Department of Molecular Microbiology, Pathology and Immunology, School of Medicine, Washington University, St. Louis, United States.
Elife. 2019 Nov 26;8:e50276. doi: 10.7554/eLife.50276.
Comprehensive knowledge of the host factors required for picornavirus infection would facilitate antiviral development. Here we demonstrate roles for three human genes, , , and , in infection by multiple picornaviruses. CRISPR deletion of , or reduced encephalomyocarditis virus (EMCV), coxsackievirus B3 (CVB3), poliovirus and enterovirus D68 infection, and chemical inhibitors of TNK2 and WASL decreased EMCV infection. Reduced EMCV lethality was observed in mice lacking TNK2. TNK2, WASL, and NCK1 were important in early stages of the viral lifecycle, and genetic epistasis analysis demonstrated that the three genes function in a common pathway. Mechanistically, reduced internalization of EMCV was observed in TNK2 deficient cells demonstrating that TNK2 functions in EMCV entry. Domain analysis of WASL demonstrated that its actin nucleation activity was necessary to facilitate viral infection. Together, these data support a model wherein TNK2, WASL, and NCK1 comprise a pathway important for multiple picornaviruses.
全面了解微小核糖核酸病毒感染所需的宿主因素将有助于抗病毒药物的开发。在这里，我们证明了三个人类基因、、和在多种微小核糖核酸病毒感染中的作用。CRISPR 缺失或减少了脑炎心肌炎病毒（EMCV）、柯萨奇病毒 B3（CVB3）、脊髓灰质炎病毒和肠道病毒 D68 的感染，而 TNK2 和 WASL 的化学抑制剂则降低了 EMCV 的感染。在缺乏 TNK2 的小鼠中观察到 EMCV 的致死性降低。TNK2、WASL 和 NCK1 在病毒生命周期的早期阶段很重要，遗传上位性分析表明这三个基因在一个共同的途径中发挥作用。从机制上讲，在 TNK2 缺陷细胞中观察到 EMCV 的内化减少，表明 TNK2 参与了 EMCV 的进入。WASL 的结构域分析表明，其肌动蛋白成核活性对于促进病毒感染是必要的。综上所述，这些数据支持了一个模型，即 TNK2、WASL 和 NCK1 构成了一个对多种微小核糖核酸病毒很重要的途径。
