Cell
Volume 184, Issue 7, 1 April 2021, Pages 1836-1857.e22
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Article
Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19

https://doi.org/10.1016/j.cell.2021.02.018Get rights and content
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Highlights

  • Multiparameter metric captures finer shades of disease severity to empower analyses

  • Network analysis reveals primary disease severity correlates in pDCs and NK cells

  • Analysis of timing effects suggests a late immune response juncture

  • Inflammatory divergence at the late juncture predicts fatal-recovery outcomes

Summary

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17–23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.

Keywords

single cell multi-omics
COVID-19
time-resolved
exhaustion
CITE-seq
immune juncture
mixed-effect statistical modeling

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These authors contributed equally

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