Immunity
Volume 54, Issue 11, 9 November 2021, Pages 2650-2669.e14
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Article
Early IFN-α signatures and persistent dysfunction are distinguishing features of NK cells in severe COVID-19

https://doi.org/10.1016/j.immuni.2021.09.002Get rights and content
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Highlights

  • Elevated IFN-α plasma levels characteristic for early severe COVID-19 (sCOVID-19)

  • Differential IFN-α vs. TNF signaling discriminates severe vs. moderate COVID-19

  • NK cells exert anti-SARS-CoV-2 activity but are functionally impaired in sCOVID-19

  • Persistent NK cell dysfunction may promote fibrotic lung disease in sCOVID-19

Summary

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

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

Data and code availability

Single-cell RNA-seq data have been deposited at the European Genome-phenome Archive (EGA) and are publicly available as of the date of publication. Accession numbers are listed in the Key resources table.

All original code is publicly available as of the date of publication. DOIs are listed in the Key resources table.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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These authors contributed equally

30

Senior author

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Lead contact