Role of Isoprenoid Biosynthesis in Listeria-based Tuberculosis Vaccine Efficacy
thesisposted on 21.07.2015 by James T. Frencher
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Tuberculosis is a leading infectious cause of death worldwide. Antibiotics are increasingly ineffective in treatment, and the only approved vaccine shows minimal protection against disease in children and no protection against disease in adults. Thus, improved treatment and vaccination strategies are needed. Using the gastrointestinal pathogen, Listeria monocytogenes, we deliver immunogenic proteins to the cytoplasm of antigen presenting cells, producing strong antigen-specific Helper and Killer T cell responses. The current studies focus on the examination of the T cell responses generated by respiratory administration of this Listeria-based Tuberculosis Vaccine, and the potential protective effect it generates against primary progressive Tuberculosis infection. In the studies describe here, we examine the protective effect of respiratory administration of a Listeria-based Tuberculosis vaccine, and demonstrate that 1 intratracheal dose provides significant improvement of bacterial burden and pulmonary pathology following respiratory Mycobacterium tuberculosis challenge, while 3 doses of the same vaccine provide minimal protection against Tuberculosis-mediated pathology. Examination of the T cell responses generated by the vaccine demonstrated that CD4 and CD8 T cells specific for select Mycobacterim tuberculosis proteins accumulate in both the blood and airways following vaccination. T cells specific for isoprenoid synthesis pathway intermediates accumulate in massive numbers in the blood and airways after a single administration of the vaccine, but the number and activity of these cells declines following repeated administration of the vaccine. In addition, these isoprenoid-sensitive T cells demonstrate markers of exhaustion and apoptosis following repeated stimulation with the vaccine, suggesting that repeated high dose vaccination could be inducing activation-induced T cell exhaustion and cell death. Using molecular biology techniques, we decrease production of isoprenoids by our vaccine, decreasing the hyper-secretion of isoprenoids recovering the vaccine’s ability to protect against pulmonary Tuberculosis. Collectively, these data support the hypothesis that Listeria-based vaccines given in repeated high doses induce exhaustion and cell death of isoprenoid-sensitive T cells. As these T cells have been demonstrated to be important components of the early response to Tuberculosis and other infections this may provide a mechanism through which repeated bacterial infection or repeated BCG infection result in poorer outcomes of Tuberculosis infection.