− At least 158 putative ISG15 target proteins are identified, with important roles in IFN-I response − Upregulation of ISGs results in an antiviral state and reduction of viral spread − Holds a critical role of innate immune response at the initial infection stages − Acts as a cytokine to exacerbate SCOV2-triggered inflammation − Regulated by viral RNA sensors, including IFIH1 (MDA5). The gene discussed is ISG15; the disease is infection.