小柯机器人

美国圣路易斯华盛顿大学Michael S. Diamond研究小组发现，LDLRAD3是委内瑞拉马脑炎病毒的受体。相关论文于2020年11月18日在线发表在《自然》杂志上。

研究人员使用基于全基因组的CRISPR–Cas9筛选，将含有低密度脂蛋白受体A类结构域的3（LDLRAD3）确定为委内瑞拉马脑炎病毒（VEEV）受体，这是清道夫受体超家族的一个高度保守但认识较少的成员。小鼠Ldlrad3或人LDLRAD3的基因编辑可显著减少病毒对神经元细胞的感染，并在与LDLRAD3互补后得以恢复。LDLRAD3直接与VEEV颗粒结合，并增强病毒附着和內吞进入宿主细胞。

遗传研究表明，LDLRAD3的结构域1（LDLRAD3（D1））对VEEV感染是必要且足够的，并且抗LDLRAD3抗体和LDLRAD3（D1）-Fc融合蛋白均可在细胞培养中阻断VEEV感染。VEEV感染的发病机制在Ldlrad3缺失的小鼠中被消除，而使用LDLRAD3（D1）-Fc消除了由VEEV几种亚型（包括高毒力株）引起的疾病。诱饵受体融合蛋白的开发是一种预防人类严重VEEV感染和相关疾病的策略。

据了解，VEEV是一种通过蚊子传播的神经营养性甲型病毒，可导致人类脑炎和死亡。VEEV是一种生物防御问题，因为它具有气溶胶扩散的潜力，并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较差。

附：英文原文

Title: LDLRAD3 is a receptor for Venezuelan equine encephalitis virus

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

Issue&Volume: 2020-11-18

Abstract: Venezuelan equine encephalitis virus (VEEV) is a neurotropic alphavirus transmitted by mosquitoes that causes encephalitis and death in humans1. 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.

DOI: 10.1038/s41586-020-2915-3

Source: https://www.nature.com/articles/s41586-020-2915-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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