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LRP8 is a receptor for tick-borne encephalitis virus

Mittler, Eva ; Tse, Alexandra L. ; Tran, Pham Tue Hung ; Florez, Catalina ; Janer, Javier ; Varnaite, Renata ; Kasikci, Ezgi ; MV, Vasantha Kumar ; Loomis, Michaela and Christ, Wanda , et al. (2025) In Nature 646(8086). p.945-952
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 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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature
volume
646
issue
8086
pages
8 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:40993380
  • scopus:105016879708
ISSN
0028-0836
DOI
10.1038/s41586-025-09500-2
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature Limited 2025.
id
7d0b3170-9691-4c53-8d13-0bd0e001e56b
date added to LUP
2025-12-09 10:19:27
date last changed
2025-12-10 08:32:10
@article{7d0b3170-9691-4c53-8d13-0bd0e001e56b,
  abstract     = {{<p>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<sup>1,2</sup>. 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.</p>}},
  author       = {{Mittler, Eva and Tse, Alexandra L. and Tran, Pham Tue Hung and Florez, Catalina and Janer, Javier and Varnaite, Renata and Kasikci, Ezgi and MV, Vasantha Kumar and Loomis, Michaela and Christ, Wanda and Cazares, Erik and Bakken, Russell R. and Martin, Caroline K. and Zeng, Xiankun and Raymond, Jo Lynne and Shahsavani, Mansoureh and Khanal, Sara and Wilkinson, Eric R. and Oktavia, Rischa Maya and Slough, Megan M. and Haslwanter, Denise and Han, Julianna and Berrigan, Jacob and Rosendal, Ebba and Kielian, Margaret and Manicassamy, Balaji and Överby, Anna K. and Falk, Anna and Barba-Spaeth, Giovanna and Rey, Felix A. and Klingström, Jonas and Gavathiotis, Evripidis and Herbert, Andrew S. and Chandran, Kartik and Gredmark-Russ, Sara}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{8086}},
  pages        = {{945--952}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{LRP8 is a receptor for tick-borne encephalitis virus}},
  url          = {{http://dx.doi.org/10.1038/s41586-025-09500-2}},
  doi          = {{10.1038/s41586-025-09500-2}},
  volume       = {{646}},
  year         = {{2025}},
}