Bovine tuberculosis (bTB) is one of the biggest challenges facing the cattle farming industry in the UK. Here we describe how current animal models of bovine tuberculosis have been identified as a major bottleneck to progress by scientists working in the field, and how the NC3Rs is working with other funders to overcome this obstacle.
Bovine TB: main challenges
Limited to only 0.01% of herds four decades ago, bTB has now spread from isolated pockets in south-west England and Wales towards more easterly and northern regions, reaching over 5% of herds in some areas. Due to the risk of cross-over to humans, compulsory control schemes include surveillance of farms and routine testing of cattle. Animals that test positive for TB are slaughtered, with the rest of the herd placed under movement control. Over the past decade more than 300,000 cattle have been slaughtered, at a cost of £500 million. Still, these methods are judged to be the most effective control measures, as vaccines or treatment options are lacking.
Another problem is the presence of bTB in wildlife: around 15% of badgers carry bTB, and evidence suggests that badgers in contact with cattle can spread the disease to otherwise healthy herds. In 2013 the Department for Environment, Food and Rural Affairs (Defra) introduced controlled trials of badger culling in some areas of Britain to assess whether this can reduce the bTB risk in the UK, although results are not yet conclusive.
“What do we need to know?”
Taking into account the economic impact of bTB as well as the consequences for wildlife and animal welfare, the Biotechnology and Biological Sciences Research Council (BBSRC) held a workshop in 2013 entitled “Bovine TB: What do we need to know in 2020 that we do not know now?”. Aiming to identify the bottlenecks in bTB research, the workshop gathered key stakeholders in the field including academics, industry, regulators and other funding agencies. Together, they looked at what hinders the development of effective diagnostics and vaccines, and which areas of research need to be prioritised to advance the field.
The main obstacle identified was the lack of basic bioscience knowledge of bTB, such as in pathogen biology and the host immune response to mycobacteria. The conclusion that emerged from the meeting was that interdisciplinary research is necessary, and that there is a need to develop novel approaches for studying the disease as alternatives to the currently used animal models.
Limitations of animal bTB models
Current animal models are a key limitation in both the basic biology and translational research, for a number of scientific and practical reasons. The most effective models are of course the cattle models themselves, but costs associated with research on large animals can be prohibitively high. Because of the highly pathogenic nature of TB, research needs to be conducted under Category 3 (CAT3) conditions. Specialist animal housing and husbandry is required for the health and safety of research staff, but this can compromise animal welfare. Due to these restrictions, there are only a handful of facilities in the UK that are able to conduct research on cattle. The most commonly used animal model for bTB research is therefore the mouse, which is not the natural host for bTB. This means key differences in pathogenesis of mycobacteria, different symptoms and disease progression than in the cattle, and, as a result, lack of clinical translation.
Following the workshop, the BBSRC approached both Defra and the NC3Rs with the aim of coming together for a joint funding call to tackle the multi-faceted problem of bTB. BBSRC have an interest in the basic bioscience aspect of the disease, while Defra is the agency responsible for diagnosis and control at the ground level. It was also seen important for the NC3Rs to be involved in this initiative, to bring together our community of experts with experience in developing cutting edge, novel approaches that replace or reduce the use of animals in research.
And so in 2014, our three agencies came together to announce a joint call totalling £7 million to provide some much needed investment in the field and the impetus to try and do things differently. BBSRC led a call with Defra inviting applications that focused on fundamental research and basic bioscience of bTB vaccinology, strain diversity, and host-pathogen interactions. In parallel, the NC3Rs in collaboration with the BBSRC invited applications that aimed to provide the new tools that researchers can exploit to improve the understanding of bTB with reduced reliance on animals.
Awards from both the BBSRC/Defra and joint NC3Rs/BBSRC calls have just been announced.
Awards from the joint NC3Rs/BBSRC call
Professor Helen McShane is a world-renowned expert in human TB, and she will now work with leading bTB researchers at the Animal and Plant Health Agency, to transfer the in vitro challenge model she developed for human TB into the bTB arena. This model aims to replace the need for mouse studies in the early phase of vaccine development. The team also aims to develop a refined model for the later stage cattle infections which will allow experiments to be done with avirulent strains of the pathogen so that CAT3 containment is not necessary – improving the welfare of the animals involved in these studies.
The award to Professor Graham Stewart at the University of Surrey completely avoids the use of mammalian models and takes the novel approach of using the social amoeba Dictyostelium discoideum as a model for investigating the basic biology of the pathogen. Mycobacteria are able to survive in Dictyostelium in a similar way to how they survive in mammalian phagocytes. This project aims to look at both host and pathogen genes during infection to identify those that may be suitable targets for potential vaccines.
A third award was made to Dr Mark Chambers at the University of Surrey. This award is in collaboration with Professor William Hope at the University of Liverpool. With funding from a previous NC3Rs project grant, Professor Hope developed an in vitro model of the human alveolus for studying Aspergillus fumigatus infection. The award to Dr Chambers aims to now transfer this model into the bovine setting, and develop it for the study of bTB.
As research supported by the grants progress, the funders plans to bring the award holders together to build a relationship and encourage collaboration and the exchange of ideas. These strategic awards clearly demonstrate how joint investment can significantly help to bolster a community. The driver for the call was the need to further the field of bTB research, recognising the contribution that the 3Rs plays in driving forward change. The boost in funding provided to further advances in this economically and socially important disease, is something that will benefit not only the bTB research community, but also the key stakeholders of farmers, consumers, and the general public.