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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 646 (8086) 945-952 [2025-10-00; online 2025-09-24]
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 neuroinflammation1,2. 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.
PubMed 40993380
DOI 10.1038/s41586-025-09500-2
Crossref 10.1038/s41586-025-09500-2
mid: NIHMS2172163
pmc: PMC13221092
pii: 10.1038/s41586-025-09500-2