LRP8 is a receptor for tick-borne encephalitis virus.

Area of Science:

• Virology
• Neuroscience
• Immunology

Background:

• Tick-borne encephalitis virus (TBEV) causes severe neuroinflammation and is a significant public health concern.
• Host factors mediating TBEV entry into the central nervous system are not well understood.
• Orthoflaviviruses, like TBEV, are enveloped RNA viruses transmitted by arthropods.

Purpose of the Study:

• To identify host factors essential for TBEV entry and infection.
• To investigate the role of identified factors in viral neuropathogenesis.
• To explore potential therapeutic targets for TBEV infection.

Main Methods:

• Genome-scale CRISPR-Cas9 screening was employed to identify host cell receptors for TBEV.
• LRP8 function in TBEV infection was assessed through downregulation and overexpression studies in human cells.
• Direct binding assays between LRP8 and the TBEV E glycoprotein were performed.
• Viral attachment and internalization mediated by LRP8 were analyzed.
• An LRP8-based soluble decoy was developed and tested for antiviral efficacy in cell lines, neuronal cells, and a mouse model.

Main Results:

• LRP8, a receptor for apolipoprotein E and reelin, was identified as a critical TBEV receptor.
• Downregulation of LRP8 significantly reduced TBEV infection, while its overexpression enhanced it.
• LRP8 directly binds to the TBEV E glycoprotein, facilitating viral attachment and cell entry.
• An LRP8-based soluble decoy effectively blocked TBEV infection in various cell types and protected mice from lethal challenge.

Conclusions:

• LRP8 is a crucial host factor for TBEV entry, mediating viral attachment and internalization.
• Targeting LRP8 presents a promising strategy for developing novel antiviral therapies against TBEV.
• Understanding LRP8's role advances knowledge of TBEV neuropathogenesis and potential treatment avenues.