Die Rolle der Ketogenese in der Immunantwort gegen SARS-CoV-2
Anästhesiologie
Zusammenfassung der Projektergebnisse
Fasting and anorexia cause a metabolic swing toward ketogenesis and the formation of ketone bodies, such as beta-hydroxybutyrate (BHB), which are host defense mechanisms against acute infection. Uncertainty persists over whether ketogenesis metabolically affects the immune response in lung infections. Here, we demonstrate that patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not those with influenza-induced ARDS have impaired BHB production. We discovered that BHB encourages CD4+ T cells to survive and produce interferon gamma. By using a metabolic-tracing analysis, we were able to determine that BHB serves as a substitute carbon source for oxidative phosphorylation (OXPHOS), which is necessary for producing glutathione, bioenergetic amino acids, and other compounds vital to maintaining the redox equilibrium. T cells from ARDS patients who had been exposed to SARS-CoV-2 were exhausted and skewed towards glycolysis, but BHB was able to metabolically reprogram them to perform OXPHOS, enhancing their functionality. Last but not least, we demonstrate in mice that a ketogenic diet and the administration of BHB as a ketone ester drink restore CD4+ T cell metabolism and function in severe respiratory infections, therefore lowering the mortality of mice infected with SARS-CoV-2. Altogether, our data show that BHB is a different carbon source that aids T cell responses in lung viral infections and that decreased ketogenesis may be a confounding factor in severe COVID-19. Although therapeutic relevance remains to be assessed, our study highlights the potential of BHB and ketogenic diet as a broadly applicable treatment to improve functional T-cell responses in nutrient-deficient settings often associated with viral infections. Data from the current study could be used as a basis for designing clinical trials. Here, thresholds for low serum BHB concentrations could be defined to identify patients who would benefit from BHB supplementation. Furthermore, the question arises at what point in the disease course from onset of respiratory symptoms to full-blown ARDS is BHB supplementation beneficial? Here, our in vivo experiments suggest that early administration of BHB in particular may favorably influence severe disease courses. In conclusion, this study contributes to a better understanding of how dysregulated host metabolic adaptations to viral infections contribute to worse outcome and lay the groundwork for the evaluation of BHB as a therapeutic option in pulmonary viral infections.
Projektbezogene Publikationen (Auswahl)
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Immundysregulation bei COVID-19-ARDS: Welche Rolle spielt die fehlende Ketogenese? Jahrestagung der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin, 2022
Peukert K., Karagiannis F., Fox M., Schulz S., Feuerborn C., Berger M., Brenner T., Putensen C., Klinman D., Steinhagen F., Wilhelm .C & Bode C.
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Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19. Nature, 609(7928), 801-807.
Karagiannis, Fotios; Peukert, Konrad; Surace, Laura; Michla, Marcel; Nikolka, Fabian; Fox, Mario; Weiss, Patricia; Feuerborn, Caroline; Maier, Paul; Schulz, Susanne; Al, Burcu; Seeliger, Benjamin; Welte, Tobias; David, Sascha; Grondman, Inge; de Nooijer Aline, H.; Pickkers, Peter; Kleiner, Jan Lukas; Berger, Marc Moritz ... & Wilhelm, Christoph
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Wissenschaftliche Arbeitstage der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin, 2022
Peukert K., Karagiannis F., Surace L., David S., Welte T., Pickkers P., Berger M., Brenner T., Putensen C., Netea M.G., Placek K., Wilhelm C. & Bode C.
