Our results from intranasal VSV infection indicated that Ifit2 induction in the brain was mediated by type I IFN that was, in all likelihood, produced by infected cells in the OB ( Figure 5A ). Virus replication and resultant IFN induction at 2 d.p.i. were similar in the OBs of wt and Ifit2 2/2 mice (Figs. 3C, 3D and 5A); presumably, the newly produced IFN diffused into the rest of the brain and induced local Ifit2 expression in the wt mouse brains, prior to the arrival of the infectious virus. If this were the case, one would anticipate that direct infection of the brain, without prior action of IFN produced in infected OB, would minimize the difference between the phenotypes of wt and Ifit2 2/2 mice. To test this idea, we injected a very low dose (10 pfu) of VSV intracranially. As hypothesized, wt and Ifit2 2/2 mice were now equally susceptible; almost all mice died by 3 d.p.i. even at this low dose ( Figure 6A ) and there were equally high virus titers and viral RNA levels in the brains of mice of both genotypes ( Figure 6B and 6C). Concomitant with virus replication, there was similar induction of Ifit1 and IFN-b ( Figure 6C ) and other cytokines and chemokines ( Figure S3B ). These results indicate that in the absence of prior induction of Ifit2 by IFN, brain neurons are highly susceptible to VSV infection.