Fig. 2.

A schematic layout on STAT dependent IFN-1 signalling, a key contributor to the cytokine storm in SARS-CoV-2 infected individuals and the action of IVM. A) The IFN-I signalling pathway showing JAK1 and TYK2 being activated upon binding of Interferon-1 (IFN-I) at the IFN-1 receptor (IFN-IR). In a normal scenario, STAT1 is predominantly activated to induce interferon-stimulated genes (ISGs)-(STAT1-ISGs) via (STAT1/STAT2/IRF9) complex, known as ISGF3 (not shown here). STAT3 activation is also present here albeit small. B) Upon SARS-CoV-2 infection the activity of STAT1 is inhibited by SARS-CoV-2 proteins (NSP1 and ORF6), leading to the upregulation of STAT3 activity that subsequently induces STAT3-ISGs. Following this, the PIAS1 and PIAS3 regulate the binding activity of STAT1 and STAT3 to the DNA respectively, via negative feedback. However, upon infection, the hyperactivation of STAT3 represses the miR-34a, an inhibitor for plasminogen activator inhibitor-1 (PAI-1), inadvertently enhancing the level of PAI-1, which in turn inhibits the activity of PIAS3. To further stress, the epidermal growth factor receptor (EGFR) produced from the reduced STAT1 activity also activates STAT3, leading to enhanced production of cytokine and chemokines. Here, IVM inhibits STAT3 activity, subsequently reducing inflammatory IL-6 cytokine production, preventing cytokine storm and ADRS. IVM also binds to the viral S protein, thereby prohibiting the attachment of S protein to the host ACE2 receptors for viral entry and reducing the viral load.