LRP8 is a receptor for tick-borne encephalitis virus

Eva Mittler (), Alexandra L. Tse, Pham-Tue-Hung Tran, Catalina Florez, Javier Janer, Renata Varnaite, Ezgi Kasikci, Vasantha Kumar Mv, Michaela Loomis, Wanda Christ, Erik Cazares, Russell R. Bakken, Caroline K. Martin, Xiankun Zeng, Jo Lynne Raymond, Mansoureh Shahsavani, Sara Khanal, Eric R. Wilkinson, Rischa Maya Oktavia, Megan M. Slough, Denise Haslwanter, Julianna Han, Jacob Berrigan, Ebba Rosendal, Margaret Kielian, Balaji Manicassamy, Anna K. Överby, Anna Falk, Giovanna Barba-Spaeth, Felix A. Rey, Jonas Klingström, Evripidis Gavathiotis, Andrew S. Herbert (), Kartik Chandran () and Sara Gredmark-Russ ()
Additional contact information
Eva Mittler: Albert Einstein College of Medicine
Alexandra L. Tse: Albert Einstein College of Medicine
Pham-Tue-Hung Tran: Karolinska Institutet
Catalina Florez: United States Army Medical Research Institute of Infectious Diseases
Javier Janer: Albert Einstein College of Medicine
Renata Varnaite: Karolinska Institutet
Ezgi Kasikci: Albert Einstein College of Medicine
Vasantha Kumar Mv: Albert Einstein College of Medicine
Michaela Loomis: United States Army Medical Research Institute of Infectious Diseases
Wanda Christ: Karolinska Institutet
Erik Cazares: United States Army Medical Research Institute of Infectious Diseases
Russell R. Bakken: United States Army Medical Research Institute of Infectious Diseases
Caroline K. Martin: Albert Einstein College of Medicine
Xiankun Zeng: United States Army Medical Research Institute of Infectious Diseases
Jo Lynne Raymond: United States Army Medical Research Institute of Infectious Diseases
Mansoureh Shahsavani: Karolinska Institutet
Sara Khanal: United States Army Medical Research Institute of Infectious Diseases
Eric R. Wilkinson: United States Army Medical Research Institute of Infectious Diseases
Rischa Maya Oktavia: Structural Virology Unit
Megan M. Slough: Albert Einstein College of Medicine
Denise Haslwanter: Albert Einstein College of Medicine
Julianna Han: University of Chicago
Jacob Berrigan: Albert Einstein College of Medicine
Ebba Rosendal: Umeå University
Margaret Kielian: Albert Einstein College of Medicine
Balaji Manicassamy: University of Iowa
Anna K. Överby: Umeå University
Anna Falk: Lund University
Giovanna Barba-Spaeth: Structural Virology Unit
Felix A. Rey: Structural Virology Unit
Jonas Klingström: Karolinska Institutet
Evripidis Gavathiotis: Albert Einstein College of Medicine
Andrew S. Herbert: United States Army Medical Research Institute of Infectious Diseases
Kartik Chandran: Albert Einstein College of Medicine
Sara Gredmark-Russ: Karolinska Institutet

Nature, 2025, vol. 646, issue 8086, 945-952

Abstract: 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 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.

Date: 2025
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DOI: 10.1038/s41586-025-09500-2

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