Structural Studies on Viruses, Viral Proteins and Cell Interactions

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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.