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LDLRAD3 is a receptor for Venezuelan equine encephalitis virus

机译：LDLRAD3是委内瑞拉大当脑脑炎病毒的受体

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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.
机译：委内瑞拉大当量脑炎病毒（VEEV）是由蚊子传播的神经促甲虫病，导致人类（1）中的脑炎和死亡。 Veev是一种生物区问题，因为它可能对气溶胶传播的潜力和目前缺乏足够的对策。 VEEV进入和感染所需的宿主因子仍然存在差。这里，使用基于基于基于基于基于基于Cas9的Cas9筛选，我们鉴定了低密度脂蛋白受体类A类含域的3（LDLRAD3）-A高度保守的尚未表征的清除剂受体超法 - 作为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降低，这在与LDLRAD3的互补后恢复。 LDLRAD3直接与VEEV颗粒结合并增强病毒附着和内化入宿主细胞。遗传研究表明，LDLRAD3（LDLRAD3（D1））的结构域1是必要的并且足以通过VEEV的感染，以及抗LDLRAD3抗体和LDLRAD3（D1）-FC融合蛋白块在细胞培养中的veev感染。 veev感染的发病机制在Ldlrad3中缺失的小鼠中消除，并且Ldlrad3（d1）-fc施用由几个veev亚型引起的疾病，包括高毒性菌株。诱饵受体融合蛋白的发展表明，预防严重的VEEV感染和人类相关疾病的策略.LDLRAD3是用委内瑞拉大麻脑炎病毒感染的受体，以及用可溶性LDLAD3缺失LDLRAD3或治疗的小鼠模型中的受体。诱饵分子废除了这种病毒引起的感染和疾病。

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  • 来源
    《Nature》 |2020年第7837期|308-314|共7页
  • 作者

    Ma Hongming; Kim Arthur S.; Kafai Natasha M.; Earnest James T.; Shah Aadit P.; Case James Brett; Basore Katherine; Gilliland Theron C.; Sun Chengqun; Nelson Christopher A.; Thackray Larissa B.; Klimstra William B.; Fremont Daved H.; Diamond Michael S.;

  • 作者单位

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA|Washington Univ Sch Med Dept Pathol & Immunol St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA|Washington Univ Sch Med Dept Pathol & Immunol St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Pathol & Immunol St Louis MO 63110 USA;

    Univ Pittsburgh Ctr Vaccine Res Dept Immunol Pittsburgh PA USA;

    Univ Pittsburgh Ctr Vaccine Res Dept Immunol Pittsburgh PA USA;

    Washington Univ Sch Med Dept Pathol & Immunol St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA;

    Univ Pittsburgh Ctr Vaccine Res Dept Immunol Pittsburgh PA USA;

    Washington Univ Sch Med Dept Pathol & Immunol St Louis MO 63110 USA|Washington Univ Sch Med Dept Biochem & Mol Biophys St Louis MO 63110 USA|Washington Univ Sch Med Andrew M & Jane M Bursky Ctr Human Immunol St Louis MO 63110 USA|Washington Univ Sch Med Immunotherapy Program St Louis MO 63110 USA|Washington Univ Sch Med Dept Mol Microbiol St Louis MO 63110 USA;

    Washington Univ Sch Med Dept Med St Louis MO 63110 USA|Washington Univ Sch Med Dept Pathol & Immunol St Louis MO 63110 USA|Washington Univ Sch Med Andrew M & Jane M Bursky Ctr Human Immunol St Louis MO 63110 USA|Washington Univ Sch Med Immunotherapy Program St Louis MO 63110 USA|Washington Univ Sch Med Dept Mol Microbiol St Louis MO 63110 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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