Mechanism of the short- and long-term effects of COVID-19-induced Alarmins on hematopoietic stem and progenitor cells.

COVID-19诱导的警报素对造血干细胞和祖细胞的短期和长期影响的机制。

• 批准号: 10319702
• 负责人: Gang Huang
• 金额: $ 40.18万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319702
• 关键词: 2019-nCoV; Acute; Apoptosis; Blood Cells; COVID-19; COVID-19 cytokine storm; COVID-19 pandemic; COVID-19 patient; Cell Differentiation process; Cells; Chronic; Clinical; Clinical Management; Data; Diagnostic; Disease; Disease Progression; Dose; Down-Regulation; Epigenetic Process; Equilibrium; Fluorouracil; Functional disorder; Generations; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune; Immune response; Immunosuppression; Impairment; In Vitro; Infection; Inflammation; Knockout Mice; Knowledge; Life; Lipopolysaccharides; Long-Term Effects; MAP Kinase Gene; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myelosuppression; Organ; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Phase; Production; Prognostic Marker; Proteins; Publishing; Recombinants; Recovery; Regulation; Role; S100A8 gene; SARS-CoV-2 infection; Severities; Severity of illness; Signal Transduction; Stress; TLR4 gene; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Variant; Work; acute infection; adverse outcome; body system; c-myc Genes; cytokine; evidence base; exhaustion; functional disability; hematopoietic stem cell differentiation; hematopoietic stem cell quiescence; human model; loss of function; mortality; mouse model; neutrophil; progenitor; receptor; response; self-renewal; severe COVID-19; stem cell function; stem cell proliferation

ABSTRACT The long-term goal of this proposal is to understand the long-term sequalae of acute COVID-19 infection on hematopoietic and immune damages, and to identify the key pathways and mechanism by which COVID-19- associated cytokine dysregulation alters HSC function and differentiation. SARS-CoV-2 infection causes local and systemic damages due to dysregulated immune response and cytokine production. Its long-term negative effects on body tissue and organ remain largely unknown. Our published work showed that SARS-CoV-2 infection dramatically increased neutrophil production and neutrophil-associated S100A8/A9 (Alarmin) release. Persistent high level of S100A8/A9 is a negative prognostic biomarker for the disease severity and mortality. Although the function of S100A8/A9 on mature blood cells have been studied, its functional effect on hematopoietic stem cells (HSCs) are unknown. Our preliminary data show that S100A8/A9 causes loss of quiescence and differentiation of HSC toward myeloid progenitors at the expense of HSCs. Toll-like receptor 4 (TLR4), the endogenous receptor of S100A8/A9, is highly expressed in HSCs, and S100A8/A9 activates its canonical downstream MAPK (mitogen-activated protein kinase) pathway. Very interestingly, S100A8/A9 causes downregulation of epigenetic regulator Setd2, leading to the c-Myc upregulation in HSCs. c-Myc is a key downstream target of both MAPK and Setd2 pathways. MAPK, Setd2 and c-Myc are important regulators of HSC proliferation and myeloid differentiation. We hypothesize that SARS-CoV-2-induced S100A8/A9 activates TLR4 signaling which converts to c-Myc in HSCs, resulting in loss of quiescence and self-renewal, myeloid differentiation skewing, and long-term impairment of hematopoiesis. Since HSC is responsible for the life-long production of blood cells, including all types of immune cells, any functional damages of HSCs would later on have profoundly negative effects on the immune response. Therefore, understanding the cellular and molecular mechanism by which S100A8/A9 regulates HSCs and hematopoiesis would contribute a new evidence base to accelerate advances in diagnostics, therapeutics, clinical management of COVID-19 patients in acute infection and recovery phases. 1

摘要 该提案的长期目标是了解急性COVID-19感染的长期后遗症， 造血和免疫损伤，并确定COVID-19- 相关的细胞因子失调改变HSC功能和分化。SARS-CoV-2感染导致局部 以及由于失调的免疫应答和细胞因子产生而引起的系统性损害。长期负面影响 对人体组织和器官的影响基本上仍不清楚。我们发表的研究表明，SARS-CoV-2 感染显著增加嗜中性粒细胞产生和嗜中性粒细胞相关的S100 A8/A9（Alarmin）释放。 持续高水平的S100 A8/A9是疾病严重程度和死亡率的阴性预后生物标志物。 尽管已经研究了S100 A8/A9对成熟血细胞的功能，但其对成熟血细胞的功能作用还不清楚。 造血干细胞（HSC）是未知的。我们的初步数据显示，S100 A8/A9导致 HSC的静止和向髓样祖细胞的分化以HSC为代价。toll样受体4 S100 A8/A9的内源性受体TLR 4在HSC中高度表达，并且S100 A8/A9激活其受体TLR 4。 典型的下游MAPK（丝裂原活化蛋白激酶）途径。非常有趣的是，S100 A8/A9导致 下调表观遗传调节因子Setd 2，导致HSC中c-Myc上调。c-Myc是一个关键 MAPK和Setd 2通路的下游靶点。MAPK、Setd 2和c-Myc是HSC的重要调节因子 增殖和髓样分化。我们推测SARS-CoV-2诱导的S100 A8/A9激活TLR 4， 在HSC中转化为c-Myc的信号传导，导致静止和自我更新的丧失， 分化偏斜和造血的长期损害。由于HSC负责终身 造血干细胞的任何功能性损伤都将在造血干细胞产生包括所有类型的免疫细胞之后， 对免疫反应有很大的负面影响。因此，了解细胞和分子 S100 A8/A9调控造血干细胞和造血功能的机制将为造血干细胞的研究提供新的证据基础。 加快推进新型冠状病毒急性感染患者的诊断、治疗和临床管理 和恢复阶段。 1