Role and Mitigation of Inflammasomes and Inflammation During COVID-19

工程摘要 由SARS-CoV-2引起的COVID-19大流行导致了人类生命的迅速和灾难性损失 在全球急性呼吸窘迫综合征（ARDS）是COVID-19最有害的结果之一 感染，可导致患者迅速恶化和死亡。急性呼吸窘迫综合征主要是由细胞因子 在COVID-19晚期释放过多炎症细胞因子的风暴。主 被认为是造成大部分损伤的细胞因子是白细胞介素1（IL-1）、白细胞介素6（IL-6）， 和肿瘤坏死因子（TNF）。目前，两项临床试验显示了IL-1抑制剂在COVID-19中的疗效。 19名患者。然而，在许多情况下，这些细胞因子在SARS-CoV-2中的机制和影响 对感染了解甚少。深入了解细胞因子诱导的机制是重要的 因为这种理解将显著影响ARDS治疗的设计和成功。本申请 集中于导致促炎细胞因子的炎性体复合物的作用和减轻， IL-1β，在ARDS中。炎性小体是一种蛋白质超分子结构，可导致半胱天冬酶1活化， 其然后切割pro-IL-1β和pro-IL-18以使IL-1β和IL-18成熟。除了释放IL-1β和IL-10外， 18，半胱天冬酶1切割gasdermin D，引起炎性细胞死亡，从而导致级联反应。 细胞死亡和炎症。炎性小体由受体或感受器组成，其中最突出的是 由NLRP 1、NLRP 3、NLRP 6、NLRC 4和AIM 2表示的那些。它还包括一个衔接分子ASC （包含CARD的凋亡相关斑点样蛋白）和效应物半胱天冬酶-1。每个受体或 传感器可被称为PAMP的特定病原体产物或细胞损伤相关分子激活 称为DAMP。来自COVID-19患者的单细胞RNAseq数据显示炎性小体显著增加 传感器用于重症COVID-19患者的支气管肺泡灌洗。另外，我们发现了一个双向的信号源- 涉及骨髓细胞和气道的炎性体活化和炎性细胞因子诱导的前向环 基质细胞这项提议将检验这一假设，即这种双向放大回路在COVID-19中很重要。 19.

Project 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 two clinical trials have shown the efficacy of IL-1 inhibitor in COVID- 19 patients. However, in many cases, the mechanism and impact of these cytokines during SARS-CoV-2 infection are poorly understood. An in-depth 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. Single cell RNAseq data from COVID-19 patients show dramatic increases of inflammasome sensors in the bronchial alveolar lavage of severe COVID-19 patients. In addition, we find a bidirectional feed- forward loop of inflammasome activation and inflammatory cytokine induction involving myeloid cells and airway stromal cells. This proposal will test the hypothesis that this two way amplification loop is important in COVID- 19.