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Flaviviruses e.g., West Nile virus, dengue virus and tick borne encephalitis virus (TBEV) are globally distributed human pathogens that cause millions of infections annually. In Europe TBEV is the most important arthropod-borne virus in humans. Despite the availability of an effective vaccine, incidences of TBEV infections have increased dramatically in many of the European countries over the recent years. TBEV causes a broad range of pathological symptoms ranging from meningitis to severe encephalitis or even hemorrhagic fevers with high mortality rates. While adaptive immunity plays an important role in preventing TBEV infections, little is known about the impact of the interferon system in TBEV antiviral response. Previously it was shown that TBEV delays IFN induction by hiding its RNA in intracellular membranes in vitro. We set out to investigate the importance of the type I interferon system in protecting mice from TBEV in vivo. We found that Langat virus (LGTV), a naturally attenuated member of the TBEV serogroup, is unable to establish viremia and induces a very low type I interferon response in wild type mice. Furthermore we were able to show that the Interferon receptor alpha (IFNAR) is crucial for protection against fatal encephalitis of LGTV infection. Our data indicate that upon LGTV infection IFNAR triggering in the periphery is necessary to limit viral spread to the CNS and that local IFN signaling in the CNS is crucial to prevent fatal encephalitis. [ABSTRACT FROM AUTHOR]