Metabolic programs define dysfunctional immune responses in severe COVID-19 patients

Elizabeth A. Thompson, Katherine Cascino, Alvaro A. Ordonez, Weiqiang Zhou, Ajay Vaghasia, Anne Hamacher-Brady, Nathan R. Brady, Im Hong Sun, Rulin Wang, Avi Z. Rosenberg, Michael Delannoy, Richard Rothman, Katherine Fenstermacher, Lauren Sauer, Kathyrn Shaw-Saliba, Evan M. Bloch, Andrew D. Redd, Aaron A.R. Tobian, Maureen Horton, Kellie SmithAndrew Pekosz, Franco R. D'Alessio, Srinivasan Yegnasubramanian, Hongkai Ji, Andrea L. Cox, Jonathan D. Powell

Research output: Contribution to journalArticlepeer-review


It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.

Original languageEnglish (US)
Article number108863
JournalCell Reports
Issue number11
StatePublished - Mar 16 2021


  • COVID-19
  • MDSCs
  • SARS-CoV-2
  • T cells
  • apoptosis
  • immunology
  • immunometabolism
  • metabolism
  • mitochondria

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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