Mittler et al.
How a tick-borne virus enters human cells. Nature. Published online September 24, 2025. doi:10.1038/s41586-025-09500-2
Host factors required for the entry of tick-borne encephalitis (TBE) virus have remained poorly defined. Mittler and colleagues used a genome-wide CRISPR–Cas9 knockout library to screen human A549 cells for host genes whose loss conferred survival following TBE virus infection. The screen yielded a single, strongly enriched hit—LRP8, which encodes the cell-surface low-density lipoprotein receptor-related protein 8, also known as apolipoprotein E receptor 2 (ApoER2).
Engineered A549 cell lines deficient in LRP8 showed markedly reduced susceptibility to infection by single-cycle flavivirus reporter particles pseudotyped with the TBE virus envelope glycoprotein E of the European subtype strain Neudörfl. Infections with authentic TBE virus strains of both European and Far Eastern subtypes were greatly reduced in these knockout cells, but susceptibility was restored by ectopic expression of LRP8. Overexpression of LRP8 via lentiviral transduction with full-length LRP8 cDNA substantially increased viral infection. This effect was specific to TBE virus and was not observed with other orthoflaviviruses.
Other LRP8-related receptors with similar structural features did not support TBE virus infection. The authors demonstrated that LRP8 directly binds to the viral glycoprotein E. In a TBE-susceptible mouse model that recapitulates brain infection, administration of a soluble decoy form of LRP8—an antibody fragment fused to the virus-binding domain of the receptor—blocked TBE virus entry and prevented lethal infection.
LRP8 thus represents the first validated receptor protein for a flavivirus. The identified LRP8–glycoprotein E interaction provides a molecular basis for viral entry and a promising target for the development of antiviral therapeutics.