ISG15 and smallpox: Since VVΔE3L pre-immunized ISG15 KO mice developed disease transiently after i.n WR challenge and the upper respiratory tract is a natural route for variola virus infection, we next evaluated disease progression in ISG15+/+ and ISG15−/− mice after i.n inoculation with WR and several E3L deletion mutants (VVΔE3L; VVE3LΔ83N and VVE3LΔ26C).