T-Cell Immunoglobulin and Mucin Domain 1 (TIM-1) Is a Functional Entry Factor for Tick-Borne Encephalitis Virus

Tick-borne encephalitis virus (TBEV) is the causative agent of a potentially fatal neurological infection affecting humans. The host factors required for viral entry have yet to be described. Here, we found that T-cell immunoglobulin and mucin domain 1 (TIM-1) acted as the cellular entry factor for TBEV. Using a virus overlay protein binding assay, TIM-1 was identified as a virion-interacting protein. Cells that were relatively resistant to TBEV infection became highly susceptible to infection when TIM-1 was ectopically expressed. TIM-1 knockout and viral RNA bypass assays showed that TIM-1 functioned in the entry phase of TBEV infection. TIM-1 mediated TBEV uptake and was cointernalized with virus particles into the cell. Antibodies for TIM-1, soluble TIM-1, or TIM-1 knockdown significantly inhibited TBEV infection in permissive cells. Furthermore, in TIM-1 knockout mice, TIM-1 deficiency markedly lowered viral burden and reduced mortality and morbidity, highlighting the functional relevance of TIM-1 in vivo. With TIM-1, we have identified a key host factor for TBEV entry and a potential target for antiviral intervention. IMPORTANCE TBEV is a tick-transmitted flavivirus that causes serious diseases in the human central nervous system in Eurasia. The host determinants required for viral entry remain poorly understood. Here, we found that TIM-1 is a cellular entry factor for TBEV. Antibodies directed at TIM-1 or soluble TIM-1 treatment decreased virus infection in cell cultures. TIM-1 was cointernalized with virus particles into cells. TIM-1 deficiency significantly lowered viral burden and attenuated pathogenesis in the murine TBEV infection model. The demonstration of TIM-1 as a cellular entry factor for TBEV will improve understanding of virus infection and provide a target for antiviral development.