While ISG15−/− mice were not more susceptible to VACV wild type virus infection, this might be explained by the capacity for VACV to inhibit IFN signaling and therefore ISG15 induction during infection in vivo. In fact, a VACV with enhanced IFN induction due to the deletion of E3L displayed higher pathogenicity in ISG15−/− mice [10]. This evidence concerns the gene ISG15 and viral infectious disease.