I19 Antiviral actions of the interferon-inducible IFIT proteins

Antiviral actions of the interferon-inducible IFIT proteins Ganes Sen, Volker Fensterl, Jamie Wetzel The ISG56/IFIT genes are a multi-member family of interferon-inducible genes; there are four members in human and three in mouse. All IFIT proteins contain multiple TPR motifs which mediate protein-protein interactions. Some, but not all, members inhibit initiation of protein synthesis by binding to the translation initiation factor eIF-3 or by binding to the 5′ end of the mRNA. The murine Ifit1 encodes P56, Ifit2 encodes P54 and Ifit3 encodes P49. For investigating the biological functions of the murine Ifit proteins, we have recently generated several knock-out mice. Challenging Ifit1-/- and Ifit2-/- mice with various viruses have revealed their strong, but selective, antiviral properties. Ifit1-mediated host restriction was shown to be evaded by 2′-O-methylation of viral mRNAs. Flavivirus (West Nile Virus), vaccinia virus and coronavirus mutants, that lack 2′-O-methylation of their mRNAs, were growth-restricted in Wt, but not in Ifit1-/-, cells and mice. Further studies revealed that the action of Ifit1 on WNV replication is highly manifested in CNS infection, a deficiency of Ifit1 causing increased neuronal death in infected mice. Ifit2, on the other hand, blocked neuro-pathogenesis caused by intranasal infection with the rhabdovirus, VSV. All Ifit proteins were induced in the CNS of the infected mice, but Ifit1-/- mice were not more susceptible than Wt mice and most of the infected mice survived. In contrast, all Ifit2-/- mice died from neuro-pathogenesis; VSV replicated efficiently in the neurons of these mice. However, there was no effect on pathogenesis by another neuro-tropic virus, EMCV. Moreover, VSV did not replicate efficiently in the liver or the lung of infected Ifit2-/- mice and in vitro, in MEF or primary fetal neurons, the sensitivity of VSV replication to IFN-treatment was similar in Wt and Ifit2-/- cells. These results demonstrated the existence of tissue-, virus- and ISG-specific antiviral actions of interferon.