School of Biomedical Sciences - Theses
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ItemDefining and developing novel host targeted therapies to eliminate Mycobacterium tuberculosis infections( 2017)Tuberculosis, caused by Mycobacterium tuberculosis (M.tb), is a massive global health problem with one third of the world’s population infected. Aproximately two billion people have been killed by tuberculosis over the last two centuries. With the growth in our understanding of tuberculosis disease and production of the Bacillus Calmette–Guérin (BCG) vaccine, the tuberculosis incidence and mortality have been dramatically reduced over the past century. However, the number of newly diagnosed tuberculosis cases per year is still very high in some parts of world. Complex issues confound our ability to tackle this disease including problems with detecting and differentiating infection and disease, inadequate sanitation, low BCG vaccination rates, poor vaccine efficacy and the emergence of drug resistant strains. These issues increase the pressure, need and urgency of developing better preventive management techniques to stop the spread of new infections and better agents to treat infection, particularly resistant infections. A characteristic of intracellular M.tb infection is its ability to cause or promote lytic forms of host cell death (e.g. necrosis). The major shortcoming of necrosis is that organisms are not killed and they escape the intracellular environment enabling them to infect more host cells. One mechanism that assists in the killing of intracellular M.tb is the activation of host cell inducible nitric oxide synthase (iNOS). Additionally, recent work in our laboratory has shown that apoptosis can be promoted during M.tb infection to help kill intracellular M.tb and clear infection. This was done using a drug that antagonises the inhibitor of apoptosis proteins (IAPs). IAPs activate a cell survival pathway downstream of TNF signalling. If IAPs are antagonised with small molecule inhibitors, TNF no longer activates a host cell survival signalling pathway but rather it activates an apoptotic signalling cascade. In my studies, I combined the IAP antagonists’ with bosentan, a clinical stage drug that has been developed to promote iNOS activity. I found that bosentan was not efficacious in reducing M.tb burdens in lung and this may be due the drugs ability to increase oxygenation in the lung. Perhaps the increased oxygenation promoted the ability of aerobic M.tb to proliferate. Interestingly, IAP antagonists reversed the negative effects of bosentan presumably by promoting apoptosis of infected cells. As well as killing intracellular M.tb, apoptosis is also thought to promote antigen presentation and hence immunity. If we are able to promote apoptotic cell death during BCG vaccination we may be able to promote more robust immunity to M.tb. So I examined the ability of IAPs antagonists to promote BCG efficacy and I found that these drugs, when administered at the correct time, did promote BCG vaccine efficacy. I additionally sought to examine the role of a subset of T cells called mucosal associated invariant T cells (MAIT cells) that have been implicated in facilitating the acquisition of adaptive immunity. MAIT cells are found in the mucosa and several organs including lung. These cells become activated when they encounter host cells presenting bacterially derived vitamin B metabolites in association with MHC class I-like molecule (MR1). I activated MAIT cells with bacterial vitamin B metabolites in both wild type and MR1 gene knock out mice and then immunized animals with BCG vaccine prior to M.tb challenge. I found that promoting MAIT cell activation had no significant effect on promoting BCG vaccine efficacy.