Probing the translational dynamics of influenza virus infection.

在细胞水平上，病毒感染的结果取决于病毒和细胞之间控制细胞生物合成机制的斗争，因为这最终决定了产生的子代病毒的数量。许多病毒编码自己的核酸聚合酶，但都依赖于细胞蛋白质合成机制。因此，核糖体是关键的战场。使用主要的人类和动物病原体A型流感病毒（IAV）作为模型系统，我们将使用新的核糖体分析技术来详细说明这一冲突的详细程度，迄今为止是不可能的。核糖体分析允许准确确定核糖体在给定时刻翻译哪些mRNA（病毒或细胞）;从而定义在控制细胞的战斗中的“前线”状态。我们的目标是：1.定义在病毒-宿主细胞组合中翻译的细胞和病毒mRNAs，其中病毒“获胜”或宿主获胜。确定影响细胞基因表达的许多病毒机制中的哪一种及其决定细胞翻译机器控制之战结果的特定靶点.测试IAV特异性操纵核糖体使其偏向病毒信使的优先翻译的假设。总体而言，该项目将从病毒和细胞的角度定义关键事件，这些事件决定了单个感染细胞是否被有效感染;数据将有助于设计新的治疗干预策略。

At the cellular level, the outcome of virus infection hinges on a battle between virus and cell for the control of the cellular biosynthetic machinery, as this ultimately determines the amount of progeny virus produced. Many viruses encode their own nucleic acid polymerases, but all are reliant on the cellular protein synthesis machinery. The ribosome therefore represents the key battleground. Using the major human and animal pathogen influenza A virus (IAV) as a model system, we will use the novel technique of ribosomal profiling to detail this conflict at a level of detail hitherto impossible. Ribosomal profiling allows the accurate determination of which mRNAs (viral or cellular) that the ribosomes are translating at a given moment; thereby defining the state of the 'frontline' in the battle for control of the cell. Our objectives are to:1. Define the cellular and viral mRNAs that are translated in virus-host cell combinations where either the virus 'wins' or where the host wins.2. To define which of the many viral mechanisms that affect cellular gene expression are and their specific targets which decide the outcome of the battle for control of the cellular translation machinery.3. Test the hypothesis that IAV specifically manipulates the ribosome to bias it towards preferential translation of viral messengers.Overall, the project will define the key events from both virus and cellular perspective that define whether an individual infected cell is productively infected; data that will aid the design of new therapeutic intervention strategies.