In this study we have demonstrated that VitD's anti-viral mechanisms can be linked to its ability to increase host IFN-α/β signaling both in vitro and in clinical settings among COVID-19 hospitalized patients by augmenting the signaling of RIG-1/MDA-5 and JAK-STAT pathways and the resultant MX-1 and ISG-15 antiviral ISGs (Fig. 5). Here, ISG15 is linked to COVID-19.