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: 10666572
• 负责人: Beverly H Koller
• 金额: $ 62.04万
• 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/10666572
• 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; Caspase; Cell Death; Cells; Cessation of life; Clinical Trials; Coculture Techniques; Complex; Conflict (Psychology); Dangerousness; Data; Deterioration; Epithelial Cells; Genes; Genetic Transcription; Human; IL18 gene; Immune; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-1 beta; Interleukin-6; Irrigation; Leukocytes; Meta-Analysis; Molecular; Mus; Myeloid Cells; Outcome; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phase; Post-Translational Protein Processing; Potassium; Process; Production; Proteins; Reporting; Role; SARS-CoV-2 infection; SARS-CoV-2 pathogenesis; Signal Transduction; Stromal Cells; Structure; Structure of parenchyma of lung; TNF gene; Testing; Urokinase Plasminogen Activator Receptor; Virus; airway epithelium; anakinra; cell injury; chemokine; cytokine; cytokine release syndrome; design; in vivo; inhibitor; interleukin-1beta-converting enzyme inhibitor; marenostrin; member; mortality; pathogen; randomized, clinical trials; 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引发的新冠肺炎大流行已造成迅速和灾难性的人类生命损失 全球范围内。急性呼吸窘迫综合征是新冠肺炎最有害的后果之一 可导致患者迅速恶化和死亡的感染。ARDS主要是由细胞因子引起的 在新冠肺炎后期释放过多炎性细胞因子的风暴。《大师》 被认为是造成大部分损害的细胞因子是白介素1(IL-1)、白介素6(IL-6) 和肿瘤坏死因子(TNF)。目前已有两项临床试验表明，IL-1抑制剂对COVID- 19例患者。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。深入理解细胞因子诱导的机制是重要的 因为这一认识将显著影响ARDS治疗的设计和成功。此应用程序 重点是炎症体复合体的作用和缓解，它导致促炎细胞因子， IL-1β，急性呼吸窘迫综合征。炎症体是一种蛋白质超分子结构，导致caspase 1激活， 然后将前IL-1β和前IL-18裂解成成熟的IL-1β和IL-18。除了释放IL-1β和IL-1外， 18，caspase 1裂解Gasdermin D导致炎性嗜酸细胞死亡，从而导致一系列 细胞死亡和炎症。炎性小体由感受器或感应器组成，其中最突出的 以NLRP1、NLRP3、NLRP6、NLRC4和AIM2为代表的基因。它还包括一个接头分子ASC (含有一张卡片的凋亡相关的斑点样蛋白)，以及效应因子caspase-1。每个受体或 传感器可以被称为PAMPs或细胞损伤相关分子的特定病原体产物激活 被称为“湿气”。新冠肺炎患者单细胞RNA序列数据显示炎症体急剧增加 重症新冠肺炎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- 涉及髓系细胞和呼吸道的炎性小体激活和炎性细胞因子诱生的前循环 基质细胞。这项提议将检验这样的假设，即这种双向扩增环在COVID中很重要- 19.