Mechanistic insights into sensitization/desensitization of IFNα signaling and its effect on patient treatment strategies.

Abstract: Interferon alpha (IFNα) orchestrates the antiviral response in hepatocytes as a key component of the innate immune system. The IFNα signal transduction pathway is known to desensitize upon activation, which constitutes a significant problem for using IFNα as a treatment against chronic viral infections or as an anti-tumor drug. However, the mechanisms that lead to this desensitization remain poorly understood. In collaboration with the German Cancer Research Center, we developed an ODE model that describes the biochemical reaction network of IFNα signaling in different hepatoma cell lines and primary human hepatocytes. This talk will present how we learned from the model that, in addition to a dose-dependent desensitization mediated by the negative feedback components SOCS1 and USP18 acting at the receptor level, the IFNα signaling pathway can also show (hyper-)sensitization/priming due to upregulation of the intra-cellular components IRF9 and STAT2. In addition, we will discuss how the findings from this research help us to understand and predict the dynamics of the production of Interferon Stimulated Genes (ISGs), which exert numerous antiviral and anti-inflammatory effector functions, and how this fosters patient-individual optimization of IFNα treatment strategies.