Virus-host interactions that regulate translation in cells infected with HSV-1

描述（由申请人提供）：mRNA翻译的关键步骤涉及将40 S核糖体亚基募集到加帽转录物的5'端。通常，多亚基翻译起始因子的集合执行该任务。病毒提供了有吸引力的模型系统来研究这一基本过程，因为它们是专性细胞内寄生虫，完全依赖于驻留在其宿主中的蛋白质合成机制。由于mRNA翻译是其复制所必需的，因此病毒不仅精通操纵宿主细胞翻译机制，而且还有效地征用调节蛋白质合成的细胞信号传导途径。本研究集中于单纯疱疹病毒-1（HSV-1），一种神经营养性疱疹病毒，其生产性复制导致一系列人类疾病，从免疫活性宿主中的自限性上皮溃疡、严重眼病和危及生命的脑炎到新生儿和免疫功能低下个体中的播散性疾病。我们的长期目标是了解HSV-1如何通过改变和重塑产生细胞和病毒多肽所需的翻译起始因子复合物来成功地接合和控制细胞蛋白质合成装置。由于这一过程对于从潜伏期和植物性病毒生长中重新激活至关重要，因此我们的分析可能会发现潜在治疗干预的新靶点。我们特别提出i）理解细胞翻译因子复合物由于HSV-1感染而改变的机制; ii）研究细胞翻译阻遏物4 E-结合蛋白-1在HSV-1感染的细胞中如何被控制;和iii）确定HSV-1如何操纵细胞激酶mTOR以适当地控制病毒蛋白质合成。公共卫生部门：像所有的病毒一样，单纯疱疹病毒-1完全依赖于在其细胞宿主内产生蛋白质的机制。通过了解病毒如何捕获和控制细胞机器，我们希望找到干扰病毒生长的新方法。这一点很重要，因为单纯疱疹病毒会引起一系列人类疾病，从简单的皮肤溃疡到严重的眼部疾病，以及免疫系统正常的人的危及生命的脑部感染;此外，新生儿和免疫系统不正常的人感染特别严重。

DESCRIPTION (provided by applicant): A critical step in mRNA translation involves the recruitment of the 40S ribosome subunit to the 5' end of capped transcripts. Typically, an ensemble of multi-subunit translation initiation factors executes this task. Viruses provide attractive model systems to study this fundamental process, as they are obligate intracellular parasites, completely dependent upon the protein synthesis machinery resident in their hosts. As mRNA translation is necessary for their replication, viruses are proficient in manipulating not only the host cell translational machinery, but also effectively commandeer the cellular signaling pathways that regulate protein synthesis. This investigation concentrates on Herpes simplex virus-1 (HSV-1), a neurotrophic herpesvirus whose productive replication is responsible for a spectrum of human diseases ranging from self- limiting epithelial sores, severe ocular disease and life threatening encephalitis in immunocompetent hosts to disseminated disease in neonates and immunocompromised individuals. Our long - term objective is to understand how HSV-1 successfully engages and controls the cellular protein synthesis apparatus by both altering and remodeling translation initiation factor complexes required for the production of both cellular and viral polypeptides. As this process is of vital importance for reactivation from latency and vegetative viral growth, our analysis is likely to uncover new targets for potential therapeutic intervention. We specifically propose to i) understand the mechanism(s) whereby cellular translation factor complexes are altered as a result of HSV-1 infection; ii) investigate how the cellular translation repressor 4E- binding protein-1 is controlled in HSV-1 infected cells; and iii) determine how HSV-1 manipulates the cellular kinase mTOR to properly control viral protein synthesis. PUBLIC HEALTH REVELANCE: Like all viruses, herpes simplex virus-1 is completely dependent upon the machinery that produces proteins within its cellular host. By understanding how the virus captures and gains control of the cellular machinery, we hope to come up with new ways of interfering with virus growth. This is important because herpes simplex virus causes a spectrum of human diseases ranging from simple skin sores, to severe eye disease and life threatening brain infections in people with normal immune systems; in addition, the infections are particularly severe in newborns and individuals whose immune systems are not working properly.