Transcription, replication, trafficking and assembly of the influenza virus RNA genome

流感病毒是重要的人类和动物病原体，有可能导致人类严重呼吸道疾病和死亡。甲型和乙型流感病毒是造成季节性流感流行的原因，甲型流感病毒也有可能引起大流行。甲型流感病毒可感染多种动物，野生水禽被认为是它们的天然宿主。人类近代史上所有四次甲型流感病毒大流行都发生在禽流感病毒直接传播到人群中，导致1918年大流行，或禽流感或猪流感病毒与人类季节性流感病毒结合，导致1957年、1968年和2009年大流行。在新出现的流感大流行病毒的情况下，最初将没有疫苗可用，抗病毒药物对于应对第一波病毒至关重要；然而，目前可用的流感抗病毒药物有限。我们研究计划的重点是流感病毒的RNA聚合酶，这是一种大型多功能酶复合物。流感病毒RNA聚合酶的功能是复制储存在RNA片段中的病毒遗传信息。在流感病毒感染细胞后，RNA聚合酶首先复制遗传物质，然后细胞“被迫”读取遗传物质以制造病毒蛋白质，这是新病毒颗粒的基本组成部分。RNA聚合酶还能复制遗传物质，将其装入新病毒中，最近的研究表明，它甚至在将新遗传物质运送到新病毒颗粒组装的细胞中发挥作用。流感病毒的RNA聚合酶被认为是开发新型抗病毒药物的主要病毒靶点；没有它，病毒就无法复制自己并传播感染更多的宿主。事实上，最近已经开发了几种聚合酶抑制剂，在少数国家获准用于紧急情况。然而，对这些抗病毒药物的耐药性的发展已经有了记录。我们的研究计划旨在确切了解流感病毒RNA聚合酶如何重新编程细胞以制造病毒蛋白质并产生新的遗传物质副本以装入新的病毒颗粒。为了实现这些功能，病毒劫持与病毒RNA聚合酶一起作用的宿主蛋白质。我们的目标是了解病毒RNA聚合酶如何与这些宿主蛋白相互作用，这些宿主蛋白如何协助RNA聚合酶促进病毒遗传物质的复制，以及这些相互作用在宿主细胞中发生的位置。我们还旨在阐明病毒RNA聚合酶在将复制的遗传物质运送到宿主细胞内病毒组装位点中的作用。实现这些目标将产生关于流感病毒感染基础生物学的新知识。因此，它还将有助于评估新出现的流感病毒株的大流行潜力，从而有可能为公共卫生政策提供信息。重要的是，这一规划的结果将为进一步开展针对病毒RNA聚合酶的抗病毒开发工作提供基础，并可能有助于开发改进的或全新的流感疫苗。为了将我们目前和拟议的研究成果转化为抗病毒疗法，我们已经与工业合作伙伴建立了联系。此外，我们积极寻求与工业合作者的新机会，以翻译所产生的知识。

Influenza viruses are important human and animal pathogens that have the potential to cause severe respiratory disease and death in humans. Influenza A and B viruses are responsible for seasonal epidemics and influenza A viruses also have the potential to cause pandemics. Influenza A viruses infect a wide range of animal species, with wild waterfowl being considered their natural reservoir. All four influenza A virus pandemics of recent human history occurred when either an avian influenza virus transmitted directly into the human population, giving rise to the 1918 pandemic, or avian or swine influenza viruses combined with human seasonal influenza virus, leading to the 1957, 1968 and 2009 pandemics. In the case of a new emerging influenza pandemic virus, no vaccines would be available initially and antivirals would be crucial to tackle the first wave of the virus; however, currently available influenza antivirals are limited.The focus of our research programme is the RNA polymerase of influenza viruses, a large multifunctional enzyme complex. The function of the influenza virus RNA polymerase is to make copies of the genetic information of the virus, stored in segments of RNA. After an influenza virus infects a cell, the RNA polymerase first makes copies of the genetic material, which the cell is then 'forced' to read to make viral proteins, building blocks of new virus particles. The RNA polymerase also makes copies of the genetic material to be packed into new viruses and recent research suggests that it even plays a role in transporting the new genetic material to the sites in the cells where new virus particles are assembled. The RNA polymerase of influenza viruses is considered a prime viral target for the development of novel antiviral drugs; without it the virus is unable to make new copies of itself and spread to infect further hosts. Indeed, several polymerase inhibitors have been developed recently which are licensed for use in emergency in a limited number of countries. However, development of resistance against these antivirals has already been documented.Our research programme aims to understand exactly how the influenza virus RNA polymerase reprogrammes the cell to make viral proteins and produce new copies of the genetic material to be packed into new virus particles. To perform these functions the virus hijacks host proteins that act together with the viral RNA polymerase. We aim to understand how the viral RNA polymerase interacts with these host proteins, how these host proteins assist the RNA polymerase in promoting the copying of the viral genetic material, and where these interactions occur in the host cell. We also aim to elucidate the role of the viral RNA polymerase in transporting the copied genetic material to the sites of virus assembly inside the host cell. Addressing these objectives will result in new knowledge about the fundamental biology of influenza virus infections. As such, it will also help with the assessment of the pandemic potential of emerging influenza virus strains and therefore has potential to inform public health policies. Importantly, results from this programme will underpin further work into targeting the viral RNA polymerase for antiviral development and could contribute to the development of improved or entirely novel influenza vaccines. To translate findings from our current and proposed research into antiviral therapies, we already have established links with industrial partners. Furthermore, we actively seek new opportunities with industrial collaborators for translating the knowledge generated.