STING inhibitors for SARS-CoV2 immunopathology

The central hypothesis is that the detrimental SARS-CoV2-driven hyperinflammation is not triggered by the virus itself, but by the virus-induced tissue damage via cGAS-STING, the mechanism used by cells to sense extracellular DNA as a danger signal that triggers innate immune responses. This hypothesis is based on three observations: 1) SARS-CoV2 pathology is associated with widespread epithelial and endothelial cell death; 2) bats have a non-functional STING gene that allows them to withstand tissue stress during flapping flight and host coronaviruses in the absence of pathology; 3) SARS-CoV2-induced skin manifestations resemble skin lesions of a rare monogenic disease characterised by an activating mutation in the STING gene (SAVI, STING-Associated Vasculopathy with onset in Infancy).

To assess cGAS-STING activation in SARS-CoV2 pathology we will analyse skin manifestations and bronchoalveolar lavage (BAL) from SARS-CoV2 patients. Both show severe epithelial and endothelial cell damage along with macrophage activation and type I IFN expression. Mechanistic studies will be performed in-vitro in SARS-CoV2-infected cultures of epithelial cells, endothelial cells and macrophages. Finally, the therapeutic potential of STING inhibition will be tested in-vivo in a mouse model of SARS-CoV2-induced pneumonia and in ex-vivo cultures of patients’ skin lesions.

We expect to find that the SARS-CoV2 induced damage of endothelial and epithelial cells triggers overt macrophage activation via cGAS-STING-driven self-DNA sensing. Activated macrophages secrete large amounts of type I IFNs leading to the fatal cytokine storm in the lungs. Blocking cGAS/STING-mediated self-DNA sensing using a small STING inhibitor decreases and inhibits inflammation in skin cultures model and blocks pathology in the SARS-CoV2 mouse pneumonia model without dampening anti-viral immune responses driven by the RNA-sensing machinery.

There is still a lack of fundamental knowledge of the mechanisms driving detrimental inflammatory responses in SARS-CoV2 infections. Furthermore, current immunomodulatory therapies used to treat SARS-CoV2 immunopathologies lack a clear rationale and appear to provide only limited clinical benefits. By combining clinical and fundamental research, this project seeks to define the role of innate DNA immunity in SARS-CoV2 pathology and provide innovative new therapeutic targets. This project is timely, as the clinical development of STING inhibitors is pursued by several world-leading pharmaceutical companies for the treatment of SAVI. The proposed studies therefore have the potential to rapidly move from bench to clinical use and potentially change the outcomes of patients with severe SARS-CoV2 pathology.

cGAS-STING-mediated self-DNA sensing in COVID-19 immunopathology