感染的有害后果可能导致病情迅速恶化和死亡 患者。 ARDS 主要是由细胞因子风暴引起的，细胞因子风暴释放出过多的 COVID-19 晚期的炎症细胞因子。主要的细胞因子是 据认为造成大部分损害的是白细胞介素 1 (IL-1)、白细胞介素 6 (IL-6) 和肿瘤坏死因子（TNF）。目前多项临床试验已经启动 测试生物抑制剂针对这些途径的功效。然而，在许多情况下， ARDS 期间这些细胞因子的机制和影响尚不清楚。深入的 对细胞因子诱导的机制理解很重要，因为这种理解将 显着影响 ARDS 治疗的设计和成功。该应用程序重点关注 导致促炎细胞因子的炎性体复合物的作用和缓解， IL-1β，用于 ARDS。炎症小体是一种蛋白质超分子结构，可产生半胱天冬酶 1 激活，然后将 pro-IL-1β 和 pro-IL-18 裂解为成熟的 IL-1β 和 IL-18。除了 IL-1β和IL-18的释放，caspase 1裂解gasdermin D引起炎性焦亡 细胞死亡，从而导致一系列细胞死亡和炎症。炎症小体是 由受体或传感器组成，其中最突出的是 NLRP1， NLRP3、NLRP6、NLRC4 和 AIM2。它还包括一个接头分子 ASC（细胞凋亡- 相关斑点样蛋白（包含 CARD）和效应器 caspase-1。每个受体 或传感器可以被称为 PAMP 的特定病原体产物或细胞损伤激活 称为 DAMP 的相关分子。 NLRP3 是研究最多的成员，因为它是由 一大堆刺激物。对 SARS 等其他冠状病毒的研究显示炎性体 由关键病毒蛋白激活。来自 COVID-19 患者的表达数据也显示出惊人的 COVID-19患者支气管肺泡灌洗液中炎症小体传感器的增加。 然而，SARS-CoV-2 激活炎症小体的机制，尤其是在人类中 系统，未知。该提案将鉴定激活人类的病毒蛋白 炎症小体，并进一步定义了特定的人类炎症小体传感器/受体 调解反应。然后我们将设计减少炎症小体激活的方法 使用现有疗法和新方法广泛治疗 SARS-CoV-2 感染 减弱炎症细胞因子。

Abstract The COVID-19 pandemic caused by SARS-CoV-2 has resulted in swift and catastrophic losses of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most detrimental outcomes of COVID-19 infection that can lead to the rapid deterioration and death of patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of inflammatory cytokines during the late stages of COVID-19. The master cytokines that are thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor (TNF). Currently several clinical trials have already been initiated to test the efficacy of biologic inhibitors to target these pathways. However, in many cases, the mechanism and impact of these cytokines during ARDS are poorly understood. An indepth mechanistic understanding of cytokine induction is important because this understanding will significantly impact the design and success of ARDS treatment. This application focuses on the role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine, IL-1β, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase 1 activation, which then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. In addition to the release of IL-1β and IL-18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is comprised of a receptor or sensor, with the most prominent ones represented by NLRP1, NLRP3, NLRP6, NLRC4 and AIM2. It also includes an adaptor molecule ASC (apoptosis- associated speck-like protein containing a CARD), and the effector caspase-1. Each receptor or sensor can be activated by specific pathogen products called PAMPs or cell damage associated molecules called DAMPs. NLRP3 is the most studied member since it is activated by a large list of stimulators. Studies of other coronavirus such as SARS show inflammasome activation by key viral proteins. Expression data from COVID-19 patients also show dramatic increases of inflammasome sensors in the bronchial alveolar lavage of COVID-19 patients. However the mechanism of inflammasome activation by SARS-CoV-2, especially in the human system, remains unknown. This proposal will identify the viral protein that activates human inflammasome, and further define the specific human inflammasome sensor/receptor that mediates the response. We will then design ways to reduce inflammasome activation during SARS-CoV-2 infection using established therapeutics as well as new approaches to broadly attenuate inflammatory cytokines.