Our results show that Ifit2 2/2 mice are highly susceptible to intranasal VSV infection and the effect is gene dosage-dependent: Ifit2 +/2 mice had an intermediate susceptibility phenotype. Infected Ifit2 2/2 mice displayed symptoms of severe neuropathogenesis late after VSV infection accompanied by efficient replication of the virus in many regions of the brain. However, virus replication was restricted to neurons and did not spread to other types of cells in the brain, such as astrocytes. Our results are consistent with the hypothesis that prior, IFN-induced, Ifit2 expression in the brain restricts VSV replication. Supporting genetic evidence for the requirement of IFN action is provided by the high susceptibility of the IFNAR 2/2 mice, which possess the functional Ifit2 gene but Ifit2 is not induced by VSV infection because these mice cannot respond to type I IFN. Additional evidence comes from a previous study using brain-specific IFNAR 2/2 mice, which displayed a pattern of susceptibility to intranasal VSV infection similar to that of our Ifit2 2/2 mice [1] . In our experimental system, the source of the IFN production was Figure 5C ). Ifit2 was also induced at this time in the rest of the brain, without any induction of IFN mRNA ( Figure 5D ) suggesting that the source of IFN was the OB. In accord with the well-established concept of IFN action, pre-induction of Ifit2 in neurons, before the onset of infection, was essential for the antiviral effect. In comparison, induction of IFN and Ifit2 that was concomitant with VSV infection failed to have an appreciable antiviral effect, as manifested by robust virus replication at directly infected sites, such as the OBs of wt mice infected intranasally ( Figure 3D ) or the brain of wt mice infected intracranially ( Figure 6B ). High mortality of the infected mice correlated with high virus titers in the brains of intranasally infected Ifit2 2/2 mice or intracranially infected wt and Ifit2 2/2 mice. In the intranasally infected Ifit2 2/2 mice, death was not preceded by widespread apoptosis in the brain ( Figure S4 ). However, as expected with high viral loads, IFN and other cytokines and chemokines were strongly induced ( Figures 5D, S2 and S3A) ; consequently, many ISGs, except Ifit2, were also induced (Table S1) .