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.
View: Text | PDF
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

×

Figure 6

Dexamethasone mitigates ROS accumulation and basigin expression and related gene signatures in COVID-19 patient T cells.

Options: View larger image (or click on image) Download as PowerPoint
Dexamethasone mitigates ROS accumulation and basigin expression and rela...
(A and B) Cohort 2 (coh2) blood samples were enriched for PBMCs, cryopreserved, and processed (see Figure 2). Heatmaps presenting hierarchically clustered and scaled expression data (filtered for absolute logFC > 1, logCPM and logRPKM > 1, and FDR < 0.05) and gene set enrichment analysis of the HALLMARK pathways, as analyzed in CI (see Figure 2, E and F) of CD4+ T cells (A) or CD14+ monocytes (B). Shown are differentially expressed genes in severe/critical patients taken in the first 14 days after dexamethasone cessation (coh2 early) or beyond (coh2 late, time point comparable to CI; 3 samples each time point, 2 paired early and late patient samples). Displayed is the comparison with CI controls (see Figure 2, A–F). Each column corresponds to an individual sample. A list of all read counts can be found in the supplemental material. (C–F) Blood samples were drawn and processed the same day. (C) Cytosolic ROS levels of CD3+ T cells from controls and severe/critical patients of CI and CII analyzed in the same period of time after ICU hospitalization (see Figure 5A). MFI, median fluorescence intensity. (D) Cytosolic ROS levels in CD4+ and CD8+ T cells and CD14+ monocytes of CII grouped according to time point analyzed. (E) Basigin expression of CD3+ T cells from controls and severe/critical patients of CI and CII analyzed in the same period of time after ICU hospitalization (see Figure 5A). Basigin expression of CD4+ and CD8+ T cells and CD14+ monocytes of CII grouped according to time point analyzed (F). Each symbol in C–F represents 1 donor. *P < 0.05; **P < 0.01; ***P < 0.001 by Mann-Whitney U test (C and E) or 1-way ANOVA with Bonferroni’s multiple comparisons test (D and F).