tetano
Editor, Senior Moderator
J Clin Invest
. 2021 Nov 15;131(22):e148225.
doi: 10.1172/JCI148225.
Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone
Peter J Siska[SUP] 1 [/SUP], Sonja-Maria Decking[SUP] 1 2 [/SUP], Nathalie Babl[SUP] 1 [/SUP], Carina Matos[SUP] 1 [/SUP], Christina Bruss[SUP] 1 [/SUP], Katrin Singer[SUP] 1 3 [/SUP], Jana Klitzke[SUP] 1 [/SUP], Marian Schön[SUP] 4 [/SUP], Jakob Simeth[SUP] 4 [/SUP], Josef Köstler[SUP] 5 [/SUP], Heiko Siegmund[SUP] 6 7 [/SUP], Ines Ugele[SUP] 3 [/SUP], Michael Paulus[SUP] 8 [/SUP], Alexander Dietl[SUP] 8 [/SUP], Kristina Kolodova[SUP] 1 2 [/SUP], Louisa Steines[SUP] 9 [/SUP], Katharina Freitag[SUP] 1 [/SUP], Alice Peuker[SUP] 1 [/SUP], Gabriele Schönhammer[SUP] 1 [/SUP], Johanna Raithel[SUP] 2 [/SUP], Bernhard Graf[SUP] 10 [/SUP], Florian Geismann[SUP] 8 [/SUP], Matthias Lubnow[SUP] 8 [/SUP], Matthias Mack[SUP] 9 [/SUP], Peter Hau[SUP] 11 [/SUP], Christopher Bohr[SUP] 3 [/SUP], Ralph Burkhardt[SUP] 12 [/SUP], Andre Gessner[SUP] 5 [/SUP], Bernd Salzberger[SUP] 13 [/SUP], Ralf Wagner[SUP] 5 [/SUP], Frank Hanses[SUP] 13 14 [/SUP], Florian Hitzenbichler[SUP] 13 [/SUP], Daniel Heudobler[SUP] 1 15 [/SUP], Florian Lüke[SUP] 1 [/SUP], Tobias Pukrop[SUP] 1 15 [/SUP], Wolfgang Herr[SUP] 1 [/SUP], Daniel Wolff[SUP] 1 2 [/SUP], Rainer Spang[SUP] 4 [/SUP], Hendrik Poeck[SUP] 1 [/SUP], Petra Hoffmann[SUP] 1 2 [/SUP], Jonathan Jantsch[SUP] 5 [/SUP], Christoph Brochhausen[SUP] 6 7 [/SUP], Dirk Lunz[SUP] 10 [/SUP], Michael Rehli[SUP] 1 2 [/SUP], Marina Kreutz[SUP] 1 2 [/SUP], Kathrin Renner[SUP] 1 2 [/SUP]
Affiliations
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.
Keywords: Inflammation; Metabolism; Mitochondria; Monocytes; T cells.
. 2021 Nov 15;131(22):e148225.
doi: 10.1172/JCI148225.
Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone
Peter J Siska[SUP] 1 [/SUP], Sonja-Maria Decking[SUP] 1 2 [/SUP], Nathalie Babl[SUP] 1 [/SUP], Carina Matos[SUP] 1 [/SUP], Christina Bruss[SUP] 1 [/SUP], Katrin Singer[SUP] 1 3 [/SUP], Jana Klitzke[SUP] 1 [/SUP], Marian Schön[SUP] 4 [/SUP], Jakob Simeth[SUP] 4 [/SUP], Josef Köstler[SUP] 5 [/SUP], Heiko Siegmund[SUP] 6 7 [/SUP], Ines Ugele[SUP] 3 [/SUP], Michael Paulus[SUP] 8 [/SUP], Alexander Dietl[SUP] 8 [/SUP], Kristina Kolodova[SUP] 1 2 [/SUP], Louisa Steines[SUP] 9 [/SUP], Katharina Freitag[SUP] 1 [/SUP], Alice Peuker[SUP] 1 [/SUP], Gabriele Schönhammer[SUP] 1 [/SUP], Johanna Raithel[SUP] 2 [/SUP], Bernhard Graf[SUP] 10 [/SUP], Florian Geismann[SUP] 8 [/SUP], Matthias Lubnow[SUP] 8 [/SUP], Matthias Mack[SUP] 9 [/SUP], Peter Hau[SUP] 11 [/SUP], Christopher Bohr[SUP] 3 [/SUP], Ralph Burkhardt[SUP] 12 [/SUP], Andre Gessner[SUP] 5 [/SUP], Bernd Salzberger[SUP] 13 [/SUP], Ralf Wagner[SUP] 5 [/SUP], Frank Hanses[SUP] 13 14 [/SUP], Florian Hitzenbichler[SUP] 13 [/SUP], Daniel Heudobler[SUP] 1 15 [/SUP], Florian Lüke[SUP] 1 [/SUP], Tobias Pukrop[SUP] 1 15 [/SUP], Wolfgang Herr[SUP] 1 [/SUP], Daniel Wolff[SUP] 1 2 [/SUP], Rainer Spang[SUP] 4 [/SUP], Hendrik Poeck[SUP] 1 [/SUP], Petra Hoffmann[SUP] 1 2 [/SUP], Jonathan Jantsch[SUP] 5 [/SUP], Christoph Brochhausen[SUP] 6 7 [/SUP], Dirk Lunz[SUP] 10 [/SUP], Michael Rehli[SUP] 1 2 [/SUP], Marina Kreutz[SUP] 1 2 [/SUP], Kathrin Renner[SUP] 1 2 [/SUP]
Affiliations
- PMID: 34779418
- DOI: 10.1172/JCI148225
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.
Keywords: Inflammation; Metabolism; Mitochondria; Monocytes; T cells.