Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone
Peter J. Siska, … , Marina Kreutz, Kathrin Renner
Peter J. Siska, … , Marina Kreutz, Kathrin Renner
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e148225. https://doi.org/10.1172/JCI148225.
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Research Article Inflammation Metabolism

Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone

Abstract

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non–COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Authors

Peter J. Siska, Sonja-Maria Decking, Nathalie Babl, Carina Matos, Christina Bruss, Katrin Singer, Jana Klitzke, Marian Schön, Jakob Simeth, Josef Köstler, Heiko Siegmund, Ines Ugele, Michael Paulus, Alexander Dietl, Kristina Kolodova, Louisa Steines, Katharina Freitag, Alice Peuker, Gabriele Schönhammer, Johanna Raithel, Bernhard Graf, Florian Geismann, Matthias Lubnow, Matthias Mack, Peter Hau, Christopher Bohr, Ralph Burkhardt, Andre Gessner, Bernd Salzberger, Ralf Wagner, Frank Hanses, Florian Hitzenbichler, Daniel Heudobler, Florian Lüke, Tobias Pukrop, Wolfgang Herr, Daniel Wolff, Rainer Spang, Hendrik Poeck, Petra Hoffmann, Jonathan Jantsch, Christoph Brochhausen, Dirk Lunz, Michael Rehli, Marina Kreutz, Kathrin Renner

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Figure 7

Dexamethasone and NOX inhibition mitigate T cell ROS accumulation and basigin expression in vitro.

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Dexamethasone and NOX inhibition mitigate T cell ROS accumulation and ba...
(A and C) Blood of donors was drawn and processed the same day. PBMCs were isolated and treated as indicated (for concentrations see Methods). (A) After 72 hours, PBMCs were stained for CD4 and CD8 and cytosolic ROS and basigin levels were analyzed. Data were normalized to anti-CD3 (aCD3) stimulation of the respective donor. (B) Log(fold change) of expression estimates for NOXA1 were determined for each cluster (as in Figure 4A and Supplemental Figure 4A). (C) PBMCs were processed as in A. Data normalized to anti-CD3 stimulation of the respective donor are shown. Summarized data are displayed as mean + SEM, with each symbol representing 1 donor. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA with Bonferroni’s multiple comparisons test (A and C; T cell population specific).