Structural Studies on Viruses, Viral Proteins and Cell Interactions

病毒的数量远远超过细胞生物，但它们在细胞内繁殖，而且通常很难被消灭。尽管流感和普通感冒等病毒性疾病已伴随我们多年，但始终存在新病毒出现的风险，对人类健康构成重大威胁。2014年的埃博拉疫情就是这种突发病毒感染的一个有力例子，支撑我研究计划的信念是，在分子和原子水平上对病毒主要谱系进行适当的结构/功能理解，将为我们对新发感染和众所周知的（再次出现的）病毒疾病（如手足口病）的治疗反应提供基础知识。一种儿童疾病，在东亚是一个特殊的问题。虽然疾病控制规划将提供一线防御，但天花和牛瘟已经被根除的事实显示了组织良好的全球疫苗接种规划以及有效疫苗的力量。疫苗是通过识别病毒衣壳的分子水平起作用的，我相信疫苗的发展已经准备好进行一场重大革命。50年前设计的高效方法，基于化学灭活或广泛传代来传递减毒病毒株，现在可能被使用重组DNA技术制造的病毒样颗粒（vlp）的传递所取代，这样可以具有高度的免疫原性，但也很安全。原则上，在原子级结构知识的指导下，这种粒子的许多方面的要求，例如，正确的组装，适当的热稳定性和化学稳定性，都可以被设计成这种粒子。病毒性疾病的其他治疗方法传统上涉及小分子药物或生物制剂，特别是抗体，以预防或治疗感染。由于临床试验的高成本，这种疗法的交付最终由大型工业公司完成，而学术研究人员的作用通常仅限于竞争前阶段。事实上，我在这里提出的工作主要是发展我们对病毒结构和功能的基础知识，而且在短期内大多不会对人类健康产生直接的好处。然而，从长远来看，这些基础工作可以找到应用，有时会开辟意想不到的治疗机会。在这个广泛的背景下，我的项目旨在使用最新的结构分析方法，特别是电子和光学显微镜以及x射线衍射，来更好地理解几种病毒的工作原理。主要的病毒群是小核糖核酸病毒，其中包括一系列人类和动物病原体，从普通感冒的病原体，到小儿麻痹症、手足口病到甲型肝炎。我还将试图阐明乙型肝炎疫苗小颗粒的结构，并了解人类轮状病毒（较贫穷国家婴儿死亡的主要原因）等病毒如何作为相当复杂的复制机器发挥作用。为了实现这一点，我们还将开发一些尖端的方法来交付改进的分析。我建议研究的大多数病毒都来自病毒家族，其中包括重要的人类病原体，但我也会探索一些非哺乳动物病毒，因为我相信仍有未开发的潜力，例如，在对抗耐药细菌的斗争中干预细菌病毒。

Viruses vastly outnumber cellular organisms, but reproduce inside cells, and are often very difficult to combat. Although virus diseases such as 'flu and the common cold have been with us for many years, there is always the risk of new viruses emerging as major threats to human health. The 2014 Ebola epidemic is a powerful example of such an emergent virus infection and the belief underpinning my research proposal is that a proper structural/functional understanding at the molecular and atomic level of the main lineages of viruses will provide fundamental knowledge to inform our therapeutic responses to both emerging infections and also to well known (re-emerging) virus diseases such as Hand-foot-and-mouth disease, a disease of children which is an especial problem in East Asia. Whilst disease control programmes will provide front-line defence, the fact that Smallpox and Rinderpest have been eradicated shows the power of well organised global vaccination programmes, combined with effective vaccines. Vaccines work by the recognition at the molecular level of the virus capsid and I believe that vaccine development is ready for a major revolution. The highly effective methods devised fifty years ago, based on chemical inactivation or extensive passage to deliver attenuated virus strains, might now be supplanted by the delivery of viral-like particles (VLPs) made using recombinant DNA technology so that can be highly immunogenic and yet safe. Many aspects of the requirements for such particles, for instance, correct assembly, appropriate thermal and chemical stability, can, in principle, be engineered into such particles, guided by knowledge of the atomic level structure. The other therapeutic approach to viral diseases has traditionally involved either small molecule drugs or biological agents, especially antibodies, to either prevent or treat an infection. Due to the high cost of clinical trials the delivery of such therapeutics is ultimately done by large industrial concerns and the role of academic researchers is usually limited to the pre-competitive stage. Indeed the work I propose here is primarily to develop our underpinning knowledge of the structure and function of viruses, and will mostly not in the short term lead to direct benefits to human health. However in the longer term such basic work finds applications, sometimes by opening up un-thought of therapeutic opportunities. In this broad context my programme aims to use the latest methods of structural analysis, especially electron and light microscopy and X-ray diffraction, to piece together a better understanding of how several viruses work. The major group of viruses are the picornaviruses, which include a range of human and animal pathogens, from agents of the common cold, through polio to hand-foot-and-mouth disease to hepatitis A. I will also try to illuminate the structure of the small particles of the hepatitis B vaccine and to understand how viruses such as human rotavirus (a major cause of infant death in poorer countries) function as rather complicated replicating machines. To enable this we will also develop some cutting edge methods to deliver improved analyses. Most of the viruses that I propose to work on are from virus families that include important human pathogens, however I will also explore some non-mammalian viruses, since I believe there is still untapped potential, for instance, to intervene with bacterial viruses in the fight against drug resistant bacteria.