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

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Immunity


. 2021 Sep 4;S1074-7613(21)00365-4.
doi: 10.1016/j.immuni.2021.09.002. Online ahead of print.
Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19


Benjamin Krämer ¹ , Rainer Knoll ² , Lorenzo Bonaguro ² , Michael ToVinh ¹ , Jan Raabe ¹ , Rosario Astaburuaga-García ³ , Jonas Schulte-Schrepping ² , Kim Melanie Kaiser ¹ , Gereon J Rieke ¹ , Jenny Bischoff ¹ , Malte B Monin ¹ , Christoph Hoffmeister ¹ , Stefan Schlabe ⁴ , Elena De Domenico ⁵ , Nico Reusch ² , Kristian Händler ⁵ , Gary Reynolds ⁶ , Nils Blüthgen ³ , Gudrun Hack ¹ , Claudia Finnemann ¹ , Hans D Nischalke ¹ , Christian P Strassburg ¹ , Emily Stephenson ⁶ , Yapeng Su ⁷ , Louis Gardner ⁶ , Dan Yuan ⁷ , Daniel Chen ⁷ , Jason Goldman ⁸ , Philipp Rosenstiel ⁹ , Susanne V Schmidt ¹⁰ , Eicke Latz ¹⁰ , Kevin Hrusovsky ¹¹ , Andrew J Ball ¹¹ , Joe M Johnson ¹¹ , Paul-Albert Koenig ¹² , Florian I Schmidt ¹² , Muzlifah Haniffa ¹³ , James R Heath ¹⁴ , Beate M Kümmerer ¹⁵ , Verena Keitel ¹⁶ , Björn Jensen ¹⁶ , Paula Stubbemann ¹⁷ , Florian Kurth ¹⁸ , Leif E Sander ¹⁸ , Birgit Sawitzki ¹⁹ , Deutsche COVID-19 OMICS Initiative (DeCOI); Anna C Aschenbrenner ²¹ , Joachim L Schultze ²² , Jacob Nattermann ²³



Collaborators, Affiliations

• PMID: 34592166
• DOI: 10.1016/j.immuni.2021.09.002

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.

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