SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses^1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and adaptive phenotype^3,4. Here we show that a decline in viral load in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA sequencing of NK cells over the time course of the COVID-19 disease spectrum reveals a distinct gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant transforming growth factor-β (TGFβ) response signature, with reduced expression of genes related to cell–cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFβ peak during the first two weeks of infection, and serum obtained from these patients severely inhibits NK cell function in a TGFβ-dependent manner. Our data reveal that an untimely production of TGFβ is a hallmark of severe COVID-19 and may inhibit NK cell function and early control of the virus.

SARS-CoV-2 是一种导致 COVID-19 的单链 RNA 病毒。鉴于其急性且通常是自限性的过程，先天免疫系统的成分很可能在控制病毒复制和确定临床结果方面发挥核心作用。自然杀伤 (NK) 细胞是先天淋巴细胞，对多种病毒具有显着活性，包括 RNA 病毒^1,2。尽管具有活化和适应性表型的 NK 细胞的代表性增加，但在 COVID-19 期间 NK 细胞功能可能会改变^3,4. 在这里，我们表明 COVID-19 中病毒载量的下降与 NK 细胞状态相关，并且 NK 细胞可以通过识别受感染的靶细胞来控制 SARS-CoV-2 复制。在严重的 COVID-19 中，NK 细胞在病毒控制、细胞因子产生和细胞介导的细胞毒性方面表现出缺陷，尽管细胞毒性效应分子的表达很高。在 COVID-19 疾病谱的时间过程中，NK 细胞的单细胞 RNA 测序揭示了一个独特的基因表达特征。干扰素驱动的 NK 细胞活化的转录网络与显性转化生长因子-β (TGFβ) 反应特征叠加，与细胞间粘附、颗粒胞吐作用和细胞介导的细胞毒性相关的基因表达降低。在重症 COVID-19 中，TGFβ 的血清水平在感染的前两周达到峰值，从这些患者获得的血清以 TGFβ 依赖性方式严重抑制 NK 细胞功能。我们的数据显示，过早产生 TGFβ 是严重 COVID-19 的标志，可能会抑制 NK 细胞功能和病毒的早期控制。