Understanding inflammatory processes in ovine footrot to inform rational vaccine design

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The aetiology of footrot is complex and multifactorial. Physical damage to the interdigital skin is required to initiate disease following exposure to damp conditions. The incidence of footrot could therefore increase in line with the climate change predictions of warmer and wetter summers in the UK. Bacterial replication in the damaged skin leads to interdigital dermatitis where the superficial epidermal layers are inflamed, damaged and slough off. This can progress to footrot with separation of the hoof horn from the underlying tissue. The essential bacterium causing footrot is Dichelobacter nodosus. However, the role of a second bacterium, Fusobacterium necrophorum, in the pathogenesis of footrot is unclear. The host response to the invasion of bacteria is characterised by inflammation of the epidermis and pressure in the hoof horn capsule. Consequently the hoof horn separates from the underlying tissue. The host immune response is a double-edged sword, while it is required for successful defence, if unbalanced it can lead to pathology. Given that separation of the hoof horn is characterised by immune-mediated inflammation, investigating how this is initiated and controlled will dramatically improve our understanding of footrot pathogenesis. Analysing the global host immune response to footrot-associated bacteria is a first step in understanding local inflammation. Together with an insight into the molecular epidemiology of D. nodosus and analysis of the correlation of sequence type with disease presentation, this will greatly enhance our understanding of the aetiology of footrot.
This proposal will help to inform the design and delivery of novel therapeutic and vaccine approaches, with the ultimate aim of facilitating strategic effective vaccine development. This proposal aligns with solutions to food security, reducing antibiotic usage in meat production and the potential for resistance, and providing a sustainable, secure supply of good quality food.

Footrot is a bacterial infection of the interdigital skin of the sheep foot resulting in lameness, and is the greatest welfare and economic concern for sheep farmers and veterinarians worldwide. In England, more than 95% of sheep flocks have footrot, with a mean daily prevalence of ~10% and an estimated cost to the UK sheep industry of £24-84 million per annum. The results from this project will help to improve our understanding and management of footrot, a disease that impacts this industry and those concerned with animal welfare. It is therefore of relevance to the sheep industry (both pedigree and commercial sheep farmers), their consultants including veterinarians and policy makers, Farm Animal Welfare Committee and the RSPCA. We will ensure that our work has high visibility through peer-reviewed publications, trade publications and through presentations at scientific, veterinary and farmer meetings. We will continue work with EBLEX, the levy body for beef and sheep farmers, and transfer knowledge as appropriate throughout the project allowing interaction and promotion of results to key stakeholders. The results are also of potentially high media interest and could lead to a radical change in the approach to managing the foot health of sheep. The farming press (Farming Today, Farmer's Weekly) are routes to communicating the outputs of this project to the farming industry. In addition, outcomes will inform teaching practice and have the potential to change prevention and treatment of footrot.
This is a collaborative, multidisciplinary project and we envisage that the proposed research will benefit a wide range of academics working in diverse fields. It will benefit immunologists studying innate immunity to bacterial infections by elucidating host recognition and signalling responses to bacteria in a farm animal species of veterinary importance. It will also provide valuable tools (ovine TLR expression constructs, ovine skin fibroblast cell lines) to study other host - microbe interactions in sheep. This research will be of interest to scientists studying mechanisms of inflammation and immunopathology in response to infections. The generated and freely available mammalian transcriptome and pathogen genome and community profiling data will benefit the research community for diverse future research. In addition, the MLST analysis is web based portable system that will allow others to 'plug and play' with their own data, thus developing an ever growing database of such information on D. nodosus globally, enabling bespoke global adaptation of project findings.
The public have a strong interest in the health and welfare of animals that are farmed for human consumption. This includes concerns over the use of antibiotics to control disease in food animals and the impact of disease on productivity that ultimately influences the quality and purchase cost of meat. Footrot in sheep impacts on all of these areas and is therefore pertinent to the global Food Security agenda. The applicants have expertise in communicating their science to broad audiences beyond the academic arena. Drs Tötemeyer and Coffey are involved in outreach activities including Science Week, Sutton Trust Summer Schools and a STEM ambassador aiming to communicate veterinary science to pupils, including pupils from widening participation backgrounds. Dr Tötemeyer also reviewed for the Wikivet project. Prof Entrican and Dr Wattegedera have communicated their science to farmers at The Royal Highland Show and open days at Moredun Research Institute. They have presented to the public at The Edinburgh International Science Festival and have delivered immunology workshops to school teachers addressing the learning objectives relating to immunology and infectious disease within the new Curriculum for Excellence.