ARF6 is a host factor for SARS-CoV-2 infection in vitro.
ARF6 is a host factor for SARS-CoV-2 infection in vitro.
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DOI：
10.1099/jgv.0.001868
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发表时间：
2023-06
影响因子：
3.8
通讯作者：
Wobus, C. E.
中科院分区：
文献类型：
--
作者：
Mirabelli, C.;Cunha, J. Bragazzi;Wotring, J. W.;Sherman, E. J.;El Saghir, J.;Harder, J.;Kretzler, M.;Sexton, J. Z.;Emmer, B. T.;Wobus, C. E.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是一种新出现的β-冠状病毒，通过两种途径进入细胞，直接融合于质膜或内吞后与晚期内体/溶酶体融合。虽然病毒受体、ACE 2、多重进入因子和病毒在质膜上的融合机制已被广泛研究，但对病毒通过内吞途径进入的了解较少。通过使用对TMPRSS 2抑制剂卡莫司他的抗病毒作用具有抗性的人肝癌细胞系Huh-7，我们发现SARS-CoV-2的进入不依赖于发动蛋白，而是依赖于胆固醇。ADP-核糖基化因子6（ARF 6）已被描述为SARS-CoV-2复制的宿主因子，并参与几种致病病毒的进入和感染。使用CRISPR/Cas9基因缺失，观察到Huh-7中SARS-CoV-2摄取和感染的适度减少。此外，小分子NAV-2729对ARF 6的药理学抑制显示病毒感染呈剂量依赖性减少。重要的是，NAV-2729还降低了更多生理感染模型中的SARS-CoV-2病毒载量：Calu-3细胞和肾类器官。这突出了ARF 6在多细胞环境中的作用。总之，这些实验表明ARF 6是开发抗SARS-CoV-2抗病毒策略的假定靶点。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged beta-coronavirus that enter cells via two routes, direct fusion at the plasma membrane or endocytosis followed by fusion with the late endosome/lysosome. While the viral receptor, ACE2, multiple entry factors and the mechanism of fusion of the virus at the plasma membrane have been investigated extensively, viral entry via the endocytic pathway is less understood. By using a human hepatocarcinoma cell line, Huh-7, which is resistant to the antiviral action of the TMPRSS2 inhibitor camostat, we discovered that SARS-CoV-2 entry is not dependent on dynamin but on cholesterol. ADP-ribosylation factor 6 (ARF6) has been described as a host factor for SARS-CoV-2 replication and is involved in the entry and infection of several pathogenic viruses. Using CRISPR/Cas9 genetic deletion, a modest reduction in SARS-CoV-2 uptake and infection in Huh-7 was observed. In addition, pharmacological inhibition of ARF6 with the small molecule NAV-2729 showed a dose-dependent reduction of viral infection. Importantly, NAV-2729 also reduced SARS-CoV-2 viral loads in more physiological models of infection: Calu-3 cells and kidney organoids. This highlighted a role for ARF6 in multiple cell contexts. Together, these experiments point to ARF6 as a putative target to develop antiviral strategies against SARS-CoV-2.
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影响因子：
4.5
作者：
Emmer BT;Sherman EJ;Lascuna PJ;Graham SE;Willer CJ;Ginsburg D
通讯作者：
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DOI：
10.1038/s41577-022-00681-9
发表时间：
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