Role and Mitigation of Inflammasomes and Inflammation During COVID-19

COVID-19 期间炎症小体和炎症的作用和缓解

• 批准号: 10521963
• 负责人: Beverly H Koller
• 金额: $ 57.14万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521963
• 关键词: 2019-nCoV; Acute Respiratory Distress Syndrome; Agonist; Alveolar; Apoptosis; Binding; Biological Markers; CASP1 gene; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19/ARDS; Cell Death; Cells; Cessation of life; Clinical Trials; Coculture Techniques; Complex; Conflict (Psychology); Consequentialism; Dangerousness; Data; Deterioration; Epithelial Cells; Genes; Genetic Transcription; Human; Immune; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 Receptors; Interleukin-18; Interleukin-6; Irrigation; Lead; Leukocytes; Meta-Analysis; Modification; Molecular; Mus; Myeloid Cells; Outcome; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phase; Potassium; Process; Production; Proteins; Randomized Clinical Trials; Reporting; Role; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Signal Transduction; Stromal Cells; Structure; Structure of parenchyma of lung; TNF gene; Testing; Translations; Urokinase Plasminogen Activator Receptor; Virus; airway epithelium; anakinra; antagonist; cell injury; chemokine; cytokine; cytokine release syndrome; design; in vivo; inhibitor; interleukin-1beta-converting enzyme inhibitor; marenostrin; member; mortality; pathogen; receptor; response; sensor; severe COVID-19; single-cell RNA sequencing; standard care; success; therapeutic target; therapeutically effective; thrombotic

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.

项目摘要 由 SARS-CoV-2 引起的 COVID-19 大流行已导致迅速而灾难性的人员伤亡 全球。急性呼吸窘迫综合征 (ARDS) 是 COVID-19 最有害的结果之一 感染可导致患者病情迅速恶化甚至死亡。 ARDS 主要由细胞因子引起 在 COVID-19 的晚期阶段，风暴会释放出大量的炎性细胞因子。大师 人们认为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）。目前两项临床试验已显示IL-1抑制剂在新冠肺炎中的疗效 19名患者。然而，在许多情况下，这些细胞因子在 SARS-CoV-2 期间的机制和影响 人们对感染知之甚少。深入了解细胞因子诱导的机制很重要 因为这种理解将显着影响 ARDS 治疗的设计和成功。这个应用程序 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，可导致 caspase 1 激活， 然后将 pro-IL-1β 和 pro-IL-18 裂解为成熟的 IL-1β 和 IL-18。除了释放IL-1β和IL- 18、caspase 1 裂解gasdermin D 导致炎性焦亡细胞死亡，从而导致级联反应 细胞死亡和炎症。炎症小体由受体或传感器组成，其中最突出的是 以NLRP1、NLRP3、NLRP6、NLRC4和AIM2为代表。它还包括一个接头分子 ASC （含有 CARD 的凋亡相关斑点样蛋白）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相关分子激活 称为 DAMP。 COVID-19 患者的单细胞 RNAseq 数据显示炎症小体急剧增加 重症 COVID-19 患者支气管肺泡灌洗中的传感器。此外，我们还发现了一种双向馈电 涉及骨髓细胞和气道的炎症小体激活和炎症细胞因子诱导的前向循环 基质细胞。该提案将检验这种双向放大环路在新冠病毒中很重要的假设。 19.