Our results revealed several layers of specificity of IFN action, some of which were not anticipated. First, compared to Ifit2 2/2 mice, Ifit1 2/2 mice were much less susceptible to intranasal VSV infection; this was true for both low and high doses of virus. This finding was surprising in view of a recent report on VSV susceptibility of Ifit1 2/2 mice [18] and the observation that Ifit1, but not Ifit2, could bind VSV leader RNA in vitro ( Figure S6) . The above results demonstrate that different Ifit proteins have nonredundant functions in vivo. The second layer of specificity was directed toward the nature of the infecting virus. Although both VSV and EMCV caused neuroinvasive disease, induced IFN-b, Ifit1 and Ifit2 in the brain and type I IFN action was required for protection against both viruses, Ifit2 was critical only for protection against VSV; the absence of either Ifit1 or Ifit2 did not exacerbate susceptibility to EMCV. The third layer of specificity was revealed by the organ-specific action of Ifit2. In the complete absence of type I IFN action in the IFNAR 2/2 mice, intranasally infected VSV replicated vigorously not only in brains, but also in livers and lungs ( Figure 7A-C) . In contrast, in Ifit2 2/2 mice, efficient VSV replication was restricted to the brain suggesting that Ifit2 does not act as an anti-VSV ISG in the liver or the lung because its absence did not impact virus titers, even though Ifit2 was induced in these organs of infected wt mice ( Figure 7D and 7E) . The efficient VSV replication in livers and lungs of IFNAR 2/2 mice, but not wt and Ifit2 2/2 mice, indicates that other ISGs must have anti-VSV effects in those organs. Further investigation is needed to determine the basis of neuronal specificity of Ifit2 action and the identities of other ISGs that inhibit VSV replication in other organs.