The protective effect of type I IFN signaling and in particular, Ifit2, against VSV neuropathogenesis prompted us to confirm its expression in OB and brain of wt mice, and whether it was induced in a type I IFN-dependent manner. In wt OB, Ifit2, Ifit1, and IFN-b mRNA was induced strongly by 2 d.p.i., and Ifit2 and Ifit1 RNA remained abundant until day 6 d.p.i. (Figure 5A ). The induction of these genes was dependent on type I IFN receptor in OB as well as in brain ( Figure 5B and 5E, and data not shown). Ifit2 suppresses VSV replication in the brain after intranasal infection. A, infectious VSV titers in wt and Ifit2 2/2 brains at 2 and 6 days after intranasal infection, plotted as pfu/g with mean on log scale; dashed line depicts threshold of detection. B, VSV RNA levels in brains of uninfected or VSV-infected wt, Ifit2 2/2 and IFNAR 2/2 mice at 2 or 6 d.p.i., plotted as mean+SD on log scale. C, VSV RNA levels in different regions of the brains of uninfected or VSV-infected wt and Ifit2 2/2 mice at 6 d.p.i., plotted as mean+SD on log scale. D, VSV P protein in midbrain neurons of Ifit2 2/2 mice at 6 d.p.i.; detection by immunohistofluorescence-labeling of VSV-P (red) and neuron (NeuN) or astrocyte (GFAP) markers (green); in A and B: n = 4-8 mice per infected group accumulated from three independent experiments; in C: n = 4 mice per infected group; in D: n = 2 mice per infected group; all infections in A-D were intranasal with 4610 2 pfu of VSV. ND, none detected. Brains in A and B were separated from OBs assayed in Figure 3D and 3C, respectively. Asterisks indicate statistical significance: *** p#0.0009; n.s.: not significant. doi:10.1371/journal.ppat.1002712.g004