A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/β-Catenin Signaling during Rift Valley Fever Virus Infection.
A Genome-Wide RNA Interference Screen Identifies a Role for Wnt/β-Catenin Signaling during Rift Valley Fever Virus Infection.
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DOI：
10.1128/jvi.00543-16
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发表时间：
2016-08-15
影响因子：
5.4
通讯作者：
Negrete OA
中科院分区：
文献类型：
--
作者：
Harmon B;Bird SW;Schudel BR;Hatch AV;Rasley A;Negrete OA
裂谷热病毒（RVFV）是布尼亚病毒科的一种虫媒病毒，能够引起人类和牲畜的严重发病和死亡。为了确定布尼亚病毒复制中涉及的宿主因素，我们采用全基因组RNA干扰（RNAi）筛选，并确定了381个基因，其敲低降低了感染。当基因命中在功能上成簇时，Wnt途径是最具代表性的途径。随着进一步的研究，我们发现RVFV感染激活Wnt信号传导，当Wnt信号传导被预激活时增强，当β-catenin被敲低时减少，并且被Wnt信号传导抑制剂阻断。使用远亲布尼亚病毒拉克罗斯病毒和加州脑炎病毒发现了类似的结果，表明Wnt信号传导在布尼亚病毒感染中的保守作用。我们提出了一个模型，其中布尼亚病毒激活Wnt响应基因来调节促进有效病毒复制所需的最佳细胞周期条件。本研究的发现有助于设计有效的宿主导向抗病毒治疗药物。重要性RVFV是一种蚊媒布尼亚病毒，在非洲流行，但已显示出在新地区出现的能力（例如，阿拉伯半岛）。作为一种主要影响牲畜的人畜共患病原体，RVFV也可在人类中引起致命的出血热和脑炎。目前，这种病毒没有治疗方法或完全许可的疫苗。使用高通量RNAi筛选，我们确定了经典Wnt信号传导作为调节RVFV感染的重要宿主途径。对于RVFV，沿着其他不同的本扬病毒，观察到Wnt信号传导的有益作用，表明涉及Wnt信号传导的保守本扬病毒复制机制。这些研究补充了我们对布尼亚病毒感染的基本机制的认识，并为针对致病性布尼亚病毒的对策发展提供了新的途径。
Rift Valley fever virus (RVFV) is an arbovirus within the Bunyaviridae family capable of causing serious morbidity and mortality in humans and livestock. To identify host factors involved in bunyavirus replication, we employed genome-wide RNA interference (RNAi) screening and identified 381 genes whose knockdown reduced infection. The Wnt pathway was the most represented pathway when gene hits were functionally clustered. With further investigation, we found that RVFV infection activated Wnt signaling, was enhanced when Wnt signaling was preactivated, was reduced with knockdown of β-catenin, and was blocked using Wnt signaling inhibitors. Similar results were found using distantly related bunyaviruses La Crosse virus and California encephalitis virus, suggesting a conserved role for Wnt signaling in bunyaviral infection. We propose a model where bunyaviruses activate Wnt-responsive genes to regulate optimal cell cycle conditions needed to promote efficient viral replication. The findings in this study should aid in the design of efficacious host-directed antiviral therapeutics. IMPORTANCE RVFV is a mosquito-borne bunyavirus that is endemic to Africa but has demonstrated a capacity for emergence in new territories (e.g., the Arabian Peninsula). As a zoonotic pathogen that primarily affects livestock, RVFV can also cause lethal hemorrhagic fever and encephalitis in humans. Currently, there are no treatments or fully licensed vaccines for this virus. Using high-throughput RNAi screening, we identified canonical Wnt signaling as an important host pathway regulating RVFV infection. The beneficial role of Wnt signaling was observed for RVFV, along with other disparate bunyaviruses, indicating a conserved bunyaviral replication mechanism involving Wnt signaling. These studies supplement our knowledge of the fundamental mechanisms of bunyavirus infection and provide new avenues for countermeasure development against pathogenic bunyaviruses.