Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19

Fotios Karagiannis, Konrad Peukert, Laura Surace, Marcel Michla, Fabian Nikolka, Mario Fox, Patricia Weiss, Caroline Feuerborn, Paul Maier, Susanne Schulz, Burcu Al, Benjamin Seeliger, Tobias Welte, Sascha David, Inge Grondman, Aline H. Nooijer, Peter Pickkers, Jan Lukas Kleiner, Marc Moritz Berger, Thorsten Brenner, Christian Putensen, Hiroki Kato, Natalio Garbi, Mihai G. Netea, Karsten Hiller, Katarzyna Placek, Christian Bode () and Christoph Wilhelm ()
Additional contact information
Fotios Karagiannis: University Hospital Bonn, University of Bonn
Konrad Peukert: University Hospital Bonn
Laura Surace: University Hospital Bonn, University of Bonn
Marcel Michla: University Hospital Bonn, University of Bonn
Fabian Nikolka: Technische Universität Braunschweig
Mario Fox: University Hospital Bonn
Patricia Weiss: University Hospital Bonn, University of Bonn
Caroline Feuerborn: University Hospital Bonn
Paul Maier: University Hospital Bonn, University of Bonn
Susanne Schulz: University Hospital Bonn
Burcu Al: University of Bonn
Benjamin Seeliger: Hannover Medical School
Tobias Welte: Hannover Medical School
Sascha David: University Hospital Zürich
Inge Grondman: Radboud University Medical Center
Aline H. Nooijer: Radboud University Medical Center
Peter Pickkers: Radboud University Medical Center
Jan Lukas Kleiner: University Hospital Bonn
Marc Moritz Berger: University Hospital Essen, University Duisburg-Essen
Thorsten Brenner: University Hospital Essen, University Duisburg-Essen
Christian Putensen: University Hospital Bonn
Hiroki Kato: University Hospital Bonn, University of Bonn
Natalio Garbi: University Hospital Bonn, University of Bonn
Mihai G. Netea: University of Bonn
Karsten Hiller: Technische Universität Braunschweig
Katarzyna Placek: University of Bonn
Christian Bode: University Hospital Bonn
Christoph Wilhelm: University Hospital Bonn, University of Bonn

Nature, 2022, vol. 609, issue 7928, 801-807

Abstract: Abstract Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including β-hydroxybutyrate (BHB)1–6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Date: 2022
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DOI: 10.1038/s41586-022-05128-8

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