tetano
Editor, Senior Moderator
Cell Rep
. 2021 Feb 26;108863.
doi: 10.1016/j.celrep.2021.108863. Online ahead of print.
Metabolic programs define dysfunctional immune responses in severe COVID-19 patients
Elizabeth A Thompson[SUP] 1 [/SUP], Katherine Cascino[SUP] 2 [/SUP], Alvaro A Ordonez[SUP] 3 [/SUP], Weiqiang Zhou[SUP] 4 [/SUP], Ajay Vaghasia[SUP] 5 [/SUP], Anne Hamacher-Brady[SUP] 6 [/SUP], Nathan R Brady[SUP] 6 [/SUP], Im-Hong Sun[SUP] 1 [/SUP], Rulin Wang[SUP] 5 [/SUP], Avi Z Rosenberg[SUP] 7 [/SUP], Michael Delannoy[SUP] 8 [/SUP], Richard Rothman[SUP] 9 [/SUP], Katherine Fenstermacher[SUP] 9 [/SUP], Lauren Sauer[SUP] 9 [/SUP], Kathyrn Shaw-Saliba[SUP] 9 [/SUP], Evan M Bloch[SUP] 7 [/SUP], Andrew D Redd[SUP] 10 [/SUP], Aaron A R Tobian[SUP] 7 [/SUP], Maureen Horton[SUP] 2 [/SUP], Kellie Smith[SUP] 1 [/SUP], Andrew Pekosz[SUP] 6 [/SUP], Franco R D'Alessio[SUP] 2 [/SUP], Srinivasan Yegnasubramanian[SUP] 11 [/SUP], Hongkai Ji[SUP] 4 [/SUP], Andrea L Cox[SUP] 12 [/SUP], Jonathan D Powell[SUP] 13 [/SUP]
Affiliations
Abstract
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.
. 2021 Feb 26;108863.
doi: 10.1016/j.celrep.2021.108863. Online ahead of print.
Metabolic programs define dysfunctional immune responses in severe COVID-19 patients
Elizabeth A Thompson[SUP] 1 [/SUP], Katherine Cascino[SUP] 2 [/SUP], Alvaro A Ordonez[SUP] 3 [/SUP], Weiqiang Zhou[SUP] 4 [/SUP], Ajay Vaghasia[SUP] 5 [/SUP], Anne Hamacher-Brady[SUP] 6 [/SUP], Nathan R Brady[SUP] 6 [/SUP], Im-Hong Sun[SUP] 1 [/SUP], Rulin Wang[SUP] 5 [/SUP], Avi Z Rosenberg[SUP] 7 [/SUP], Michael Delannoy[SUP] 8 [/SUP], Richard Rothman[SUP] 9 [/SUP], Katherine Fenstermacher[SUP] 9 [/SUP], Lauren Sauer[SUP] 9 [/SUP], Kathyrn Shaw-Saliba[SUP] 9 [/SUP], Evan M Bloch[SUP] 7 [/SUP], Andrew D Redd[SUP] 10 [/SUP], Aaron A R Tobian[SUP] 7 [/SUP], Maureen Horton[SUP] 2 [/SUP], Kellie Smith[SUP] 1 [/SUP], Andrew Pekosz[SUP] 6 [/SUP], Franco R D'Alessio[SUP] 2 [/SUP], Srinivasan Yegnasubramanian[SUP] 11 [/SUP], Hongkai Ji[SUP] 4 [/SUP], Andrea L Cox[SUP] 12 [/SUP], Jonathan D Powell[SUP] 13 [/SUP]
Affiliations
- PMID: 33691089
- DOI: 10.1016/j.celrep.2021.108863
Abstract
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.