The interferon-induced tetratricopeptide repeat protein (Ifit2) protects mice from lethal neurotropic viruses. Neurotropic coronavirus MHV-RSA59 infection of Ifit2 -/- mice caused pronounced morbidity and mortality accompanied by rampant virus replication and spread throughout the brain. In spite of the higher virus load, induction of many cytokines and chemokines in the brains of infected Ifit2 -/- mice were similar to that in wild-type mice. In contrast, infected Ifit2 -/- mice revealed significantly impaired microglial activation as well as reduced recruitment of NK1.1 T cells and CD4 T cells to the brain, possibly contributing to the lack of viral clearance. These two deficiencies were associated with a lower level of microglial expression of CX3CR1, the receptor of the CX3CL1 (Fractalkine) chemokine, which plays a critical role in both microglial activation and leukocyte recruitment. The above results uncovered a new potential role of an interferon-induced protein in immune protection. Author summary Interferons (IFNs) are known to protect from virus dissemination and pathogenesis. Several IFN stimulated genes (ISG) regulate neuropathogenesis but the mechanisms underlying the antiviral effects are not clearly understood. IFN induced tetratricopeptide repeats (Ifit) are a class of ISGs. Among the Ifits, Ifit2 is known to play a beneficial role in restricting neurotropic viral replication. To provide better cellular insights into the protective mechanisms of Ifit2 functions, using a neurotropic coronavirus infection in Ifit2 depleted mice we report that in the absence of Ifit2, viral replication is dramatically increased and mice develop severe clinical signs and symptoms of neurological deficit. Despite the enormous viral load, Ifit2 deficient mice are impaired in microglial activation and recruitment of peripheral leukocytes into the CNS. This impaired leuocyte infiltration in Ifit2 deficient mice was also associated with reduced expression of a novel chemokine receptor CX3CR1,which is important for viral induced microglial activation and maintaining tissue homeostasis.
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