LRP8 is a receptor for tick-borne encephalitis virus

Mittler E, Tse AL, Tran PT, Florez C, Janer J, Varnaite R, Kasikci E, Mv VK, Loomis M, Christ W, Cazares E, Bakken RR, Martin CK, Zeng X, Raymond JL, Shahsavani M, Khanal S, Wilkinson ER, Oktavia RM, Slough MM, Haslwanter D, Han J, Berrigan J, Rosendal E, Kielian M, Manicassamy B, Överby AK, Falk A, Barba-Spaeth G, Rey FA, Klingström J, Gavathiotis E, Herbert AS, Chandran K, Gredmark-Russ S.

Nature. 2025. Epub ahead of print. Sep 24.

[doi: 10.1038/s41586-025-09500-2] [Full text]


ABSTRACT

Tick-borne encephalitis virus (TBEV) causes tick-borne encephalitis (TBE), a severe and sometimes life-threatening disease characterized by viral invasion of the central nervous system with symptoms of neuroinflammation. As with other orthoflaviviruses-enveloped, arthropod-borne RNA viruses-host factors required for TBEV entry remain poorly defined. Here we used a genome-scale CRISPR-Cas9-based screen to identify LRP8, an apolipoprotein E and reelin receptor with high expression in the brain, as a TBEV receptor. LRP8 downregulation reduced TBEV infection in human cells, and its overexpression enhanced infection. LRP8 bound directly to the TBEV E glycoprotein and mediated viral attachment and internalization into cells. An LRP8-based soluble decoy blocked infection of human cell lines and neuronal cells and protected mice from lethal TBEV challenge. LRP8's role as a TBEV receptor has implications for TBEV neuropathogenesis and the development of antiviral countermeasures.