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

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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