LRP8 is an entry receptor for tick-borne encephalitis viruses

Area of Science:

• Virology
• Neuroscience
• Molecular Biology

Background:

• Orthoflaviviruses, including tick-borne encephalitis virus (TBEV), cause significant global morbidity and mortality.
• TBEV is responsible for severe neurological disease in humans, but its cell entry receptors remain largely unknown.
• The low-density lipoprotein receptor (LDLR) family has been implicated as potential receptors for related viruses.

Purpose of the Study:

• To identify the specific entry receptors for TBEV strains.
• To investigate the role of LDLR family members in TBEV cell tropism and infection.

Main Methods:

• Screening of transgenic cells expressing LDLR family members.
• Genetic ablation and complementation studies of LRP8 in neuronal cells.
• Binding assays with TBEV envelope proteins and LRP8.
• Functional experiments using soluble LRP8-Fc decoy receptors and knockout mice.

Main Results:

• LRP8 (ApoER2) was identified as a candidate receptor for TBEV strains across five subtypes.
• Genetic inactivation of LRP8 impaired TBEV infection, while its expression enhanced it.
• LRP8 directly binds TBEV envelope proteins, promoting viral attachment and internalization via its LDLR type A domains 1 and 2.
• Soluble LRP8-Fc neutralized TBEV, and Lrp8 knockout mice showed reduced viral infection.

Conclusions:

• LRP8 is a crucial receptor for TBEV entry and infection in neuronal cells.
• Understanding LRP8's role has implications for developing novel TBEV therapeutics, including soluble receptor-based and antibody-based strategies.