Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus transmitted by mosquitoes that causes encephalitis and death in humans 1 . VEEV is a biodefence concern because of its potential for aerosol spread and the current lack of sufficient countermeasures. The host factors that are required for VEEV entry and infection remain poorly characterized. Here, using a genome-wide CRISPR–Cas9-based screen, we identify low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3)—a highly conserved yet poorly characterized 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 with LDLRAD3. LDLRAD3 binds directly to VEEV particles and enhances virus attachment and internalization into host cells. Genetic studies indicate that domain 1 of LDLRAD3 (LDLRAD3(D1)) is necessary and sufficient to support infection by VEEV, and both anti-LDLRAD3 antibodies and an LDLRAD3(D1)–Fc fusion protein block VEEV infection in cell culture. The pathogenesis of VEEV infection is abrogated in mice with deletions in Ldlrad3 , and administration of LDLRAD3(D1)–Fc abolishes disease caused by several subtypes of VEEV, including highly virulent strains. The development of a decoy-receptor fusion protein suggests a strategy for the prevention of severe VEEV infection and associated disease in humans. LDLRAD3 is a receptor for infection with Venezuelan equine encephalitis virus, and in mouse models deletion of Ldlrad3 or treatment with a soluble LDLRAD3 decoy molecule abrogates infection and disease caused by this virus.

中文翻译：

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LDLRAD3 是委内瑞拉马脑炎病毒的受体

委内瑞拉马脑炎病毒 (VEEV) 是一种由蚊子传播的嗜神经甲病毒，可导致人类脑炎和死亡 1 。VEEV 是一个生物防御问题，因为它有可能传播气溶胶，而且目前缺乏足够的对策。VEEV 进入和感染所需的宿主因素的特征仍然很差。在这里，我们使用基于全基因组 CRISPR-Cas9 的筛选，将低密度脂蛋白受体 A 类结构域 3 (LDLRAD3)——清道夫受体超家族中高度保守但特征不明确的成员——鉴定为 VEEV 的受体。小鼠 Ldlrad3 或人 LDLRAD3 的基因编辑导致神经元细胞的病毒感染显着减少，这在与 LDLRAD3 互补后恢复。LDLRAD3 直接结合 VEEV 颗粒并增强病毒附着和内化到宿主细胞中。遗传学研究表明，LDLRAD3 (LDLRAD3(D1)) 的结构域 1 是支持 VEEV 感染所必需且充分的，抗 LDLRAD3 抗体和 LDLRAD3(D1)–Fc 融合蛋白均能阻断细胞培养中的 VEEV 感染。VEEV 感染的发病机制在 Ldlrad3 缺失的小鼠中被消除，LDLRAD3(D1)-Fc 的施用消除了由 VEEV 的几种亚型引起的疾病，包括高毒力菌株。诱饵-受体融合蛋白的开发提出了一种预防人类严重 VEEV 感染和相关疾病的策略。LDLRAD3 是委内瑞拉马脑炎病毒感染的受体，