1. Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.
- Author
-
Krämer B, Knoll R, Bonaguro L, ToVinh M, Raabe J, Astaburuaga-García R, Schulte-Schrepping J, Kaiser KM, Rieke GJ, Bischoff J, Monin MB, Hoffmeister C, Schlabe S, De Domenico E, Reusch N, Händler K, Reynolds G, Blüthgen N, Hack G, Finnemann C, Nischalke HD, Strassburg CP, Stephenson E, Su Y, Gardner L, Yuan D, Chen D, Goldman J, Rosenstiel P, Schmidt SV, Latz E, Hrusovsky K, Ball AJ, Johnson JM, Koenig PA, Schmidt FI, Haniffa M, Heath JR, Kümmerer BM, Keitel V, Jensen B, Stubbemann P, Kurth F, Sander LE, Sawitzki B, Aschenbrenner AC, Schultze JL, and Nattermann J
- Subjects
- Base Sequence, Humans, Immunity, Innate immunology, Inflammation immunology, Interferon-alpha blood, Pulmonary Fibrosis pathology, RNA-Seq, Severity of Illness Index, Transcriptome genetics, United Kingdom, United States, COVID-19 immunology, Interferon-alpha immunology, Killer Cells, Natural immunology, SARS-CoV-2 immunology, Tumor Necrosis Factor-alpha metabolism
- Abstract
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., Competing Interests: Declaration of interests P.-A.K. and F.I.S. are cofounders and shareholders of Dioscure Therapeutics SE. F.I.S. is a consultant and shareholder of IFM Therapeutics. J.R.H. is founder and board member of Isoplexis and PACT Pharma. J.D.G. declares contracted research with Gilead, Lilly, and Regeneron. K.H., J.M.J., and A.J.B. work at Quanterix Corporation. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF