科學家首次鑑定出委內瑞拉馬腦炎病毒的受體
作者：
小柯機器人發布時間：2020/11/20 14:35:04
美國聖路易斯華盛頓大學Michael S. Diamond研究小組發現，LDLRAD3是委內瑞拉馬腦炎病毒的受體。相關論文於2020年11月18日在線發表在《自然》雜誌上。
研究人員使用基於全基因組的CRISPR–Cas9篩選，將含有低密度脂蛋白受體A類結構域的3（LDLRAD3）確定為委內瑞拉馬腦炎病毒（VEEV）受體，這是清道夫受體超家族的一個高度保守但認識較少的成員。小鼠Ldlrad3或人LDLRAD3的基因編輯可顯著減少病毒對神經元細胞的感染，並在與LDLRAD3互補後得以恢復。LDLRAD3直接與VEEV顆粒結合，並增強病毒附著和內吞進入宿主細胞。
遺傳研究表明，LDLRAD3的結構域1（LDLRAD3（D1））對VEEV感染是必要且足夠的，並且抗LDLRAD3抗體和LDLRAD3（D1）-Fc融合蛋白均可在細胞培養中阻斷VEEV感染。VEEV感染的發病機制在Ldlrad3缺失的小鼠中被消除，而使用LDLRAD3（D1）-Fc消除了由VEEV幾種亞型（包括高毒力株）引起的疾病。誘餌受體融合蛋白的開發是一種預防人類嚴重VEEV感染和相關疾病的策略。
據了解，VEEV是一種通過蚊子傳播的神經營養性甲型病毒，可導致人類腦炎和死亡。VEEV是一種生物防禦問題，因為它具有氣溶膠擴散的潛力，並且目前缺乏足夠的對策。VEEV進入和感染所需的宿主因素的特徵仍然較差。
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