Role and Mitigation of Inflammasomes and Inflammation During COVID-19

摘要 由SARS-CoV-2引起的COVID-19大流行导致了迅速和灾难性的损失 全球人类生活的一部分。急性呼吸窘迫综合征（ARDS）是目前世界上最常见的 COVID-19感染的有害后果，可能导致患者的迅速恶化和死亡， 患者急性呼吸窘迫综合征主要是由细胞因子风暴引起的， COVID-19晚期的炎症细胞因子。主要的细胞因子 被认为是造成大部分损伤的原因是白细胞介素1（IL-1），白细胞介素6（IL-6）， 和肿瘤坏死因子（TNF）。目前已经启动了几项临床试验， 测试生物抑制剂针对这些途径的功效。然而，在许多情况下， 这些细胞因子在ARDS中的作用机制和影响尚不清楚。深入的 对细胞因子诱导机制的理解是重要的，因为这种理解将 严重影响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。炎性体是一种导致半胱天冬酶的蛋白质超分子结构 1活化，然后切割pro-IL-1β和pro-IL-18以使IL-1β和IL-18成熟。除了 IL-1β和IL-18的释放，半胱天冬酶1切割gasdermin D，引起炎性热原 细胞死亡，从而导致细胞死亡和炎症级联。炎性小体是 由受体或传感器组成，其中最突出的由NLRP 1代表， NLRP 3、NLRP 6、NLRC 4和AIM 2。它还包括一个衔接分子ASC（凋亡- 相关的含有CARD的斑点样蛋白）和效应物半胱天冬酶-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DAMPs的相关分子。NLRP 3是研究最多的成员，因为它被激活， 一大堆刺激物对其他冠状病毒如SARS的研究表明， 关键病毒蛋白的激活。来自COVID-19患者的表达数据也显示了显着的 COVID-19患者支气管肺泡灌洗中炎性小体传感器的增加。 然而，SARS-CoV-2激活炎性小体的机制，特别是在人类中， 系统，仍然未知。这项提案将确定激活人类的病毒蛋白质， 本发明还涉及特异性人炎性体传感器/受体，其 调解回应。然后，我们将设计方法，以减少炎性小体激活， SARS-CoV-2感染使用已建立的治疗方法以及新的方法，以广泛 减弱炎性细胞因子。

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.