Do post-receptor binding events decide the fate of mycobacteria in bovine macrophages?

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Bovine tuberculosis (TB) is a disease of cattle caused by the bacterium Mycobacterium bovis (M.bovis), which has severe consequences for animal welfare in addition to financial implications. In the UK, the number of cases of bovine TB continues to increase, despite the application of control measures. Vaccination may be a better means of control, compared to the skin test that is currently used to identify infected cattle which have to be destroyed to prevent spread of disease. The vaccine BCG (derived from M.bovis) is currently used against TB in humans, and has been tested for its suitability in preventing bovine TB. As in humans, BCG use in cattle has been shown to be partially protective against disease. At present, BCG is the best vaccine against TB, but we do not completely understand why infection with M.bovis results in disease and infection with BCG results in protection. Interestingly, M.tuberculosis, which causes TB in humans, does not cause disease in cattle, while M.bovis is able to cause TB in cattle and humans. Antigen presenting cells (APC) are the first cells of the body's internal defence system (the immune system) to come into contact with disease-causing bacteria (pathogens). APC are responsible for the onset of the response of the immune system towards controlling and eliminating pathogens. Pathogens are recognised by APC through special molecules on their surface, known as pattern recognition receptors, which play a vital role in the development of the immune response. However, mycobacteria are able to influence the response of APC, so rather than killing the pathogen the APC's defence mechanisms are altered - allowing the bacterium to survive, multiply and go on to cause disease. The interaction between the APC and mycobacteria triggers a series of events, known as signalling cascades, resulting in the expression of molecules that determine whether APC will initiate a protective response or allow the progression towards disease. This proposal aims to study one of the major APC, called the alveolar macrophage. Residing in the lung, this cell is one of the first APC to come into contact with bacteria invading the body through the respiratory route. We will study how this bovine cell interacts with the TB-causing cattle strain M.bovis (which also causes TB in humans), BCG (vaccine strain) and M.tuberculosis (which causes disease in humans but not cattle). By comparing the response of the cell to the three different bacteria, we aim to identify alveolar macrophage responses only seen with the TB causing cattle strain, M.bovis. This should allow us to identify stages in the immune response where a particular reaction is critical if the bacterium is then going to cause disease rather than immunity, as seen with BCG and M.tuberculosis in cattle. This proposal aims to test the hypothesis that M.bovis ensures its survival within bovine alveolar macrophages and, as a consequence the progression of disease, by specific pattern recognition receptor usage and interference with the signalling cascades - influencing the outcome of the immune response. This contrasts with the receptors used and signalling cascades activated by BCG or M.tuberculosis, leading to the secretion of specific molecules by the infected cells that result in immunity rather than active disease. We propose that the difference in host specificity of M.bovis (includes cattle and humans) and M.tuberculosis (host specificity - only humans) and the virulence (ability to cause disease) of M.bovis (causes TB) and BCG (no disease, can develop immunity) in the bovine alveolar macrophage are key to the response of the cell and subsequent bacterial killing, and consequently critical to the outcome of exposure to the mycobacteria. A better understanding of the mechanisms in bovine alveolar macrophages that lead either to protective immunity or allow disease to develop is important for the development of novel therapies and vaccines.