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

Cell Rep. 2021 Mar 16;34(11):108863. doi: 10.1016/j.celrep.2021.108863. Epub 2021 Feb 26.


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.

Keywords: COVID-19; MDSCs; SARS-CoV-2; T cells; apoptosis; immunology; immunometabolism; metabolism; mitochondria.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / immunology
  • COVID-19 / immunology*
  • COVID-19 / metabolism*
  • Caspases / immunology
  • Caspases / metabolism
  • Female
  • Humans
  • Immunity / immunology*
  • Lymphopenia / immunology
  • Lymphopenia / metabolism
  • Male
  • Middle Aged
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Myeloid-Derived Suppressor Cells / immunology
  • Myeloid-Derived Suppressor Cells / metabolism
  • SARS-CoV-2 / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Voltage-Dependent Anion Channel 1 / metabolism
  • Young Adult


  • Voltage-Dependent Anion Channel 1
  • Caspases