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

描述(由申请人提供)：信使核糖核酸翻译的关键步骤包括将40S核糖体亚基招募到被封顶的转录本的5‘端。通常，多亚基翻译起始因子的集合执行这一任务。病毒提供了吸引人的模型系统来研究这一基本过程，因为它们是专性的细胞内寄生虫，完全依赖于驻留在宿主中的蛋白质合成机制。由于mRNA翻译是病毒复制所必需的，病毒不仅擅长操纵宿主细胞的翻译机制，而且还有效地霸占了调节蛋白质合成的细胞信号通路。这项研究集中在单纯疱疹病毒-1(HSV-1)，这是一种神经营养性疱疹病毒，其高效复制导致了一系列人类疾病，从免疫能力强的宿主中的自限性上皮疮、严重的眼部疾病和危及生命的脑炎，到新生儿和免疫受损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细胞和病毒多肽产生所需的翻译起始因子复合体，成功地参与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病毒生长中重新激活至关重要，我们的分析可能会发现潜在的治疗干预的新靶点。我们特别建议：1)了解单纯疱疹病毒1型感染导致细胞翻译因子复合体改变的机制(S)；2)研究细胞翻译抑制物4E结合蛋白-1在单纯疱疹病毒1感染细胞中是如何受到控制的；以及3)确定单纯疱疹病毒1如何操纵细胞内的激酶mTOR来适当地控制病毒蛋白质的合成。公共卫生：像所有病毒一样，单纯疱疹病毒-1完全依赖于其细胞宿主内产生蛋白质的机制。通过了解病毒是如何捕获和控制细胞结构的，我们希望能想出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导致一系列人类疾病，从简单的皮肤溃疡到免疫系统正常的人的严重眼病和危及生命的脑部感染；此外，这些感染在新生儿和免疫系统工作不正常的人中尤为严重。

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.