Structural Studies on Viruses, Viral Proteins and Cell Interactions

病毒的数量远远超过细胞生物，但在细胞内繁殖，而且往往很难抗击。虽然像流感和普通感冒这样的病毒疾病已经伴随我们很多年了，但总有新病毒出现的风险，成为对人类健康的主要威胁。2014年的埃博拉疫情是这种紧急病毒感染的一个强有力的例子，支持我的研究建议的信念是，在分子和原子水平上对主要病毒谱系的结构/功能进行适当的了解，将提供基本知识，为我们对新出现的感染和众所周知的(重新出现的)病毒疾病的治疗反应提供信息，例如手足口病，这是一种儿童疾病，在东亚是一个特殊的问题。虽然疾病控制方案将提供前线防御，但天花和牛瘟已被根除的事实表明，组织良好的全球疫苗接种方案与有效的疫苗相结合具有强大的力量。疫苗的工作原理是在病毒衣壳的分子水平上进行识别，我相信疫苗开发已经为一场重大革命做好了准备。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，现在可能被利用重组DNA技术制造的病毒样颗粒(VLP)的传递所取代，因此它可以具有高度的免疫原性，但又是安全的。原则上，在原子级结构知识的指导下，对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，都可以被设计成这样的粒子。另一种治疗病毒疾病的方法传统上是使用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是由大型工业公司完成的，学术研究人员的作用通常限于竞争前阶段。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，在短期内大多不会给人类健康带来直接好处。然而，从长远来看，这种基础工作得到了应用，有时是通过打开意想不到的治疗机会。在这种广泛的背景下，我的计划旨在使用最新的结构分析方法，特别是电子显微镜和光学显微镜以及X射线衍射，以更好地了解几种病毒是如何工作的。主要的病毒是微小核糖核酸病毒，其中包括一系列人类和动物的病原体，从普通感冒的病原体，到小儿麻痹症，手足口病，再到甲型肝炎。我还将试图阐明乙肝疫苗小颗粒的结构，并了解人类轮状病毒(在较贫穷国家导致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方法来提供改进的分析。我提议研究的大多数病毒来自病毒家族，其中包括重要的人类病原体，但我也将探索一些非哺乳动物病毒，因为我相信仍有尚未开发的潜力，例如，在对抗抗药性细菌方面与细菌病毒进行干预。

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.