Durable Alterations of Hematopoiesis and Chromatin post-COVID-19 [MultiomeRNA]

Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant. To discover changes in chromatin post-SARS-CoV-2 infection, RNA-seq was performed on CD34+ HSPCs and CD14+ monocytes sorted from PBMC of healthy, non-COVID-19 post-ICU pateitns, mild convalescent, and severe convalescent COVID-19 patients.

急性严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染通常伴随强烈炎症反应且病程迁延。近年研究进展证实，炎症可通过表观遗传机制触发先天免疫记忆，并对造血发育产生持久影响。然而，此类表型及其分子与细胞特征在人类中的相关研究仍十分有限。本研究揭示了新冠病毒感染后先天免疫细胞与造血干细胞及祖细胞（HSPC）中的表观基因组改变，且不同疾病严重程度下存在差异化的分子调控程序。借助外周血造血研究的新型实验手段，我们发现HSPC的表观遗传调控程序可存续数月至一年，并传递至寿命较短的子代单核细胞。此类表观遗传改变与髓系细胞分化增强及炎症、抗病毒相关调控程序的激活密切相关。本研究为感染后HSPC与先天免疫细胞的表观遗传改变提供了具有广泛参考价值的见解。为探究新冠病毒感染后染色质的改变，研究团队对来自健康个体、非新冠重症监护病房（ICU）后康复患者、轻症新冠康复患者及重症新冠康复患者的外周血单个核细胞（PBMC）中分选得到的CD34+造血干细胞及祖细胞（HSPC）与CD14+单核细胞进行了RNA测序（RNA-seq）。