PROJECT SUMMARY Infection causes inflammation, which contributes to pathogen clearance and survival of the host organism. However, failure to regulate the inflammatory response can often lead to multiple organ damage and lethality for the host. In the current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with elevated cytokine levels are often associated with severe symptoms and mortality. This indicates hyper-activation of specific inflammatory molecules might be as much a contributing factor to mortality and morbidity as the virus itself. Thus, there is a dire need to better understand the gene activation dynamics upon infection and develop therapies to manage the inflammatory response. In 2016 we have shown that epigenetic inhibition of factors controlling chromatin remodeling of inflammatory genes, like Topoisomerase 1, can reduce inflammatory gene expression and rescue lethality during bacterial and viral infection, suggesting that these effects may be applicable in the setting of COVID-19 as well. Topoisomerase 1 inhibitors are FDA approved and in the list of WHO essential medicines, thus their widespread usage and cheap cost can be leverage if they are active against COVID-19 as they are in many other infections. In this proposal, we will characterize the role of Top1 and epigenetic factors controlling chromatin topology during SARS-CoV-2 infection and will test the feasibility of use of Top1 inhibitors as drugs for the treatment of COVID-19 in animal models. We will perform mechanistic and preclinical test using epigenetic inhibitors in comparison with immune blockers used in clinical trials and the current standard of care (glucocorticoids).