biostudies-literatureKramer BNational Institute for Health Research (NIHR)Wellcome TrustAcademy of Medical Sciences2650-2669.e14https://www.ebi.ac.uk/biostudies/studies/S-EPMC8416549biostudies-literatureUnknown54(11)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 coronImmunityEarly IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.PMC8416549CL-2015-01-002SGL015\1021214539/Z/18/ZACF-2020-01-007Ludwig KUHaniffa MFranzenburg SStephenson ESchiffer Pvon Kleist MNattermann JBoyke BMcHardy ACBitzer MWieczorek DGoldman JHrusovsky KKoenig PAKeppler OTReusch NSu YGopel SSharaf MLLandthaler MVogel JGauder MHubschmann DFischer NHorn FSczyrba ABlumert CWalter JKorbel JYuan DKeller AKramer BUlas TColome-Tatche MKim-Hellmuth SNunes da Rocha UHanses FMonin MBKohlbacher OScheithauer SSchlabe SStrassburg CPStegle OHoffmeister CPink IRieß OVolland SHack GDiefenbach ANischalke HDKuhnert DKeitel VKallies RHeath JRKurth IGabernet GRaabe JKurth FKaiser KMRajewsky NSchneider WNothen MTheis FToVinh MSonnabend MMakarewicz OGardner LOvermann JPoetsch ARGoesmann AKlein CSchmidt SVHoeper MSchmid-Burgk JJanssen SSaliba AELatz EGanzenmueller TSander LEWinkler SBluthgen NSingh YVehreschild JKnoll RHeimbach ASchultze JLHandler KKummerer BMSchmidt FIReynolds GDeutsche COVID-19 OMICS Initiative (DeCOI)Bonifacio EHummel MRalser MKehr BMunchhoff MBezdan DKohrer KProtzer UIftner ARosenstiel PJohnson JMSchulte ECStoye JSchulte-Schrepping JChen DGeißert JLi YCasadei NKalinowski JGrundhoff AOssowski SIftner TCornberg MRieke GJHehr UPeter SGagneur JBecker MStubbemann PDe La Rosa Velazquez IAPuhler ABartholomaus AFrick JSBall AJJensen BIllig TRipke SNurnberg PVelavan TPReiche KWalker AHain TMarz MBischoff JAltmuller JClavel TForstner KGrundmann HMertes CZiebuhr JBlum HDe Domenico EBork PFinnemann CAschenbrenner ACAngelov AKnop MPfeffer KBals RNtoumi FAstaburuaga-Garcia RBonaguro LSawitzki BDilthey AMarini FKremsner PGNahnsen SBecker AfalseEarly 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 coron2021-01-01T00:00:00Z2021 Nov2026-05-08T00:43:42.455Z2022-02-11T13:14:22.691ZS-EPMC84165493459216610.1016/j.immuni.2021.09.002