Understanding the negative sense intermediate in the replication of foot-and-mouth-disease virus

The UK 2001 outbreak of foot-and-mouth disease resulted in billions of pounds of losses to the agriculture and tourism industries. This disease is widespread 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. The disease-causing agent is a virus and we are studying how copies of its genetic material are made inside cells to spread infection. Aspects of this process are unique to this virus and an understanding of the fine details could therefore lead to better disease control in the future, such as safer vaccines.

Foot-and-mouth disease virus (FMDV) is a pathogen of great agricultural and economic importance not just in the UK, but worldwide. The UK 2001 outbreak of foot-and-mouth disease resulted in billions of pounds of losses to the agriculture and tourism industries. Genome replication is a key step in the lifecycle of every virus and an understanding of the establishment and maintenance of sites of replication (replication complexes) can therefore lead to novel strategies of disease control. Yet it is clear that there are subtle but important differences between viruses. This project aims to dissect steps in the replication of FMDV at the biochemical level. The viral positive sense RNA genome is replicated via negative sense RNA intermediates. This is an essential step in viral replication, yet many steps in this process are poorly understood. Therefore, how this process might be targeted for therapeutic intervention is not known. We will define both the proteins and RNA elements that are involved in negative strand synthesis, the RNA intermediates formed in the process and how they are used to subsequently generate new positive sense RNA genomes. Our studies employ replicons - mini-genomes that allow the study of replication in a safe virus-free way, as the viral capsid proteins are replaced with reporter genes. Mutations which disable replication can be incorporated into virus to create safer vaccine strains for use in the production of inactivated vaccines in the future. Furthermore, the generation of an immutable virus could be employed as a live attenuated vaccine in outbreak situations.

The current proposal is for fundamental research, with the long-term outcome of the research being to underpin/enable the development of better strategies of disease control. 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 more widely will be pursued in four main areas. Firstly, the UK/global economy will benefit through the development of a researcher (SD), with high level scientific and transferable skills. 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. This is of particular relevance to the farming community. In addition, the research community beyond academia (notably the Pirbright Institute which is home to the FMD world reference laboratory) and also 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), we will further develop our relationship with vaccine manufacturers and with our collaborators at the Pirbright Institute. There will be joint 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 FMDV 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 a safe and 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 losses of income to tourist/leisure/farming-related businesses of ~£15 billion at today's rates). 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.
The capacity of the Faculty of Biological Sciences at the University of Leeds to generate high quality impact from excellent research was demonstrated in the recent assessment of quality of research in UK Universities (the 2014 Research Excellence Framework, REF 2014). For the Faculty of Biological Sciences (FBS), submissions were made in REF2014 to the Biological Sciences and Sports Sciences units of assessment. In both of these units of assessment, all the elements of the impact submissions were rated as 4* (outstanding impacts) or 3* (very considerable impacts), and for both units of assessment, the University was in sixth place overall for 4* graded impact.