Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.

先天免疫系统的纵向分析，包括最早的时间点，对于了解冠状病毒病 (COVID-19) 的免疫发病机制和临床过程至关重要。在这里，我们使用单细胞转录组学和蛋白质组学以及功能研究对来自四个独立队列的 205 名患者（403 个样本；症状出现后第 2 至 41 天）的自然杀伤 (NK) 细胞进行了详细表征。我们发现早期严重 COVD-19 中干扰素 (IFN)-α 血浆水平升高，同时 NK 细胞表达 IFN 刺激基因 (ISG) 和参与 IFN-α 信号传导的基因增加，同时肿瘤坏死因子 (TNF) 诱导的上调在中度疾病中观察到基因。NK 细胞发挥抗 SARS-CoV-2（严重急性呼吸系统综合症冠状病毒 2）活性，但在严重 COVID-19 中功能受损。此外，NK 细胞功能障碍可能与严重 COVID-19 中纤维化肺病的发展有关，因为 NK 细胞表现出受损的抗纤维化活性。我们的研究表明分别在重度和中度 COVID-19 中有优先的 IFN-α 和 TNF 反应，并且将延长的 IFN-α 诱导的 NK 细胞反应与较差的疾病结果相关联。