Understanding the catalytic and non-catalytic roles of the essential 3D protein in the FMDV replication complex

Foot-and-mouth disease virus causes a livestock disease of great economic importance. The UK 2001 outbreak resulted in billions of pounds of losses to the agriculture and tourism industries. This disease is endemic in many parts of the world (including outbreaks in countries bordering Europe) and transmits between animals very rapidly. Therefore, despite trade restrictions, another UK outbreak is inevitable. We strive to understand the lifecycle of the disease-causing agent; foot-and-mouth disease virus. We are studying the strategies that the virus uses to replicate inside cells in order to make further viruses to spread infection. A key to this is the virus polymerase. This enzyme is responsible for making copies of the virus genetic material. This is a unique function of the virus - mammalian cells do not possess this ability - and therefore potentially key in the development of new approaches to disease control.

Many viruses replicate their genomes in 'replication organelles' also termed 'replication complexes', thought to both improve efficiency and protect this vulnerable part of the lifecycle. As a result of our recent work, we now have the tools available to define the replication complex of foot-and-mouth disease virus (FMDV), a pathogen of great agricultural importance in the UK. Our studies employ replicons - mini-genomes that allow the study of replication in a safe virus-free way, as they do not encode the virus capsid proteins. We have developed a reciprocal complementation system, using replicons incorporating different reporter genes. This allows us to investigate whether individual replication-defective mutations in the viral genome can be 'recovered' by expression of the viral non-structural proteins using 'helper' replicon constructs. Using this approach (together with state-of-the art imaging and structural techniques) will allow us to dissect the functions of both the RNA and protein components of replication complex and ultimately allow the development of novel strategies for disease control, e.g. via novel vaccine design. By defining which components of the replication machinery can be supplied by a 'helper' construct, we can create new, safer vaccine strains in the future.

The proposal is for fundamental research, with the long-term outcome of the research being to underpin/enable the development of a new vaccine. In the lifetime of this grant, the research will primarily be of benefit to the academic community (as described in more detail in the Academic Beneficiaries section). The delivery of impact during the grant to non-academic beneficiaries will be pursued in four main areas. Firstly, the UK/global economy will benefit through the development of a highly skilled researcher (MRH), with high level scientific and transferable skills equipping him to continue on the pathway to an independent research career. Secondly, the general public (both adults and children) will benefit through a range of public engagement events, leading to improved understanding of the science of animal diseases, viruses and specifically foot-and-mouth disease, FMD. In addition, the research community beyond academia (for example animal health companies) will benefit from this research through having access to the development of techniques/approaches with the potential to lead to development of novel FMD vaccines, and for wider application in the area of vaccine development. Finally, government organisations in developing countries may benefit from this research through increased knowledge and understanding of the biology of FMD.

In the short-medium term (towards the end of this grant and beyond), the relationship with our current partner company will be developed, by further visits (NJS and MRH) and short-term staff exchange. In addition, the PI has established links with a Government-funded institution in Bangladesh, the Bangladesh Livestock Research Institute (BLRI), and this relationship will also be developed during this grant. The BLRI, our collaborators at the Pirbright Institute and the applicants will benefit through reciprocal access to samples, materials and knowledge. In the long term (15+ years beyond this grant) the potential for the research to deliver impact through underpinning development of a new vaccine leads to a wide range of potential beneficiaries of this research. UK and global societies and economies (in countries where FMD is endemic) will benefit through the prevention of loss of livestock and livelihoods. Animal health companies would benefit via vaccine production and sales. Farming communities in developing countries where FMD is endemic will benefit if an affordable vaccine is developed, since controlling FMD could make the difference between survival and malnutrition for small farming communities. In the UK and other developed countries, farming communities would benefit through there being a reduced risk of FMD outbreak as a consequence of better vaccination/disease control in other countries. The general public would benefit though the prevention of reduced access to outdoor activities (e.g. during the 2001 UK FMD outbreak, public access to public rights of way through farmland was prohibited for an extensive period of time, leading to approx. £8 billion losses of income to tourist/leisure/farming-related businesses). At a government level, countries would benefit through improved policies for management of FMD overseas - i.e. vaccination programmes for farmed livestock - leading to reduced risk of importing infected animals.