Fig. 2

Interferon (IFN) therapy following SARS-CoV-2 infection induces cytokine storm, organ damage, and lethality. SARS-CoV-2 has evolved to evade innate immune sensing mechanisms. Several components from SARS-CoV-2 inhibit type I IFN production by interfering with molecules involved in IFN production such as melanoma differentiation-associated protein 5 (MDA5), mitochondrial antiviral signaling (MAVS), tumor necrosis factor receptor-associated factor (TRAF)-associated NF-κΒ (TANK)-binding kinase 1 (TBK1), and IFN regulatory factor 3 (IRF3). To overcome this, IFN therapy has been suggested to treat patients with COVID-19. However, IFNs induce multiple IFN stimulated genes (ISGs), which can have both anti-viral as well as pro-death functions. Z-DNA binding protein 1 (ZBP1) is one such molecule which senses viral RNA to assemble the ZBP1-PANoptosome, thereby executing PANoptosis to drive cytokine storm, organ damage, and even lethality. This can impact the efficacy of IFN therapy in COVID-19. Strategies to inhibit ZBP1 could improve the efficacy of IFN therapy in patients with COVID-19