Abstract
Tick-borne encephalitis virus (TBEV) is a tick-borne flavivirus that causes severe encephalitis disease1,2. Host proteins required for TBEV entry remain largely unknown3. Here we performed a genome-wide CRISPR-Cas9 knockout screen and identified G-protein-coupled receptor glucagon-like peptide-2 receptor (GLP2R) as a receptor for TBEV to infect nerve cells. Knockdown or knockout of GLP2R reduced TBEV infection of different nerve cells; trans supply of GLP2R restored viral infection. GLP2R directly binds to viral envelope domain III through its extracellular loop 1 (ECL1). TBEV infection can be blocked by the ECL1 peptide, a functional ligand to GLP2R, or GLP2R antibodies. GLP2R-deficient mice were generated to validate the role of GLP2R in TBEV infection and pathogenesis. Wild-type mice succumbed to TBEV infection and developed >107 TCID50 (median tissue culture infectious dose) virus per gram of brain tissue. In contrast, all GLP2R-deficient mice survived TBEV infection without detectable infectious virus in brain. Altogether, our results support GLP2R as a receptor for TBEV to infect nerve cells.
Adaptive genetic diversifications among tick-borne encephalitis virus subtypes: A genome-wide perspective
