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: 10836902
• 负责人: Gang Huang
• 金额: $ 43.57万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836902
• 关键词: 2019-nCoV; Acceleration; Acute; Apoptosis; Blood Cells; COVID-19; COVID-19 pandemic; COVID-19 patient; Cell Differentiation process; Cells; Chronic; Clinical; Clinical Management; Data; Diagnostic; Disease; Disease Progression; Dose; Down-Regulation; Equilibrium; Fluorouracil; Functional disorder; Generations; Goals; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Immune; Immune response; Immunosuppression; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Knockout Mice; Knowledge; Lipopolysaccharides; Mediating; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myelosuppression; Organ; Outcome; Pathway interactions; Patients; Phase; Production; Prognostic Marker; Proliferating; Proteins; Publishing; Recombinants; Recovery; Regulation; Role; S100A8 gene; SARS-CoV-2 infection; Severities; Severity of illness; Signal Transduction; Stress; System; TLR4 gene; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Variant; Work; acute infection; adverse outcome; antagonist; c-myc Genes; cytokine; cytokine release syndrome; epigenetic regulation; evidence base; exhaustion; functional disability; hematopoietic differentiation; hematopoietic stem cell quiescence; human model; long term consequences of COVID-19; long-term sequelae; 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

抽象的 该提案的长期目标是了解急性共卷19对急性共同感染的长期序列 造血和免疫损害，并确定COVID-19--的关键途径和机制 相关的细胞因子失调会改变HSC功能和分化。 SARS-COV-2感染会引起本地 以及由于免疫反应和细胞因子产生失调而导致的全身损害。它的长期负面 对人体组织和器官的影响在很大程度上未知。我们发表的工作表明SARS-COV-2 感染大大增加了中性粒细胞的产生和中性粒细胞相关的S100A8/A9（Alarmin）释放。 S100A8/A9的持续高水平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S100A8/A9对成熟血细胞的功能，但其功能影响 造血干细胞（HSC）尚不清楚。我们的初步数据表明，S100A8/A9导致损失 HSC向髓样祖细胞的静止和分化为HSC。 Toll样受体4 （TLR4），S100A8/A9的内源性受体，在HSC中高度表达，S100A8/A9激活其 典型的下游MAPK（有丝分裂原激活的蛋白激酶）途径。有趣的是，S100A8/A9引起 表观遗传调节剂SETD2的下调，导致HSC中的C-Myc上调。 C-MYC是关键 MAPK和SETD2途径的下游目标。 MAPK，SETD2和C-MYC是HSC的重要调节剂 增殖和髓样分化。我们假设SARS-COV-2诱导的S100A8/A9激活TLR4 信号转换为HSC中C-MYC，导致静止和自我更新的损失 分化偏差和造血的长期损害。由于HSC负责终身 血液细胞的产生，包括所有类型的免疫细胞，HSC的任何功能损害都将在以后 对免疫反应产生深远的负面影响。因此，了解细胞和分子 S100A8/A9调节HSC和造血的机制将为新的证据基础贡献 加速诊断，治疗学，急性感染患者的临床管理的进步 和恢复阶段。 1