Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.

需要对与严重 COVID-19 疾病轨迹相关的细胞特征进行时间解析，以了解偏差的免疫反应和定义结果的预测因子。在这里，我们使用 14 名患者的两个中心队列进行了纵向多组学研究。我们分析了从多达 5 个时间点采集的外周血样本的大量转录组、大量 DNA 甲基化组和单细胞转录组（>358,000 个细胞，包括 BCR 谱）。在两个独立的 COVID-19 患者队列中进行了验证。重症 COVID-19 的特征是增殖、代谢过度活跃的浆母细胞增多。与危重病相吻合，我们还发现干扰素激活的循环巨核细胞增多，红细胞生成增加，具有缺氧信号传导的特征。巨核细胞和红细胞衍生的共表达模块可预测致命的疾病结果。该研究证明了 SARS-CoV-2 感染对适应性免疫细胞以外的广泛细胞影响，并为开发生物标志物和 COVID-19 患者的靶向治疗提供了一个切入点。