The role of cellular RNA editing in human respiratory syncytial virus and influenza virus biology.

甲型流感病毒(IAV)和人类呼吸道合胞病毒(HRSV)是两种对全球健康具有重大意义的非常重要的呼吸道病毒。这两种病毒都会在英国的冬季月份引起感染，IAV也有可能导致重大流行病。这两种病毒都可以感染成年人群的HRSV，也可以感染所有两岁以下的儿童。虽然有针对季节性IAV的有效疫苗和可以服用的抗病毒药物，但对HRSV没有同等的治疗方法。同样，大流行性IAV可以非常迅速地传播到全球，因此总是需要有效的治疗对策。因此，迫切而尚未得到满足的医疗保健需要确保强有力的战略，以降低这些病毒造成的当前和未来的疾病负担。对于这两种病毒来说，它们都严重依赖于它们感染的细胞来进行多产和有效的感染。然而，这些细胞就像一个战场，病毒攻击细胞，细胞试图破坏和减少病毒感染的影响。某些宿主细胞蛋白质在这些过程之间的平衡中起着关键作用，有时这被称为“进化军备竞赛”。我们已经确定了一组类似的细胞蛋白，我们认为它们是这些关键蛋白之一，可以在病毒感染的平衡中起到有利的作用。它们统称为作用于RNA的腺苷脱氨酶(ADAR)，其功能是改变病毒遗传物质的序列。最初，人们认为这是为了细胞的利益，因为它会导致有害突变的积聚，从而阻止病毒发挥作用。然而，我们的初步和发表的数据结合其他研究小组的数据表明，对于一些医学上重要的病毒，包括IAV和HRSV以及HIV-1和疱疹病毒等病毒，这些病毒实际上是亲病毒的，病毒利用它们来促进病毒感染和宿主细胞的费用。我们的建议是调查与ADAR的相互作用如何以及为什么对IAV和HRSV实现这种亲病毒活性，我们拥有进行这项研究所需的所有专家简易性。我们想要确定ADAR在病毒遗传物质上的哪里起作用，在细胞中发生在哪里，以及这如何对病毒生物学和遗传物质的多样性产生有利影响。后一点非常重要，因为由于ADAR被许多病毒用作积极的亲病毒因子，从治疗上操纵ADAR活性的能力将是医学上的好处，因为它可以提供针对许多不同病毒的非专利疗法的潜力。建议将重点放在罗斯林研究所的IAV和利兹大学的HRSV上。然而，我们认为，将这一项目作为一个联合项目进行将允许许多不同试剂的有效共享更重要的是识别和研究两种呼吸道病毒ADAR活性的共同机制。

Influenza A virus (IAV) and human respiratory syncytial virus (HRSV) are two very important respiratory viruses of major significance for global health. Both viruses cause infections in winter months in the UK with IAV also having the potential to cause major pandemics. Both viruses can infect the adult population with HRSV also infecting all children under the age of two. Whilst there are effective vaccines to seasonal IAV and also anti-viral drugs that can be taken there are no equivalent therapies for HRSV. Likewise, pandemic IAV can go global very quickly and therefore effective therapeutic countermeasures are always needed. Thus there is an urgent and unmet healthcare need to ensure robust strategies to lower the current and future disease burden caused by these viruses.For both viruses they rely critically on the cell they infect to mount productive and efficient infections. However, these cells resemble a battleground with the virus attacking the cell and the cell trying to sabotage and reduce the impact of virus infection. Certain host cell proteins are key players in the balance between these processes and sometime this is referred to as an 'evolutionary arms race'. We have identified a group of similar cellular proteins that we propose are one of these key proteins that can tip the favour in the balance of virus infection. Collectively they are known as Adenosine Deaminase Acting on RNA (ADAR), and their function is to change the sequence of the viral genetic material. Originally it was thought this worked for the benefit of the cell by causing the buildup of harmful mutations that prevent the virus from working. However, our preliminary and published data combined with that from other research groups suggests that for a number of medically important viruses, including IAV and HRSV and viruses such as HIV-1 and herpesviruses that these are actually pro-viral and the viruses use them to promote virus infection and the expense of the host cell.Our proposal is to investigate how and why the interaction with ADAR achieves this pro-viral activity for IAV and HRSV and we have all the expert ease necessary to conduct this research. We want to determine where on the virus genetic material ADAR works, where in the cell this occurs and how this causes beneficial effect for virus biology and diversity of the genetic material. This latter point is very important because as ADAR is used by many viruses as a positive pro-viral factor, the ability to therapeutically manipulate ADAR activity would be of medical benefit as it could provide the potential for a generic therapy against many different viruses.The proposal will focus on IAV at the Roslin Institute and HRSV at the University of Leeds. However, we propose that undertaking this as a combined project will allow the efficient sharing of many different reagents are more important identify and investigate common mechanisms of ADAR activity for both respiratory viruses.