Unlike the brain, other organs of Ifit2 2/2 mice are not more susceptible to intranasal VSV infection IFNAR 2/2 mice succumbed within two days after VSV infection without accumulating very high VSV RNA levels in the brain ( Figure 4B ). These mice did not develop CNS-related signs of disease, but showed severe lethargy before death, suggesting that death was due to efficient replication of the virus in peripheral organs, due to the absence of an otherwise effective type I IFN-mediated antiviral protection of the same organs in wt mice. To test this, we assessed the kinetics of VSV accumulation in brains, livers and lungs of wt, IFNAR 2/2 and Ifit2 2/2 mice (Figure 7) . At 2 d.p.i., VSV titers were very high in the liver of IFNAR 2/2 mice, reaching 10 9 pfu/g ( Figure 7A ). In contrast, no or little infectious virus was detected in the liver of wt mice at 2 or 6 d.p.i., indicating efficient IFN-dependent suppression of VSV replication; intriguingly, this was also observed in Ifit2 2/2 mice, demonstrating that Ifit2 did not mediate the anti-VSV effects of type I IFN in the liver. In lungs, which directly received a part of the virus inoculum from intranasal inhalation of VSV, the virus also replicated efficiently in IFNAR 2/2 mice, reaching 10 8 pfu/g before death ( Figure 7B ). In comparison, lungs of wt and Ifit2 2/2 mice exhibited much lower levels of VSV at 2 and 4 d.p.i. (3,000 to 10,000-fold lower for wt and Ifit2 2/2 compared to IFNAR 2/2 mice, all p,0.05). By days 5 and 6 d.p.i., the virus was cleared from the lungs of a subset of wt and Ifit2 2/2 mice. In contrast, in brains from the same animals, 10 to 100-fold higher average titers (p,0.05) of VSV accumulated in Ifit2 2/2 compared to wt mice at all time points between 2 and 6 d.p.i. ( Figure 7C ). As expected, in wt mice, both Ifit1 and Ifit2 were induced not only in brains ( Figure 5D ), but also in livers ( Figure 7D ) and lungs ( Figure 7E ); IFN-b was also induced in lungs, but not livers. Ifit1, Ifit2 and IFN-b mRNAs were also induced in the brains of EMCV-infected wt mice ( Figure S3C ). These findings demonstrate an unexpected brain-restricted and virus-restricted function of Ifit2 in the context of the type I IFN-mediated antiviral response to VSV infection. They also indicate that in Ifit2 2/2 mice, other ISGs, which presumably protect the peripheral organs of VSV-infected wt mice, are either not induced in neurons or insufficient to protect them.