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

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.

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