Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19.
washington; seattle; swedish; isb; Base Sequence; COVID-19; Humans; Immunity, Innate; Inflammation; Interferon-alpha; Killer Cells, Natural; Pulmonary Fibrosis; RNA-Seq; SARS-CoV-2; Severity of Illness Index; Transcriptome; Tumor Necrosis Factor-alpha; United Kingdom; United States
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.
Institute for Systems Biology
Krämer, Benjamin; Knoll, Rainer; Bonaguro, Lorenzo; ToVinh, Michael; Raabe, Jan; Astaburuaga-García, Rosario; Schulte-Schrepping, Jonas; Kaiser, Kim Melanie; Rieke, Gereon J; Bischoff, Jenny; Monin, Malte B; Hoffmeister, Christoph; Schlabe, Stefan; De Domenico, Elena; Reusch, Nico; Händler, Kristian; Reynolds, Gary; Blüthgen, Nils; Hack, Gudrun; Finnemann, Claudia; Nischalke, Hans D; Strassburg, Christian P; Stephenson, Emily; Su, Yapeng; Gardner, Louis; Yuan, Dan; Chen, Daniel; Goldman, Jason D; Rosenstiel, Philipp; Schmidt, Susanne V; Latz, Eicke; Hrusovsky, Kevin; Ball, Andrew J; Johnson, Joe M; Koenig, Paul-Albert; Schmidt, Florian I; Haniffa, Muzlifah; Heath, James R; Kümmerer, Beate M; Keitel, Verena; Jensen, Björn; Stubbemann, Paula; Kurth, Florian; Sander, Leif E; Sawitzki, Birgit; Deutsche COVID-19 OMICS Initiative (DeCOI); Aschenbrenner, Anna C; Schultze, Joachim L; and Nattermann, Jacob, "Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19." (2021). Articles, Abstracts, and Reports. 5356.