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Rna Interference Screen For Human Genes Associated With West Nile Virus Infection

机译：Rna干扰筛查与西尼罗河病毒感染有关的人类基因

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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 such flaviviruses with mammalian host cells is limited, WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection1. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticu-lum, 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 that affect 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 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 a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.
机译：西尼罗河病毒（WNV）和相关的黄病毒，例如tick传脑炎，日本脑炎，黄热病和登革热病毒，构成了严重的全球人类健康问题。但是，我们对这种黄病毒与哺乳动物宿主细胞的分子相互作用的理解是有限的，WNV仅编码10种蛋白质，这意味着它可能使用许多细胞蛋白质进行感染1。 WNV通过pH依赖的内吞作用进入细胞质，经历翻译和复制循环，与内质网结合组装后代病毒体，并沿着分泌途径排出，RNA干扰（RNAi）提供了一种强有力的正向遗传学方法来分离病毒-宿主细胞相互作用。在这里，我们报告使用人类全基因组范围的RNAi筛查鉴定305种影响WNV感染的宿主蛋白。基因的功能聚类揭示了该病毒对宿主细胞生理的复杂依赖性，需要多种分子和细胞途径才能成功感染。我们进一步证明了在WNV内在化中对遍在蛋白连接酶CBLL1的需求，内质网相关的降解途径在病毒感染中的进入后作用以及单羧酸转运蛋白MCT4作为病毒复制抗性因子。通过将这项研究扩展到登革热病毒，我们表明黄病毒与宿主细胞具有重叠和独特的相互作用策略。这项研究提供了WNV与人细胞相互作用的全面分子画像，形成了理解单个正链RNA病毒感染的模型，并揭示了潜在的抗病毒目标。

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