Supply of T-cells with adequate energy carriers deficient in patients suffering from Covid-19
In Covid-19 patients, the metabolism produces energy-rich ketone bodies in insufficient amounts. However, these energy carriers are needed by both helper and killer T-cells in order to fight the virus effectively. Perhaps this finding explains why some people become much more seriously ill than others. A study led by ImmunoSensation2 member Prof. Christoph Wilhelm at least points in this direction. The results have now been published in the journal Nature. They also give hope for new therapeutic approaches.
Infections often are accompanied by a loss in appetite. The consequence is a reduced supply with carbohydrates, which induces a metabolic switch towards fat burning. In this, ketone bodies generated from Acetyl-CoA, provide a high energy source, helping our bodies cope better with pathogens.
At least that is what the results of the current study suggest. "We found that patients with viral flu produce ketone bodies in large quantities," explains Prof. Dr. Christoph Wilhelm from the Institute of Clinical Chemistry and Clinical Pharmacology at the University Hospital Bonn. "In contrast, we saw little increase in Covid-19 patients, at least in those with a moderate or severe course."
It was furthermore noticeable that those infected with the coronavirus had lower levels of cytokines in their blood. This was especially true for interferon-gamma, secreted by helper T cells in order to recruit macrophages and further immune cells to the site of infection. For this, however, the helper T cells apparently require an adequate supply of ketone bodies. If this is missing, they produce less interferon-gamma. Moreover, the helper cells then die earlier.
Ketone bodies make immune system more powerful
The researchers also saw similar effects in another important group of immune cells, the killer T cells. "They too require ketone bodies to function well and effectively eliminate the virus," says Dr. Christian Bode, lecturer at the Department of Anesthesiology and Surgical Intensive Care Medicine at the University Hospital Bonn. Apparently, the ketone bodies cause a certain metabolic pathway to be activated in the immune cells. This not only ensures improved energy production, but also provides molecules needed for interferon production.
"Without an adequate supply of ketone bodies, on the other hand, the killer T cells and helper T cells show signs of exhaustion," Bode explains. "In this depleted state, they can no longer perform their function adequately." However, the researchers were able to revive the immune cells by placing sick mice on a ketogenic, or low-carbohydrate, diet or by administering ketone bodies directly. The animals were then better able to eliminate the virus. They also developed significantly less lung damage.
Hope for new treatment options
The results therefore also give hope for new treatment options. "It may be possible to increase the clout of the body's defenses by making specific dietary changes," Wilhelm says. "Further studies must now show whether this really works." The researchers expressly advise against self-experimentation with dietary supplements or diets, which could do more harm than good.
The new findings could also be relevant in other infections. In the medium term, they may even contribute to new strategies to help the body fight tumors.
Participating institutions and funding
In addition to the University Hospital and the University of Bonn, the TU Braunschweig and the University Hospitals of Hannover, Zurich, Nijmegen and Essen were involved in the study. The study was funded by the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), the European Research Council (ERC), and the Netherlands Organization for Scientific Research (NWO).
Publication
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 de Nooijer, Peter Pickkers, Jan Lukas Kleiner, Marc Moritz Berger, Thorsten Brenner, Christian, Putensen, Bonn COVIMMUNE Consortium, Hiroki Kato, Natalio Garbi, Mihai G. Netea,Karsten Hiller, Katarzyna Placek, Christian Bode & Christoph Wilhelm; Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19; Nature; https://www.nature.com/articles/s41586-022-05128-8
Contact
Institute for Clinical Chemistry and Clinical Pharmacology
University Hospital Bonn
Tel.: +49 (0)228/287-51721
E-Mail: cwilhelm(at)uni-bonn.de
