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

摘要 这项建议的长期目标是了解急性新冠肺炎感染的长期后遗症 造血和免疫损伤，并找出新冠肺炎- 相关的细胞因子失调改变了HSC的功能和分化。SARS-CoV-2感染导致当地 以及免疫反应和细胞因子产生失调造成的全身性损害。它的长期负面影响 对身体组织和器官的影响在很大程度上仍不清楚。我们发表的工作显示，SARS-CoV-2 感染显著增加了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是病情严重程度和死亡率的负面预后生物标志物。 虽然S100A8/A9对成熟血细胞的作用已有研究，但其对成熟血细胞的作用 造血干细胞(HSCs)是未知的。我们的初步数据显示，S100A8/A9导致 以牺牲HSC为代价，HSC向髓系祖细胞的静止和分化。Toll样受体4 S100A8/A9的内源性受体(TLR4)在HSC中高表达，S100A8/A9激活其 经典的下游MAPK(丝裂原活化蛋白激酶)途径。非常有趣的是，S100A8/A9引起 表观遗传调控因子SETD2下调，导致HSC中c-Myc上调。C-Myc是关键 MAPK和SETD2通路的下游靶点。MAPK、SETD2和c-Myc是HSC的重要调节因子 增殖和髓系分化。我们推测SARS-CoV-2诱导的S100A8/A9激活TLR4 在HSCs中转化为c-Myc的信号，导致失去静止和自我更新，髓系 分化偏斜，造血功能长期受损。因为HSC负责终身的 产生血细胞，包括所有类型的免疫细胞，任何肝星状细胞的功能损害都会在以后 对免疫反应有深远的负面影响。因此，理解细胞和分子 S100A8/A9调节HSCs和造血的机制将为HSCs和造血的研究提供新的证据基础 加快新冠肺炎急性感染的诊断、治疗和临床处理 和恢复阶段。 1

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