Bovine mastitis usually arises as a result of intramammary infection by bacteria. The inflammatory reaction associated with mastitis results in a lower rate of milk production and a gross deterioration of the quality of the secretion. Our understanding of how mastitis-causing pathogens evade the local immune system is incomplete. Yet, a good understanding of this process at the molecular level is of strategic importance to the dairy industry as well as for treatments of these infections in cattle. Recent evidence from the groups of both supervisors as well as unpublished information from collaborating partners (H.-M. Seyfert, FBN Dummerstorf, Germany) suggests that several mastitis-causing agents interact with receptors of the innate immune system, such as Toll-like receptors (TLR) in a different way. Thus, whereas Escherichia coli or its cell-wall component LPS seems to induce a dose-dependent stimulation of the signalling cascade downstream of TLRs, others such as Streptococcus (S).uberis or its cell-wall component peptidoglycan (PGN) and lipoteichoidacid (LTA) fail to do so. This is accompanied by the failure of the immune system to produce cytokines in response to these stimuli, potentially due to thee fact that some mastitis-causing bacteria may secrete proteins which prevent TLR signalling, similar to those recently described((1); Metcalfe and Werling, unpublished data). These factors represent a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins (Tcps) which interact with the main adaptor protein of TLRs, MyD88, preventing downstream signalling. Related strains of S.uberis have recently been isolated from cows with transient and persistent mastitis (2), and the above described observation may contribute to the differences in persistence of these pathogens. Furthermore, mastitis-causing pathogens isolated from cattle or women have been shown to originate from a common ancestor, suggesting that evasion strategies are identical between different host species (3). Our hypothesis is that Gram-positive and Gram-negative mastitis-causing pathogens have developed a number of strategies to evade immune recognition in the udder. To test the hypothesis, the student will identify the presence/absence of Tcps in bacterial strains isolated from mastitis cases and assess their potential interactions with TLR-signalling by: 1) Analysing the genomes of different mastitis-causing bacteria for the presence of Tcps and compare their structures to known inhibitors of TLR signalling 2) Cloning the identified genes into mammalian expression-systems and assess their effects in established TLR-reporter assays 3) Assessing the response of milk-derived macrophages to either recombinant Tcps, whole bacteria or a combination of both Understanding how different bacterial strains are able to evade immune recognition in the udder has the potential to revolutionize novel drug/vaccine development and lead to advances in the control of this important infectious disease across species. 1. Cirl, C., Wieser, A., Yadav, M., Duerr, S., Schubert, S., Fischer, H., Stappert, D., Wantia, N., Rodriguez, N., Wagner, H., Svanborg, C., and Miethke, T. (2008) Nat Med 14, 399-406 2. Pullinger, G. D., Coffey, T. J., Maiden, M. C., and Leigh, J. A. (2007) Vet Microbiol 119, 194-204 3. Coffey, T. J., Pullinger, G. D., Urwin, R., Jolley, K. A., Wilson, S. M., Maiden, M. C., and Leigh, J. A. (2006) Appl Environ Microbiol 72, 1420-1428

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This course provides MSc level training in veterinary epidemiology targeted at veterinarians and related sciences graduates. The students obtain high level generic skills in research methods related to investigation of health problems in animal populations as well as design of appropriate control and prevention programs. Particular attention is paid to developing mathematical skills in veterinary and science graduates to a level required to analyse disease problems at the population level and deal with uncertainty. The course is taught jointly by the Royal Veterinary College and the London School of Hygiene and Tropical Medicine, with contributions from the Veterinary Laboratories Agency and the Department for Environment, Food and Rural Affairs. Through this unique combination of teaching institutions, the students are provided with an integrated training in animal and human health epidemiology that stretches from research to policy development and implementation, thereby teaching the students very much in a 'one world - one health' philosophy. Graduates of this course fill a current and future pressing national need in government, industry and academia for veterinarians and animal science graduates with a combination of knowledge of how to investigate disease outbreaks in the field and the quantitative skills to use field data to predict the effect of proposed control measures. A new addition to the skills training we can provide is in Agricultural Economics so students can evaluate the economic case of control measures. The contributions from VLA and DEFRA ensure the training maintains the perspective of UK national needs. The mixture of home and overseas students provides an international perspective on disease control which is becoming increasingly important with global spread of diseases emerging in developing countries. The vibrant alumnus association developing between graduates of this course means that professional veterinary epidemiologists working in positions of responsibility in their respective countries have strong links with those in the UK and with those involved in human disease. Completion of the MSc in Veterinary Epidemiology represents a component of the Royal Veterinary College's Veterinary Public Health Residency Program which was recently approved by the European College of Veterinary Public Health. In short, the unique strengths of this course are: - The one world - one health philosophy - The quantitative generic skills training provided for health care professionals - The involvement of UK government agencies to tailor the course to national needs - The global perspective provided by the mix of students trained