Li et al.
LRP8 Is an Entry Receptor for Tick-borne Encephalitis Viruses. Proc Natl Acad Sci U S A. 2025;():e252577122. Published online October 30, 2025. doi:10.1073/pnas.252577122
Recently, the cell-surface low-density lipoprotein receptor–related protein 8 (LRP8) was identified as a receptor for tick-borne encephalitis (TBE) virus (see Snapshot week 43/2025). A study by Li et al. confirmed these findings and demonstrated that LRP8 functions as a receptor for TBE virus strains representing five different subtypes: Hypr and Neudörfl (European subtype), Sofjin (Far Eastern subtype), Vasilchenko (Siberian subtype), Himalaya-1 (Himalayan subtype), and 886-84 (Balkalian subtype).
The authors also examined whether LRP8 expression influences infection by other, more distantly related tick- and mosquito-borne orthoflaviviruses. Expression of LRP8 in K562 cells promoted infection by TBE reporter virus particles encoding the structural proteins of Omsk hemorrhagic fever virus, Louping ill virus, Alkhurma hemorrhagic fever virus, and Kyasanur Forest disease virus. In contrast, LRP8 did not enhance infection by other tick-borne viruses (Powassan virus, Langat virus), Gadgets Gully virus, or mosquito-borne viruses such as Japanese encephalitis virus, West Nile virus, Zika virus, or dengue virus 2. These results indicate that the ability to use LRP8 as an entry receptor is restricted to TBE virus strains and several closely related members of the TBE serocomplex.
Analysis of LRP8 orthologs from other mammalian species suggests that the interaction with TBE virus is conserved, potentially contributing to the broad mammalian host range of these viruses, which includes humans, rodents, hedgehogs, dogs, deer, and shrews, among other species.
In both mice and humans, RNA-sequencing datasets and protein expression atlases show that LRP8 is preferentially expressed in neurons of the brain.
Together, these findings establish a role for LRP8 in TBE virus entry and infection, with implications for the development of soluble-receptor, antibody-based, and vaccine countermeasures.
Along with this publication, TIM-1 (T-cell immunoglobulin and mucin domain) and AXL (AXL receptor tyrosine kinase) have been identified as receptors for the flaviviral tick-transmitted Powassan and deer tick virus (endemic in North America). Daskou et al., iScience, available online 3 November 2025, 113930.