Glycyrrhizin prevents SARS-CoV-2 S1 and 3a induced High Mobility Group Box 1 (HMGB1) release and inhibits viral replication

Gowda, Pruthvi; Patrick, Shruti; Dutt Joshi, Shankar; Kumar Kumawat, Rajesh; Sen, Ellora

Efforts to understand host factors critical for COVID-19 pathogenesis have identified high mobility group box 1 (HMGB1) to be crucial for regulating susceptibility to SARS-CoV-2. COVID19 disease severity is correlated with heightened inflammatory responses, and HMGB1 is an important extracellular mediator in inflammation processes.In this study, we evaluated the effect of HMGB1 inhibitor Glycyrrhizin on the cellular perturbations in lung cells expressing SARS-CoV-2 viral proteins. Pyroptosis in lung cells transfected with SARS-CoV-2 S-RBD- and Orf3a, was accompanied by elevation of extracellular HMGB1 and IL-1β levels. Glycyrrhizin mitigated viral proteins- induced lung cell pyroptosis and activation of macrophages. Heightened release of pro-inflammatory cytokines IL-1β, IL-6 and IL-8 as well as ferritin from macrophages, cultured in conditioned media from lung cells expressing SARS-CoV-2 S-RBD and Orf3a was attenuated by glycyrrhizin. Importantly, Glycyrrhizin inhibited SARS-CoV-2 replication in Vero E6 cells without exhibiting cytotoxicity at high doses. The dual ability of Glycyrrhizin to concomitantly halt virus replication and dampen pro-inflammatory mediators might constitute a viable therapeutic option in patients with SARS-CoV-2 infection.