LDLRAD3 is a receptor for Venezuelan equine encephalitis virus.

Abstract

Venezuelan equine encephalitis virus (VEEV) is a mosquito-transmitted neurotropic alphavirus that causes encephalitis and death in humans1. VEEV is a biodefense concern because of its potential for aerosol spread and lack of sufficient countermeasures. The host factors required for VEEV entry and infection remain poorly characterized. Using a genome-wide CRISPR/Cas9-based screen, we identify Ldlrad3, a highly conserved member of the scavenger receptor superfamily, as a receptor for VEEV. Gene editing of mouse Ldlrad3 or human LDLRAD3 results in markedly reduced viral infection of neuronal cells, which is restored upon complementation. Ldlrad3 binds directly to VEEV particles and enhances virus attachment and internalization into cells. Genetic studies indicate that domain 1 (D1) of Ldlrad3 is necessary and sufficient to support VEEV infection, and both anti-Ldlrad3 antibodies and a Ldlrad3-D1-Fc fusion protein block VEEV infection in cell culture. Remarkably, VEEV pathogenesis is abrogated in mice with deletions in Ldlrad3, and administration of Ldlrad3-D1-Fc abolishes disease caused by multiple VEEV subtypes including highly virulent strains. The development of a decoy receptor fusion protein creates a strategy for preventing severe VEEV infection and disease in humans.