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。

基本信息

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
项目类别：
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

项目摘要

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 COVID-19 感染的长期后遗症造血和免疫损伤，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 感染导致局部以及由于免疫反应和细胞因子产生失调引起的系统性损害。其长期负面影响对身体组织和器官的影响仍然很大程度上未知。我们发表的工作表明 SARS-CoV-2 感染显着增加中性粒细胞的产生和中性粒细胞相关的 S100A8/A9 (Alarmin) 的释放。持续高水平的 S100A8/A9 是疾病严重程度和死亡率的负面预后生物标志物。尽管已经研究了S100A8/A9对成熟血细胞的功能，但其对成熟血细胞的功能影响造血干细胞（HSC）尚不清楚。我们的初步数据显示，S100A8/A9 造成的损失 HSC 向骨髓祖细胞的静止和分化，以牺牲 HSC 为代价。 Toll样受体4 TLR4是S100A8/A9的内源性受体，在HSC中高表达，S100A8/A9激活其典型的下游 MAPK（丝裂原激活蛋白激酶）途径。非常有趣的是，S100A8/A9导致表观遗传调节因子 Setd2 的下调，导致 HSC 中 c-Myc 的上调。 c-Myc 是关键 MAPK 和 Setd2 途径的下游靶点。 MAPK、Setd2 和 c-Myc 是 HSC 的重要调节因子增殖和骨髓分化。我们假设 SARS-CoV-2 诱导的 S100A8/A9 激活 TLR4 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，骨髓细胞分化倾斜和造血功能的长期损害。由于 HSC 负责终身血细胞（包括所有类型的免疫细胞）的产生，造血干细胞的任何功能损伤都会在以后发生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 和造血的机制将为以下方面提供新的证据基础加速 COVID-19 急性感染患者的诊断、治疗和临床管理方面的进步和恢复阶段。 1