Type I Interferon Protects Mice from Fatal Neurotropic Infection with Langat Virus by Systemic and Local Antiviral Responses

Vector-borne flaviviruses, such as tick-borne encephalitis virus (TBEV), West Nile virus, and dengue virus, cause millions of in-fections in humans. TBEV causes a broad range of pathological symptoms, ranging frommeningitis to severe encephalitis or even hemorrhagic fever, with highmortality. Despite the availability of an effective vaccine, the incidence of TBEV infections is increasing. Not much is known about the role of the innate immune system in the control of TBEV infections. Here, we show that the type I interferon (IFN) system is essential for protection against TBEV and Langat virus (LGTV) in mice. In the absence of a functional IFN system, mice rapidly develop neurological symptoms and succumb to LGTV and TBEV infections. Type I IFN system deficiency results in severe neuroinflammation in LGTV-infected mice, characterized by breakdown of the blood-brain barrier and infiltration of macrophages into the central nervous system (CNS). Using mice with tissue-specific IFN receptor dele-tions, we show that coordinated activation of the type I IFN system in peripheral tissues as well as in the CNS is indispensable for viral control and protection against virus induced inflammation and fatal encephalitis. IMPORTANCE The type I interferon (IFN) system is important to control viral infections; however, the interactions between tick-borne enceph-alitis virus (TBEV) and the type I IFN system are poorly characterized. TBEV causes severe infections in humans that are charac-terized by fever and debilitating encephalitis, which can progress to chronic illness or death. No treatment options are available