Project offered for Ker Memorial PhD Studentship in Infectious Diseases
Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, is a significant endemic disease affecting large numbers of UK cattle herds with devastating economic impacts. Key to the issues of controlling bTB is a failure of current diagnostic tests to accurately identify all infected cattle (1). One reason for this is co-infection with other infectious agents which likely alters the immune response in cattle such that the sensitivity of diagnosis is significantly reduced (2).
In humans, co-infection with HIV and M. tuberculosis has a highly significant negative impact on morbidity and mortality caused by TB (3). We have shown that cattle herds affected by bovine immunodeficiency virus (BIV) have altered responses to bTB diagnostic tests and hypothesise that co-infection with BIV leads to greater numbers of false negative reactions and persistence of bTB. Preliminary studies of cattle with BIV +/- bTB demonstrated alterations in the frequency and phenotype of blood cell populations that are likely to be associated with diagnostic test failure.
This project will examine the mechanisms by which BIV infection can impact the immune response to M. bovis. The project will use a combined approach to understanding co-infection impacts on cellular and humoral immune responses. The student will use in vitro models of the bovine lung in Objective 1; these are currently being established in Jayne Hope’s lab. We have ongoing collaborations with Prof Mark Chambers, University of Surrey and Prof Dirk Werling, Royal Veterinary College, who have published models of the bovine lung already and who will provide expertise as required. The lung models will be infected with M. bovis alone or with BIV at a range of infection rates and the kinetics of cytokine expression and changes to cell populations will be assessed. The survival and persistence of M. bovis will be measured.
In Objective 2 blood and tissue samples from cattle herds with bovine TB and BIV will be used to assess and confirm that the altered immune responses observed in Objective 1 are also seen in vivo. We have a biobank of samples from bovine TB/BIV affected cattle already and will collect additional samples through ongoing trials. Through collaboration with MV diagnostics we will also be able to further assess how co-infection impacts diagnostic accuracy, and design tests that could be utilised for more accurate identification of bovine TB affected cattle where BIV co-infection confounds the diagnosis.
While the main outputs from this project will relate to bovine TB, there are clear parallels with TB in humans where co-infection with HIV and M. tuberculosis has a significant impact on the outcome of vaccination regimes and diagnostic accuracy. This represents a One Health approach. Through existing collaborations with researchers in human TB (Helen McShane and Iman Satti at the Jenner Institute, Oxford) we will discuss the findings from our study and how these might be relevant to human TB.
Training and skills development
The student will have access to a large range of training courses for professional and personal development through the Institute for Academic Development, as well as locally at Easter Bush where our Career Development Committee actively seeks out and provides training for students. The student will have a Thesis Committee with a pastoral mentor, external expert as well as the supervisors who will guide progress. At the start of the PhD we will complete a personal development plan and this will be reviewed (at least) annually. The student will gain skills in cell culture, molecular biology, microbiology and will be trained to work at high containment. Alongside in vivo skills gained in Objective 2 this will give the student a wide range of skills including those that are classed as ‘rare’ and therefore vital for the maintenance of a skills pool in veterinary research. Through interactions with a commercial company the student will gain knowledge of commercial industry and the development and deployment of diagnostic tests.
The student will be actively encouraged to write papers, and to attend a range of conferences to present and discuss their data as well as to develop networking skills that will be vital to a successful career. We anticipate that this will include Veterinary Immunology, Virology and Animal Medicine conferences given the wide potential impact of the study.
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