Type I interferons (IFN-ฮฑ/ฮฒ) limit viral dissemination prior to the emergence of adaptive immune responses through the concerted action of interferon-stimulated genes (ISGs). Although IFN-ฮฑ/ฮฒ induction by coronaviruses is modest, it effectively limits viral spread within the central nervous system (CNS) and protects against mortality. The protective roles of specific ISGs against the mouse hepatitis virus (MHV) members of the coronaviruses are largely unknown. This study demonstrates a protective role of the ISG Ifit2 in encephalitis induced by the dual hepato- and neurotropic MHV-A59. Contrasting the mild encephalitis and 100% survival of MHV-A59-infected wild-type (wt) mice, nearly 60% of infected Ifit2-/- mice exhibited severe encephalitis and succumbed between 6 and 8 days postinfection. Increased clinical disease in Ifit2-/- mice coincided with higher viral loads and enhanced viral spread throughout the CNS parenchyma. Ifit2-/- mice also expressed significantly reduced IFN-ฮฑ/ฮฒ and downstream ISG mRNAs Ifit1, Isg15, and Pkr, while expression of proinflammatory cytokines and chemokines was only modestly affected in the CNS. Impaired IFN-ฮฑ/ฮฒ induction in the absence of Ifit2 was confirmed by ex vivo mRNA analysis of microglia and macrophages, the prominent cell types producing IFN-ฮฑ/ฮฒ following MHV CNS infection. Furthermore, both IFN-ฮฑ/ฮฒ mRNA and protein production were significantly reduced in MHV-infected Ifit2-/- relative to wt bone marrow-derived macrophages. Collectively, the data implicate Ifit2 as a positive regulator of IFN-ฮฑ/ฮฒ expression, rather than direct antiviral mediator, during MHV-induced encephalitis. ยฉ 2014, American Society for Microbiology.