RNA interference screen for human genes associated with West Nile virus infection.
RNA interference screen for human genes associated with West Nile virus infection.
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DOI：
10.1038/nature07207
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发表时间：
2008-09-11
期刊：
影响因子：
64.8
通讯作者：
Fikrig, Erol
中科院分区：
文献类型：
--
作者：
Krishnan, Manoj N.;Ng, Aylwin;Sukumaran, Bindu;Gilfoy, Felicia D.;Uchil, Pradeep D.;Sultana, Hameeda;Brass, Abraham L.;Adametz, Rachel;Tsui, Melody;Qian, Feng;Montgomery, Ruth R.;Lev, Sima;Mason, Peter W.;Koski, Raymond A.;Elledge, Stephen J.;Xavier, Ramnik J.;Agaisse, Herve;Fikrig, Erol
西尼罗河病毒（WNV）以及相关的黄病毒，如蜱传脑炎病毒、日本脑炎病毒、黄热病毒和登革病毒，构成了一个重大的全球人类健康问题。然而，我们对西尼罗河病毒（及相关黄病毒）与哺乳动物宿主细胞的分子相互作用的了解有限。西尼罗河病毒仅编码10种蛋白质，这意味着该病毒可能利用许多细胞蛋白质来进行感染。西尼罗河病毒通过依赖pH的内吞作用进入细胞质，经历翻译和复制循环，与内质网相关联组装子代病毒粒子，并沿着分泌途径排出。RNA干扰（RNAi）提供了一种强大的正向遗传学方法来剖析病毒 - 宿主细胞相互作用。在此我们报告通过一项人类全基因组RNAi筛选鉴定出305种影响西尼罗河病毒感染的宿主蛋白质。对这些基因进行功能聚类分析揭示了该病毒对宿主细胞生理的复杂依赖性，成功感染需要各种各样的分子和细胞途径。我们进一步证明了泛素连接酶CBLL1在西尼罗河病毒内化过程中的必要性，内质网相关降解（ERAD）途径在病毒感染中的进入后作用，以及单羧酸转运蛋白MCT4作为一种病毒复制抗性因子。通过将这项研究扩展到登革病毒，我们表明黄病毒与宿主细胞既有重叠的又有独特的相互作用策略。这项研究提供了西尼罗河病毒 - 人类细胞相互作用的第一幅全面的分子画像，为理解单正链RNA病毒感染形成了一个范例，并揭示了潜在的抗病毒靶点。
West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of WNV (and related flaviviruses) with mammalian host cells is limited. WNV encodes only 10 proteins, implying that the virus may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA-interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins impacting WNV infection, using a human genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic reticulum-associated degradation (ERAD) pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides the first comprehensive molecular portrait of WNV-human cell interactions that forms a paradigm for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.
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影响因子：
5.4
作者：
Samuel, Melanie A.;Whitby, Kevin;Diamond, Michael S.
通讯作者：
Diamond, Michael S.
影响因子：
5.4
作者：
Krishnan, Manoj N.;Sukumaran, Bindu;Fikrig, Erol
通讯作者：
Fikrig, Erol
DOI：
10.1073/pnas.0703348104
发表时间：
2007-05-22
影响因子：
11.1
作者：
Emara, Mohamed M.;Brinton, Margo A.
通讯作者：
Brinton, Margo A.
影响因子：
64.8
作者：
Pelkmans, L;Fava, E;Zerial, M
通讯作者：
Zerial, M
影响因子：
4.5
作者：
Khor, R;McElroy, LJ;Whittaker, GR
通讯作者：
Whittaker, GR