Profiling the glucocorticoid receptor activation during SARS-CoV-2 infection (ProGReS)

• Applicants: Dr. Nils Gassen; Professor Dr. Marcel Müller
• Subject Area: Virology ; Clinical Immunology and Allergology ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535619751

Coronavirus disease-2019 (COVID-19) poses an ongoing threat to global health and economic welfare. The successful introduction of vaccines, antivirals (paxlovid, molnupiravir) and anti-inflammatory glucocorticoids (GCs) such as dexamethasone have contributed to reduced mortality and improved patient outcomes. Nevertheless, affordable and accessible treatments are still urgently needed for those who have limited access to vaccines or expensive drugs, and for those who experience vaccine failures with subsequent breakthrough infections. In addition, the continued emergence of SARS-CoV-2 variants of concern, harboring mutations with receptor and immune escape properties, and the threat of newly emerging pathogens encourage the identification of broad-acting host-directed antiviral and/or anti-inflammatory drugs. GCs have been widely used during the SARS-CoV-2 pandemic with overall beneficial outcomes for COVID-19 patients. However, correct timing and dosage of GC applications is crucial, as GC treatment in the absence of severe disease not requiring respiratory support has been shown to worsen patient outcomes. Little is currently known about how GCs influence coronavirus propagation and virus-host interaction on a mechanistic level. Our own published and preliminary studies suggest that highly pathogenic viruses like SARS-CoV-2 exploit the GC-activating, evolutionary conserved, glucocorticoid receptor (GR) signaling pathway and disrupt the cellular immunometabolism to create an optimal environment for virus propagation. In this proposal, we therefore hypothesize that the GR signaling pathway is a promising target for the development of new GR-modulating drugs with combined broad-range antiviral and anti-inflammatory features. To achieve our goals, we first aim to characterize the dynamics of distinct GR signaling transduction cycles by monitoring post-translational GR regulation and signaling targets during SARS-CoV-2 infection in cell culture models. Secondly, we want to identify novel key modulators of immunometabolic pathways during defined GR activation cycles in SARS-CoV-2-infected epithelial and immune cells. Thirdly, we aim to confirm newly identified key cellular GR signaling modulators by loss- and gain-of-function, identify SARS-CoV-2-relevant protein interactions, and test GR-based treatment strategies using cell- and patient-reflecting organoid-based in vitro models. By characterizing the mechanistic details of GR signaling during SARS-CoV-2 infection, we aim to identify novel targets for combined antiviral and immunomodulatory interventions and, as a long-term goal, use rational drug design as an approach to developing GR-based clinical therapies.

• DFG Programme: Research Grants