Although no viral production was observed in both ISG15+/+ and ISG15−/− macrophages (Figure S2), when we visualized the effect of FluV infection by phase-contrast microscopy, a clear CPE was evident in the ISG15+/+ macrophages with the course of infection, whereas the ISG15−/− macrophages remained unaltered with no obvious signs of viral infection-induced cell death (Fig. 5C). This evidence concerns the gene ISG15 and viral infectious disease.