Interferon action in triply deficient mice reveals the existence of alternative antiviral pathways

Antiviral proteins encoded by the interferon (IFN)-stimulated genes provide a front-line defense against viral infections. In particular, PKR, RNase L , and Mx are considered to be the principal proteins through which IFNs mou nt: an antiviral state. To determine whether alternative antiviral pathways exist, RNase L-/- mice and PKR-/- mice were crossed onto an Mx1(-/-) backg round to generate a strain of triply deficient (TD) mice. After infections with encephalomyocarditis virus, the TD mice died 3-4 days earlier than inf ected, wild-type mice. However, there was an IFN dose-dependent increase in survival times after encephalomyocarditis virus infections for both the TD and wild-type mice. Mice that were deficient for PKR or RNase L showed int ermediate survival times between those of the TD and wild-type mice. Surpri singly, cultured embryonic fibroblasts lacking RNase L, PKR, or both protei ns were still able to mount a substantial residual antiviral response again st encephalomyocarditis virus or vesicular stomatitis virus after IFN-alpha treatments. These results confirm the antiviral functions of RNase L and P KR in vivo but also provide unequivocal evidence for the existence of novel , innate immune pathways against viruses. (C) 1999 Academic Press.