Glycyrrhizin prevents SARS-CoV-2 S1 and Orf3a induced high mobility group box 1 (HMGB1) release and inhibits viral replication

• Published in: Cytokine (Philadelphia, Pa.) Pa.), 2021-06, Vol.142, p.155496-155496, Article 155496
• Main Authors: Gowda, Pruthvi, Patrick, Shruti, Joshi, Shanker Datt, Kumawat, Rajesh Kumar, Sen, Ellora
• Format: Article
• Language: English
• Subjects: A549 Cells; COVID-19; COVID-19 - genetics; COVID-19 - metabolism; COVID-19 Drug Treatment; Cytokine; Ferritin; Glycyrrhizic Acid - pharmacology; HMGB1; HMGB1 Protein - genetics; HMGB1 Protein - metabolism; Humans; Macrophages; SARS-CoV-2; SARS-CoV-2 - physiology; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; U937 Cells; Viroporin Proteins - genetics; Viroporin Proteins - metabolism; Virus Replication - drug effects
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2021.155496

[Display omitted] •SARS-CoV-2 viral proteins S-RBD and Orf3a-induced extracellular HMGB1 triggers pyroptosis in lung cells.•S-RBD and Orf3a induce the release of HMGB1, IL-6, IL-8 and ferritin from macrophages.•HMGB1 inhibitor glycyrrhizin attenuates cytokine and ferritin release from macrophages.•Glycyrrhizin inhibits SARS-CoV-2 replication in a dose-dependent manner in Vero E6 cells. 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. COVID-19 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 IL-1β and extracellular HMGB1 levels. Glycyrrhizin mitigated viral proteins-induced lung cell pyroptosis and activation of macrophages. Heightened release of proinflammatory 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 proinflammatory mediators might constitute a viable therapeutic option in patients with SARS-CoV-2 infection.