To determine the impact of Ifit2 on the outcome of viral infections in vivo, we compared susceptibilities of Ifit2 2/2 and wt mice to VSV infection, using IFNAR 2/2 mice as positive controls of enhanced susceptibility. Virus was administered at a low dose [4610 2 plaque forming units (pfu)], intranasally, reflecting a natural route of infection for VSV [22] . As seen previously, 100% of IFNAR 2/2 mice rapidly succumbed to VSV infection within 2 days ( Figure 2A , and [1] ), after suffering symptoms of lethargy. On the other hand, 79% of wt mice survived, the remaining 21% succumbed to VSV, and this occurred later, at 7-10 days post infection (d.p.i.). In contrast, 100% of Ifit2 2/2 mice died by 7 d.p.i. (Figure 2A ), with most succumbing by 6 d.p.i.; thus, we observed uniform and more rapidly occurring death of Ifit2 2/2 compared to wt mice after VSV infection. Within 24 h before death, both wt and Ifit2 2/2 mice developed neurological signs including ataxia, hind limb paralysis, and hyper-excitability. Ifit2 +/2 mice displayed an intermediate survival curve, demonstrating a gene dosage effect ( Figure 2B ). Next, the role of a related gene, Ifit1, in VSV pathogenesis was evaluated by infecting Ifit1 2/2 mice. Unlike the results observed with Ifit2 2/2 mice, no statistically significant increase in mortality was observed in Ifit1 2/2 mice ( Figure 2B , 21% death for wt versus 36% for Ifit1 2/2 , respectively; p.0.25). Consistent with this, survival kinetics of Ifit1 2/2 and wt mice were similar. Increasing the virus dose by 10,000-fold (to 4610 6 pfu) did not appreciably change the survival curves of wt, Ifit1 2/2 , or Ifit2 2/2 mice ( Figure 2C ). These results demonstrate functional differences between the two closely related proteins encoded by Ifit1 and Ifit2. The virus-specificity of the antiviral action of Ifit2 was evaluated by infecting Ifit2 2/2 mice with EMCV, an unrelated neurovirulent positive-strand RNA virus of the picornavirus family ( Figure 2D ). IFNAR 2/2 mice were highly susceptible to EMCV infection with all mice succumbing within 2 d.p.i.; in contrast, wt mice died with a slower kinetics and at a rate of only 80%. Notably, Ifit2 2/2 mice behaved similarly to the wt mice, without enhanced or accelerated mortality ( Figure 2D ). The same conclusion was true for a lower dose of EMCV ( Figure S1 ). The survival pattern of EMCV-infected Ifit1 2/2 mice also was similar to that of the wt mice ( Figure 2D ). Mice of all genotypes either succumbed after developing neurological symptoms, mainly hind limb paralysis, or survived without symptoms. These results demonstrate that the antiviral action of Ifit2 is both virus-and Ifitspecific.