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 1

ROS accumulation in T cells from progressed COVID-19 patients is reversible and correlates with changes in mitochondrial mass and architecture.

Options: View larger image (or click on image) Download as PowerPoint
ROS accumulation in T cells from progressed COVID-19 patients is reversi...
Blood was drawn and processed the same day. Erythrocytes were removed and immune cells were stained for population-specific surface markers. The results show comparisons between specified COVID-19 patient subgroups, critically ill non–COVID-19 patients (ICU non-COVID), and healthy controls. (A) ROS levels, (B) mitochondrial content in CD3+ T cells, and (C) percentage of CD3+ cells among viable cells. MFI, median fluorescence intensity. (D) Cytosolic ROS levels, (E) mitochondrial content in CD14+ monocytes, and (F) proportion of CD14+ monocytes among the CD11b+ myeloid population. (G) Cytosolic ROS levels, (H) mitochondrial content in CD66b+ granulocytes, and (I) proportion of CD66b+ granulocytes among CD11b+ myeloid cells. Shown are representative histograms of ROS staining in CD3+ and CD14+ cells of each group. Shown is the median + SEM, and each symbol represents 1 donor. *P < 0.05; **P < 0.01; ***P < 0.001 by 1-way ANOVA with Bonferroni’s multiple comparisons test. Analysis of mitochondrial structure by electron microscopy in lymphocytes from healthy control cells, a COVID-19 patient with mild symptoms (J), of 2 COVID-19 patients with severe symptoms (K), and a critically ill non–COVID-19 patient (L). Scale bars: 10 μm. Shown are representative examples.