The role of the Mycobacterium tuberculosis SecA2 protein export pathway in virulence

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  • March 22, 2019
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  • Sullivan, Jonathan T.
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Mycobacterium tuberculosis is an intracellular bacterial pathogen that replicates in macrophages in the lung of the host. The ability to replicate in these cells of the immune system is critical to the virulence of this important pathogen. M. tuberculosis is thought to maintain a hospitable niche in the host through several mechanisms. M. tuberculosis suppresses the host innate immune response by dampening cytokine secretion and production of reactive nitrogen and oxygen species that can be toxic to bacteria. Additionally, M. tuberculosis manipulates macrophages by arresting the normal process of phagosome maturation into acidified and hydrolytic phagolysosomes. The process of each of these immunosuppressive functions by M. tuberculosis is not fully understood. Other intracellular pathogens that control the host immune response use specialized protein export systems to deliver effectors to the host cell. In M. tuberculosis, the accessory SecA2 system is a specialized protein export system that is required for intracellular growth in macrophages. However, we do not understand the role of SecA2 in promoting growth in macrophages. The SecA2 system has a role in dampening the host cytokine and reactive nitrogen response. However, we show that the role of SecA2 in dampening these inflammatory responses cannot explain the intracellular growth defect. In this study we discovered that SecA2 is also required for blocking phagosome maturation. We showed that inhibitors of phagosome acidification rescued the intracellular growth defect of the [delta]secA2 mutant, which demonstrated that the phagosome maturation arrest defect of the [delta]secA2 mutant is responsible for the intracellular growth defect. Our data suggests there are effectors of phagosome maturation that are exported into the host environment by the accessory SecA2 system. Thus, we tested a set of putative effectors of M. tuberculosis phagosome maturation for SecA2 dependent export. We found that the level of one of these proteins, the secreted acid phosphatase (SapM), was reduced in the [delta]secA2 mutant. The research presented in this thesis establishes a role for SecA2 in promoting M. tuberculosis growth in macrophages. Additionally, we demonstrate an important causal link between phagosome maturation and arrest of M. tuberculosis intracellular replication.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Microbiology and Immunology.
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  • Braunstein, Miriam
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