DIFFERENTIATION AND FUNCTION OF MONOCYTES AND MACROPHAGES

单核细胞和巨噬细胞的分化和功能

• 批准号: 10158696
• 负责人: Gwendalyn J Randolph
• 金额: $ 16.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-19 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158696
• 关键词: 2019-nCoV; Address; Affect; Agonist; Antigen-Antibody Complex; Blood; CD32 Antigens; COVID-19; Cells; Cessation of life; Characteristics; Clinical; Clinical Research; Clinical Trials; Coagulation Process; Coupled; Critical Illness; Data; Dendritic Cells; Dengue Infection; Disease; Disease Progression; Down-Regulation; Drug Targeting; Ebola; Ebola virus; Freezing; Gene Expression; HIF1A gene; HIV; HIV Infections; Hospitals; Hypoxia; Immune response; Immunoglobulin G; In Vitro; Infection; Interferon Type I; Interferons; Interleukin 6 Receptor; Interleukin-6; Laboratories; Lead; Leukocytes; Ligands; Lung; Mediating; Methods; Nature; Output; Oxygen; Participant; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Production; Publications; Resources; Ribonucleoproteins; Role; Secondary to; Serum; Severities; Severity of illness; Signal Transduction; Source; Stains; Stimulus; Surface; TLR7 gene; TLR8 gene; TNF gene; Thromboplastin; Time; Universities; Viral; Virus Diseases; Washington; Whole Blood; Work; base; comorbidity; coronavirus disease; cytokine; cytokine release syndrome; follow-up; follower of religion Jewish; improved; longitudinal dataset; macrophage; medical schools; monocyte; phase III trial; receptor; receptor internalization; recruit; resiquimod; response; stem; transcription factor; translational research program; uptake; ventilation; viral RNA

Project Summary Although much remains unclear with respect to the pathogenesis of COVID-19, the possibilities that cytokine storm and altered coagulation contribute to adverse disease pathogenesis have emerged. Both the cytokine output and promotion of coagulation may be mediated by activated monocytes. Monocytes, for instance, are the central leukocyte in blood to express tissue factor (F3) and initiate coagulation and this activity promotes comorbidity in Ebola and HIV infections. One cytokine that seems most notably elevated in plasma of COVID patients is IL-6. In keeping with the potential importance of IL-6 in cytokine storm, our preliminary data reveal that blood monocytes, of all subsets, are a major source of IL-6 in COVID leukocytes and that their production of IL-6 positively correlates with adverse disease progression. Surprisingly, though monocytes produce cytokines, other features of canonical activation were not present in monocyte subsets of COVID patients. Particularly, induction of functional tissue factor in IL-6-producing monocytes was minimal to absent. This was in striking contrast to control monocytes from healthy subjects treated ex vivo with LPS or resiquimod. Given the clinical concern that coagulation may be altered in COVID-19 and contribute to pathogenesis of adverse disease and given the very robust expression of IL-6, we were especially surprised that tissue factor was not induced. Overall, it appears that the stimulus for activation of monocytes in COVID-19 patients is distinct from canonical responses that also induce tissue factor in cytokine-producing cells, or perhaps a subset of monocytes able to activate the tissue factor pathway is missing or in extracted COVID-19 PBMCs. The overarching aim of this work is to define, using a robust longitudinal dataset, whether proinflammatory activation of monocyte subsets in blood associates with disease severity and to define the core characteristics of such activation. We will also carry out exploratory analyses in search of signals that lead to such activation. A key resource for our proposal is access to a bank of frozen PBMC, serum, plasma and whole blood in which longitudinal blood draws are being collected on 300 COVID-19 patients of differing disease severity admitted to Barnes Jewish Hospital. This bank has been established by the Institutional Clinical and Translational Research program at Washington University School of Medicine. Resources from this bank will be coupled with a stock of frozen PBMCs from >50 control participants in our laboratory and PBMCs from HIV subjects, where the state of monocyte activation will be compared with that of monocytes derived from COVID patients.

项目概要 尽管关于 COVID-19 的发病机制尚不清楚，但细胞因子的可能性 风暴和凝血功能改变导致不良疾病的发病机制已经出现。两种细胞因子 凝血的输出和促进可以由活化的单核细胞介导。例如，单核细胞是 血液中的中央白细胞表达组织因子（F3）并启动凝血，这种活性促进 埃博拉病毒和艾滋病毒感染的合并症。一种细胞因子在新冠病毒患者血浆中似乎显着升高 患者是IL-6。与 IL-6 在细胞因子风暴中的潜在重要性相一致，我们的初步数据显示 所有亚群中的血液单核细胞是新冠肺炎白细胞中 IL-6 的主要来源，并且它们的产生 IL-6 的水平与不良疾病进展呈正相关。令人惊讶的是，尽管单核细胞产生 COVID 患者的单核细胞亚群中不存在细胞因子、典型激活的其他特征。 特别是，产生 IL-6 的单核细胞中功能性组织因子的诱导很少甚至不存在。这是 与来自用 LPS 或瑞西莫德离体治疗的健康受试者的对照单核细胞形成鲜明对比。给定 临床担心 COVID-19 中的凝血功能可能会改变并导致不良反应的发病机制 考虑到 IL-6 的强烈表达，我们特别惊讶的是组织因子并没有 诱发。总体而言，COVID-19 患者单核细胞激活的刺激似乎不同于 在细胞因子产生细胞中诱导组织因子的典型反应，或者可能是细胞因子的一个子集 提取的 COVID-19 PBMC 中缺少或存在能够激活组织因子途径的单核细胞。这 这项工作的首要目标是使用强大的纵向数据集来定义促炎症是否 血液中单核细胞亚群的激活与疾病严重程度相关并确定核心特征 此类激活。我们还将进行探索性分析，寻找导致这种激活的信号。 我们提案的一个关键资源是获得冷冻 PBMC、血清、血浆和全血库，其中 正在对入院治疗的 300 名不同疾病严重程度的 COVID-19 患者进行纵向抽血 巴恩斯犹太医院。该银行是由临床和转化机构建立的 华盛顿大学医学院的研究项目。该银行的资源将被耦合 拥有来自我们实验室超过 50 名对照参与者的冷冻 PBMC 和来自 HIV 受试者的 PBMC， 其中单核细胞的激活状态将与来自新冠肺炎患者的单核细胞的激活状态进行比较。