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Freiburg researchers decipher crucial differences in the signal transmission of antiviral warning systems / A therapy based on this could switch off out-of-control parts of the immune system without weakening the defense against infection

In an international collaboration, scientists at the Medical Center - University of Freiburg have deciphered crucial differences in the signal transduction of two antiviral defense systems. In rare cases, the so-called type I interferon system gets out of control and can trigger severe inflammatory diseases. These diseases are currently treated with drugs, which, however, also unintentionally suppress other parts of the immune system and thus promote an increased risk of infection. The newly discovered differences in the two defense systems make it possible to specifically switch off only the pathogenic part of the immune system. The study was published on May 14 in the renowned journal Science Immunology.

"We were able to decipher an important difference in the signal transmission of two antiviral defense systems. Thanks to this new finding, excessive immune reactions can be treated in a much more targeted manner in the future," says Prof. Dr. Peter Stäheli, research group leader at the Institute for Virology at the Medical Center - University of Freiburg.

If viral infections are recognized by individual cells in the body, these produce warning substances, so-called interferons, which warn neighbouring cells of the impending threat. These can then prepare themselves accordingly and fight off the infection more effectively. While type I interferons act on almost all cells in the body, type III interferons specifically protect the cells in the body that shield us from the outside world and form a protective barrier against infection. If rare genetic defects are present, this can lead to a permanent activation of the antiviral defense systems. An excessive type I interferon reaction then leads to severe inflammatory diseases, which are classified as type I interferonopathies.

Drugs that have already been clinically tested can help

As the effects of type I and type III interferon on the respective target cells are almost identical, it was long assumed that there was no difference in signal transduction between the two systems. Building on previously published findings by the research group led by Prof. Dr. Stephan Ehl, Medical Director of the Center for Chronic Immunodeficiency at the Medical Center - University of Freiburg, scientists from the Institute for Virology in Peter Stäheli's research group have now been able to show the following: The signal transduction of potentially pathogenic type I interferons is much more dependent on the signaling protein TYK2 than that of protective type III interferons. Clinically tested inhibitors that specifically block TYK2 were able to successfully suppress the effect of type I interferon in the new study, while the protective effects of type III interferon were maintained. It was also shown in the mouse model that type III interferons, but not type I interferons, protect against severe influenza virus infection in the absence of TYK2.

"These findings could enable clinicians to offer patients an improved treatment option with a significantly lower risk of infection in the future," explains Dr. Daniel Schnepf from the Institute for Virology at the Medical Center - University of Freiburg, who led the experimental study.

The scientists now want to extend their work to the question of whether such a targeted influence on parts of the immune response could also reduce collateral damage caused by the immune system in viral infections with influenza viruses or SARS-CoV-2.

Original title of the paper: Selective Janus Kinase Inhibition Preserves Interferon-λ-mediated Antiviral Responses.

DOI: 10.1126/sciimmunol.abd5318

Link to the study:https://immunology.sciencemag.org/content/6/59/eabd5318

Contact:
Dr. Daniel Schnepf
Institute for Virology
Uniklinik Freiburg
Phone: 0761 203-6583
daniel.schnepf@uniklinik-freiburg.de