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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Benjamin Krämer, Rainer Knoll, Lorenzo Bonaguro, Michael ToVinh, Jan Raabe, Rosario Astaburuaga-García, Jonas Schulte-Schrepping, Kim Melanie Kaiser, Gereon J Rieke, Jenny Bischoff, Malte B Monin, Christoph Hoffmeister, Stefan Schlabe, Elena De Domenico, Nico Reusch, Kristian Händler, Gary Reynolds, Nils Blüthgen, Gudrun Hack, Claudia Finnemann, Hans D Nischalke, Christian P Strassburg, Emily Stephenson, Yapeng Su, Louis Gardner, Dan Yuan, Daniel Chen, Jason Goldman, Philipp Rosenstiel, Susanne V Schmidt, Eicke Latz, Kevin Hrusovsky, Andrew J Ball, Joe M Johnson, Paul-Albert Koenig, Florian I Schmidt, Muzlifah Haniffa, James R Heath, Beate M Kümmerer, Verena Keitel, Björn Jensen, Paula Stubbemann, Florian Kurth, Leif E Sander, Birgit Sawitzki, Deutsche COVID-19 OMICS Initiative (DeCOI), Anna C Aschenbrenner, Joachim L Schultze, Jacob Nattermann. Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19. Immunity. 2021 Nov 09;54(11):2650-2669.e14

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PMID: 34592166

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