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


  • B. Krämer
  • R. Knoll
  • L. Bonaguro
  • M. ToVinh
  • J. Raabe
  • R. Astaburuaga-García
  • J. Schulte-Schrepping
  • K.M. Kaiser
  • G.J. Rieke
  • J. Bischoff
  • M.B. Monin
  • C. Hoffmeister
  • S. Schlabe
  • E. De Domenico
  • N. Reusch
  • K. Händler
  • G. Reynolds
  • N. Blüthgen
  • G. Hack
  • C. Finnemann
  • H.D. Nischalke
  • C.P. Strassburg
  • E. Stephenson
  • Y. Su
  • L. Gardner
  • D. Yuan
  • D. Chen
  • J. Goldman
  • P. Rosenstiel
  • S.V. Schmidt
  • E. Latz
  • K. Hrusovsky
  • A.J. Ball
  • J.M. Johnson
  • P.A. Koenig
  • F.I. Schmidt
  • M. Haniffa
  • J.R. Heath
  • B.M. Kümmerer
  • V. Keitel
  • B. Jensen
  • P. Stubbemann
  • F. Kurth
  • L.E. Sander
  • B. Sawitzki
  • A.C. Aschenbrenner
  • J.L. Schultze
  • J. Nattermann


  • Immunity


  • Immunity 54 (11): 2650-2669


  • 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.