Pre-induced Ifit2 prevents efficient VSV replication in the brain, most probably by blocking one or more essential step of the viral life cycle including viral entry, uncoating, primary transcription, viral protein synthesis, RNA replication, virion assembly or egress. It also might block trans-synaptic spread of the virus, although unlike another rhabdovirus, rabies virus, VSV is not known to depend on transit from neuron to neuron. In this context, it is important to note the observations made by Iannacone et al. [37] using a footpad VSV infection model. They concluded that type I IFN, produced by infected macrophages and plasmacytoid dendritic cells in infected mice, blocked infection of peripheral neurons resulting in lowered infection of the CNS and prevention of neuropathogenesis. It is worth noting that in our studies, the absence of Ifit2 did not affect IFN induction by VSV (Figures 5A  and 6C ). Further investigation of the biochemical mechanism behind the observed in vivo effect of Ifit2 2/2 is hampered by the absence of a suitable cell culture model of the phenomenon. For example, Ifit2 was not required for mediating the anti-VSV effect of IFN in mouse embryonic fibroblasts ( Figure S5 ), in primary fetal neurons or in Ifit2-ablated neuroblastoma cells (data not shown), results that are not surprising given the strong tissuespecificity of Ifit2 action observed in vivo (Figure 7) . Specific RNAbinding properties of Ifit proteins have been recently reported [18] . Following this lead, we examined the RNA-binding properties of recombinant murine Ifit1 and Ifit2 using VSV leader RNA as the probe in an electrophoretic mobility shift assay: Ifit1 bound RNA with a 59-ppp end but not with a 59-OH end; however, Ifit2 bound neither ( Figure S6 ). To obtain meaningful leads, future investigation of this kind may require using brain extracts from infected mice to detect protein-viral RNA complexes that may contain Ifit2 along with adult neuronspecific proteins.