Early IFN-a signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19
Immunity | September 4, 2021
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 P-A, 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
This study was performed using Simoa Homebrew assay(s).
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.