Tick-borne encephalitis virus (TBEV) is a leading cause of vector-borne viral encephalitis with expanding endemic regions across Europe. In this study we tested in mice the efficacy of preinfection with a closely related low-virulent flavivirus, Langat virus (LGTV strain TP21), or a naturally avirulent TBEV strain (TBEV-280) in providing protection against lethal infection with the highly virulent TBEV strain (referred to as TBEV-Hypr). We show that prior infection with TP21 or TBEV-280 is efficient in protecting mice from lethal TBEV-Hypr challenge. Histopathological analysis of brains from nonimmunized mice revealed neuronal TBEV infection and necrosis. Neuroinflammation, gliosis, and neuronal necrosis was however also observed in some of the TP21 and TBEV-280 preinfected mice although at reduced frequency as compared to the nonimmunized TBEV-Hypr infected mice. qPCR detected the presence of viral RNA in the CNS of both TP21 and TBEV-280 immunized mice after TBEV-Hypr challenge, but significantly reduced compared to mock-immunized mice. Our results indicate that although TBEV-Hypr infection is effectively controlled in the periphery upon immunization with low-virulent LGTV or naturally avirulent TBEV 280, it may still enter the CNS of these animals. These findings contribute to our understanding of causes for vaccine failure in individuals vaccinated with TBE vaccines.

Center of Behavioral Brain Sciences Otto von Guericke University 39120 Magdeburg Germany

Department of Pathology University of Veterinary Medicine Hannover Foundation Bünteweg 17 30559 Hannover Germany

Department of Virology Paul Ehrlich Institut 63225 Langen Germany

Department of Viroscience Erasmus Medical Center Dr Molewaterplein 50 3015GE Rotterdam The Netherlands

Innate Immunity and Infection Helmholtz Centre for Infection Research 38124 Braunschweig Germany

Institute of Medical Microbiology and Hospital Hygiene Otto von Guericke University Leipziger Strasse 44 39120 Magdeburg Germany

Institute of Parasitology Biology Centre of Czech Academy of Science Branisovska 31 CZ 37005 Ceske Budejovice Czech Republic

Research Center for Emerging Infections and Zoonoses University of Veterinary Medicine Hannover Foundation Bünteweg 17 30559 Hannover Germany

Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic

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The Role of IFITM Proteins in Tick-Borne Encephalitis Virus Infection