Bovine tuberculosis (TB), caused by the bacterium Mycobacterium bovis, is acknowledged as 'one of the most difficult animal health problems currently facing the farming industry in Great Britain' (see http://www.defra.gov.uk/animalh/tb/index.htm). Despite the test-and-slaughter policy for cattle, the incidence of TB continues to increase with implications for animal health and welfare, in addition to causing major economic losses. The overall cost of bovine TB control has also increased from £25 million in 1998/1999 to £99 million in 2005/2006. This, combined with the potential for bovine TB to cause disease in people, has maintained the impetus for understanding and controlling this disease. It is recognized that elimination of the disease in both cattle and humans will depend on effective vaccines and sensitive, specific diagnostic tests. Vaccination has been proposed as a possible control measure. The attenuated strain of M. bovis bacillus Calmette-Guerin (BCG) is to date the most successful vaccine against TB in humans and has also been used to vaccinate cattle. However, the efficacy of BCG has been shown to vary from 0% to 80% in both humans and cattle; the reasons for this are not known. The immune response to mycobacteria is complex and although necessary for protection, it is also thought to contribute to disease development (pathogenesis). The distinction between protective and pathogenic immune responses during bovine TB is an absolute requirement for the development of more efficacious and safer vaccines. The focus of research at IAH on bovine TB is to understand the basic cellular immune responses to mycobacteria and the testing of vaccination strategies that may contribute to control of this important disease. Within the programme of research into bovine TB, we are studying: 1. Molecular aspects of the interaction of mycobacteria with bovine antigen presenting cells. Our main focus is the analysis of host-pathogen interactions in order to improve understanding of the bovine immune system. In particular, we are using molecular techniques to investigate how cells of the bovine immune system respond during infection with pathogens that cause diseases of significant economic impact, and with consequences for animal health and welfare. Our research interests include analysing the role of immune cells, using gene expression technologies, in the pathogenesis of TB and mastitis. In addition, we are studying the receptors on bovine immune cells, the ensuing activation of signalling cascades, and the subsequent production of bovine cytokines, chemokines and other immunologically important molecules. 2. The interaction of antigen presenting cells with cells of the innate and adaptive immune response, such as natural killer cells and T-cells Our research is focussed on understanding immune responses in the context of bovine TB. One of our goals is to determine the efficacy of the human BCG (Bacille Calmette Guerin) TB vaccine for protection of cattle against bovine TB. This is funded by DEFRA and being carried out in collaboration with colleagues at Veterinary Laboratories Agency, Weybridge. We have demonstrated that in neonatal calves BCG does induce a significant level of protection against bTB. We are currently investigating how long this immunity lasts and why neonates are protected more effectively than adult cattle. Neonatal calves have high levels of circulating innate immune cells: natural killer (NK) cells and T cells which can secrete high levels of interferon gamma (IFN), a key cytokine in protective immune responses. We are exploring whether NK or T cell responses can be boosted by vaccination, and the role that these cells play in protective immunity. We are also investigating how these cells interact with dendritic cells (DC). The capacity to analyze ex vivo DC in cattle following cannulation of afferent lymphatic vessels enables us to characterize the properties of bovine DC subsets in detail and investigate the potential for targeted vaccination strategies. One prerequisite for the use of a bovine TB vaccine is a test that can distinguish vaccinated cattle from those which are infected with bovine TB. We have recently developed such a test, and are currently working towards adapting it for on-farm use. Translation of our rapid test to human TB diagnosis is a possibility that is being explored with partners at Northwick Park Hospital and Trinity College Dublin. 3. The development of T-cell responses associated with the killing of mycobacteria A major interest of the group is the distinction between protective and disease-inducing responses. We are currently doing laboratory and animal studies to characterise the protective immune responses induced by the BCG tuberculosis (TB) vaccine. We have found that vaccination with BCG induces T-cells that produced molecules involved in the killing of TB mycobacteria in the laboratory (Figure 1) and in the standing animal (Figure 2). In collaboration with Dr. Martin Vordermeier and Prof. Glyn Hewinson of the Veterinary Laboratories Agency we are also testing the protective efficacy of prime-boost vaccination regimens as currently being tested in humans. The protective efficacy of these regimens will be related to the immune responses induced. These experiments will help develop correlates of immunity to TB and may contribute not only to the development of safer vaccines but also to the development of improved diagnostics responses. The multidisciplinary approach developed in this programme will provide an understanding of the bovine immune system that will contribute to the rational development of improved measures for the control of bovine TB and of other disease causing pathogens. |
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