Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19

Immunity. 2021 Nov 9;54(11):2650-2669.e14. doi: 10.1016/j.immuni.2021.09.002. Epub 2021 Sep 4.


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.

Keywords: COVID-19; NK cells; TNF; antiviral; lung fibrosis; moderate; proteomics; scRNA-seq; severe; type 1 IFN.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • COVID-19 / immunology*
  • Humans
  • Immunity, Innate / immunology
  • Inflammation / immunology
  • Interferon-alpha / blood
  • Interferon-alpha / immunology*
  • Killer Cells, Natural / immunology*
  • Pulmonary Fibrosis / pathology
  • RNA-Seq
  • SARS-CoV-2 / immunology*
  • Severity of Illness Index
  • Transcriptome / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • United Kingdom
  • United States


  • IFNA1 protein, human
  • Interferon-alpha
  • Tumor Necrosis Factor-alpha