Evasion of antiviral responses in the host cell nucleus

了解病毒感染细胞时如何被检测的基本过程，以及细胞用来对抗此类病毒的防御机制，对于改善人类、动物和植物的健康和福祉至关重要。许多重要的宿主防御途径依赖于宿主细胞核中启动和/或起作用的过程。本研究旨在了解我们发现的疱疹病毒逃避感染细胞核内抗病毒反应的新途径。疱疹病毒是高度流行的动物病原体，在马、牛、猪和家禽业造成重大疾病和经济损失。人类疱疹病毒也可能导致严重或危及生命的疾病，特别是在免疫抑制的人群中，并且被认为会增加多发性硬化症和阿尔茨海默病的风险。疱疹病毒感染是终身的——在最初的“原发性”感染之后，这些病毒在其宿主中建立了潜伏性感染，例如在神经细胞中，随后通常在宿主的一生中反复发作再激活，病毒从其藏身之处出现，引起“继发性”感染（例如唇疱疹）并传播给新的宿主。由于疱疹病毒感染造成很高的疾病负担，显然需要开发新的和改进的抗病毒药物和疫苗，以治疗动物和人类感染这些病毒。这项研究的重点是揭示我们最近发现的疱疹病毒可以抵抗宿主细胞防御的新途径的细节。这种以前未知的途径涉及两种病毒蛋白的复合物，其中一种是保守蛋白“激酶”，一种通过将磷酸盐分子附着在其他蛋白质上来修饰其功能的酶。我们将使用最先进的技术来了解在疱疹病毒感染期间，这种病毒蛋白复合物如何，为什么以及在何处靶向和修饰特定的细胞蛋白。重要的是，这项研究将为有效对抗多种不同病毒的抗病毒途径提供新的重要知识。我们将从这项研究中获得关于病毒如何与宿主相互作用的新认识，这将支持开发新的和改进的方法来对抗疱疹病毒，以及许多其他在世界各地引起重大动物和人类疾病的重要病毒。

Understanding the fundamental processes of how viruses are detected when they infect a cell and the defence mechanisms that cells employ to combat such viruses is crucial for improving the health and wellbeing of humans, animals and plants. Many important host defence pathways rely on processes initiated and/or functioning in the host cell nucleus. This research seeks to understand a new pathway we have discovered by which herpesviruses can evade antiviral responses within the nucleus of infected cells. Herpesviruses are highly prevalent pathogens of animals that cause significant disease and economic losses in the horse, cow, pig and poultry industries. Human herpesviruses can also cause severe or life-threatening disease, especially in immuno-suppressed people, and are thought to increase the risk of multiple sclerosis and Alzheimer's disease. Herpesvirus infections are for life - after the initial 'primary' infection these viruses establish a latent infection of their hosts, for example in nerve cells, which is commonly followed by repeated episodes of reactivation over the lifetime of the host, where the virus emerges from its hiding place to cause 'secondary' infections (e.g. cold sores) and spread to new hosts. Because of the high disease-burden caused by herpesvirus infections, there is a clear need to develop new and improved antiviral drugs and vaccines to treat infections with these viruses in animals and humans.The focus of this research is to uncover the details of the new pathway we have recently discovered by which herpesviruses can counteract host defences in cells. This previously unknown pathway involves a complex of two virus proteins, one of which is a conserved protein "kinase", an enzyme that modifies the function of other proteins by attaching a phosphate molecule to them. Will we use state-of-the-art techniques to understand how, why and where specific cellular proteins are targeted and modified by this virus protein complex during herpesvirus infection. Importantly, this research will provide new and important knowledge about antiviral pathways that are effective against a diverse range of different viruses. The new understanding of how viruses interact with their hosts that we will gain from this research will underpin the development of new and improved ways of fighting herpesviruses, as well as many other important viruses, that cause significant animal and human diseases throughout the world.