Considering these factors and observations in the STAT1-CC model system, we designed a cell-based luciferase reporter assay for measuring type I-dependent ISRE activity. This assay proved to yield excellent signal-to-background and Z factors, specificity for IFN-b treatment over IFN-c treatment, and suitability for automation and screening. Furthermore, because the construct design uses the Click Beetle Green luciferase, the assay can be paired with other luciferase reporter genes to develop dual color assays to report activity of other signaling pathways, including the type II IFN-c activated sequence (GAS) promoter activity that mediates defense against intracellular bacteria. A related approach was used to screen for small molecules that increase GAS activity for anti-proliferative and pro-apoptotic effects in cancer cells [39] . Others screened for compounds that inhibit Type I IFN production and signaling [40] . An ISRE-RFP reporter system has also been used to screen for assessing the effects of immunostimulatory RNA [41] . Others have used a less directed approach to screen for compounds that might use any mechanism to decrease viral levels [40, [42] [43] [44] [45] . However, to our knowledge, the present study conducts the first semi-quantitative screen measuring ISRE activity to discover small molecule enhancers of the type I IFN signaling pathway as broad-spectrum antiviral therapeutics.