Journal Article

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

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

2021

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adult / Apoptosis / Basigin - physiology / Biomedical research / CD147 antigen / Cell metabolism / Coronaviruses / COVID-19 / COVID-19 - immunology / COVID-19 - metabolism / Cyclophilin A - physiology / Dexamethasone / Dexamethasone - pharmacology / Diabetes / Disease / Fatty acids / Fatty Acids - metabolism / Female / Glucose / Health aspects / Humans / Hypoxia / Immune response / Infections / Leukocytes (granulocytic) / Ligands / Lymphocytes / Lymphocytes T / Male / Membrane proteins / Metabolic pathways / Metabolic regulation / Metabolism / Middle Aged / Mitochondria / Mitochondria - pathology / Monocytes / Oxidative stress / Pathogenesis / Patients / Reactive oxygen species / Reactive Oxygen Species - metabolism / Recovery (Medical) / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Spike protein / Steroids / T cells / T-Lymphocytes - metabolism / Transcription / Viral infections