In mammals, the first line of defense against virus infection is the interferon system. Viruses induce synthesis of interferon in the infected cells and its secretion to circulation. Interferon acts upon the as yet uninfected cells and protects them from oncoming infection by inducing the synthesis of hundreds of new proteins, many of which interfere with virus replication. Vesicular stomatitis virus (VSV), a virus similar to rabies virus, is very sensitive to interferon but it is not known which interferon-induced protein inhibits its replication. Here, we have identified a single interferon-induced protein as the protector of mice from death by VSV infection. Knocking out the gene encoding this protein, Ifit2, made mice very vulnerable to neuropathogenesis caused by VSV infection; a related protein, Ifit1, did not share this property. Moreover, Ifit2 failed to protect mice from another neurotropic virus, encephalomyocarditis virus, nor was it necessary for protecting organs other than brain from infection by VSV. Our observation that a single IFN-induced protein protects a specific organ from infection by a specific virus revealed an unexpected degree of specificity of the antiviral action of IFN. shared wt mice (n = number of animals used). C, survival of Ifit2 2/2 , Ifit1 2/2 and wt mice after intranasal infection with a higher dose of VSV (4610 6 pfu). D, survival of Ifit2 2/2 , Ifit1 2/2 , IFNAR 2/2 and wt mice after infection with 5610 2 pfu of EMCV. In A-D, data are cumulative from at least two independent experiments (exceptions: Figure 2B , Ifit2 +/2 mice and Figure 2D , Ifit1 2/2 mice infected in a single experiment). Statistical significance of survival differences relative to wt mice is indicated by p-values; n.s., not significant; i.n., intranasal. doi:10.1371/journal.ppat.1002712.g002 the nasal epithelia including olfactory sensor neurons, which project to the outer layer of the olfactory bulbs (OB) [23] . This represents the entry step into the CNS, which we examined by immunostaining of OB sections. In wt mice, VSV P protein was detected exclusively within the glomeruli of the OB at 2 d.p.i. ( Figure 3B , upper right panel and [1] ), whereas in IFNAR 2/2 mice, VSV antigen had spread into deeper layers of the OB ( Figure 3B , lower left panel). In Ifit2 2/2 mice OB, viral antigen was restricted to the glomeruli, as seen in wt mice ( Figure 3B , lower right panel). This similar pattern of viral antigen expression between wt and Ifit2 2/2 mice was reflected in the equivalent levels of viral RNA in OB at 2 d.p.i. ( Figure 3C ). In contrast, ,10 times more VSV RNA was present in OB of IFNAR 2/2 mice ( Figure 3C , right panel, p,0.05). A comparison of the infectious viral burden between wt and Ifit2 2/2 mice in the OB confirmed these findings: at 2 d.p.i., ,10 6 pfu/g of VSV was present in both wt and Ifit2 2/2 mice ( Figure 3D , p = 1.0).