Discovering cellular responses targeted by herpesvirus tegument enzymes that are delivered by the entering virion

疱疹病毒是一个非常大的病毒家族，在动物和人类中引起许多疾病。特别地，许多属于α疱疹病毒亚科的病毒在马、牛、猪和家禽业中引起显著的疾病和经济损失。这种感染人类的疱疹病毒亚科的病毒通常会在健康人中引起相对良性的疾病，如唇疱疹和生殖器疱疹（单纯疱疹病毒）或水痘和带状疱疹（水痘带状疱疹病毒）。然而，这些病毒确实会导致严重或危及生命的疾病，特别是在免疫抑制的人群中，例如疱疹性角膜炎是失明的主要原因，疱疹性脑炎即使在抗病毒药物治疗后也通常是致命的。一旦被这些病毒感染，它们就会终生存在：所有疱疹病毒都会在宿主的一生中建立一种休眠（所谓的潜伏）感染，通常是在感觉神经系统内的α疱疹病毒，这不能用可用的药物治疗或可用的疫苗预防。这些潜伏感染细胞的周期性病毒再活化可导致疾病复发，并使病毒传播到未感染的生物体。由于这些病毒在动物和人类中引起的许多疾病，迫切需要开发改进的抗病毒药物和疫苗。为了能够有效地对抗病毒感染，尽可能多地了解病毒如何感染并在体内细胞内繁殖至关重要。细胞有许多方法来保护自己免受病毒的侵害，相反，病毒也进化出了许多克服这些防御的方法。关于这些“宿主防御”和“病毒对策”，我们仍然有很多不了解的地方，我们越能发现细胞如何自我防御，以及病毒如何克服这些防御，本研究的重点是发现疱疹病毒中含有的特定病毒酶对宿主细胞的影响，这些病毒酶对于疱疹病毒逃避宿主防御至关重要，尽管我们几乎不知道这些酶的具体作用，因为它们被病毒释放到细胞中。我们将使用最先进的蛋白质分析技术，使我们能够同时检测和定量数千种蛋白质，以发现这些病毒酶靶向的细胞特异性蛋白质。我们还将使用尖端的显微镜（所谓的超分辨率显微镜）来分析这些病毒酶的命运，因为它们被传入的病毒传递到细胞中;这些强大的新成像技术现在为我们提供了检测和监测细胞中单个分子的能力，使我们能够以前所未有的细节水平观察病毒-宿主相互作用。在这项工作中，我们将使用人类病原体单纯疱疹病毒，作为这个重要病毒家族中最明确和最易处理的模型，这项工作所揭示的细胞途径可能包括许多细胞防御系统，这些系统对细胞抵御病毒感染至关重要，因此毫无疑问将成为对抗广泛病毒的重要防御系统，感染不同的生物体我们将在这些研究中发现的新信息将使我们更好地了解细胞如何对感染做出反应，以及病毒如何克服这些防御。这将最终导致新的和改进的方法来对抗疱疹病毒，以及在世界各地引起重大动物和人类疾病的许多其他重要病毒。

Herpesviruses are a very large family of viruses that cause many diseases in animals and humans. In particular many viruses that belong to the alphaherpesvirus subfamily cause significant disease and economic losses in the horse, cow, pig and poultry industries. Viruses of this herpesviruses subfamily that infect humans generally cause relatively benign diseases in healthy people, such as cold sores and genital herpes (herpes simplex virus) or chickenpox and shingles (varicella-zoster virus). However, these viruses do cause severe or life-threatening conditions, especially in immuno-suppressed people, such as herpes keratitis that is a leading cause of blindness, and herpes encephalitis that is commonly fatal even after antiviral drug treatment. Once infected with these viruses, they are there for life: all herpesviruses establish a dormant (so called latent) infection for the lifetime of the host, usually within the sensory nervous system for alphaherpesviruses, which cannot be treated with available drugs or prevented by available vaccines. Periodic episodes of virus reactivation from these latently infected cells can cause recurrence of disease and allows the virus to spread to uninfected organisms. Because of the many diseases caused by these viruses in such a wide range of animals as well as humans, there is an urgent need to develop improved antiviral drugs and vaccines.To be able to effectively fight virus infections it is vital to understand as much as possible about how they infect and reproduce inside the cells of the body. Cells have many ways of protecting themselves from viruses, and conversely viruses have evolved many ways of overcoming these defences. There is still a great deal we don't understand about these 'host defences' and 'virus countermeasures' and the more we can discover about how cells defend themselves, and how viruses overcome these defences, the better able we will be to develop new ways of fighting infection.The focus of this research is to discover the changes to host cells that are brought about by specific viral enzymes that are contained within herpesvirus particles and released into the infected cell as soon as the virus enters it. These viral enzymes are vital for herpesvirus to evade host defences, although we know virtually nothing about the specific effects of these enzymes as they are released into a cell by the virus. We will use state-of-the-art protein analysis techniques that enable us to detect and quantify thousands of proteins at once to discover the specific proteins of the cell that are targeted by these delivered viral enzymes. We will also use cutting-edge microscopy (so called super-resolution microscopy) to analyse the fate of these viral enzymes as they are delivered into cells by the incoming virus; these powerful new imaging techniques now provide us with the ability to detect and monitor single molecules in cells, allowing us to observe virus-host interactions at an unprecedented level of detail. For this work we will be using the human pathogen herpes simplex virus, as the most well-defined and tractable model of this important family of viruses, so we can make rapid and efficient progress in this research The cellular pathways uncovered by this work are likely to include many cell defence systems that are crucial for cells to repel virus infection and so undoubtedly will be important defences against a broad range of viruses that infect different organisms. The new information that we will discover in these studies will provide a much greater understanding of how cells respond to infection as well as ways viruses can overcome these defences. This will ultimately lead to new and improved ways of fighting herpesviruses, as well as many other important viruses that cause significant animal and human diseases throughout the world.