Mycobacterium tuberculosis is an intracellular pathogen that arrests phagosome maturation to survive within macrophages and cause disease. The process of phagosome maturation is important for the innate immunity against intracellular pathogens as well as the adaptive immunity and antigen processing. Activation by cytokines such as IFN-γ can modulate immune responses to infection. Several Rab GTPases regulate M. tuberculosis phagosome maturation, highlighting the importance of intracellular trafficking in this process. There is compelling evidence that M. tuberculosis can colonise several niches within macrophages, both in heterogeneous membrane-bound compartments as well as in the cytosol. In this thesis, the control of M. tuberculosis infection by IFN-γ through modulation of intracellular trafficking and thereby the intracellular niche occupied by this pathogen was investigated. First, a novel IFN-γ/Rab20 dependent pathway that targets pathogens into spacious phagosomes for elimination in macrophages is described. IFN-γ induced Rab20 expression and association with phagosomes. The analysis of spatiotemporal dynamics of M. tuberculosis phagosomes showed that in contrast to Rab5, PI3P or Rab7; EGFP-Rab20 was retained on M. tuberculosis phagosomes for up to 24 hours, which was comparable to endogenous Rab20 association with M. tuberculosis phagosomes in IFN-γ activated macrophages. IFN-γ increased interaction of M. tuberculosis phagosomes with the endosomal network via Rab20, targeting mycobacteria to spacious, proteolytic compartments resulting in inhibition of M. tuberculosis growth. Furthermore, this targeting of M. tuberculosis to spacious phagosomes reduced phagosomal damage and access of mycobacteria to the cytosol. In resting macrophages, M. tuberculosis was able to subvert this targeting to spacious compartments in a manner that was dependent on its ESX-1 secretion system. Altogether, this work reports a cell-autonomous, IFN-γ/Rab20 dependent pathway that results in elimination of M. tuberculosis by retention of mycobacteria in membrane-bound spacious compartments.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:763149 |
| Date | January 2016 |
| Creators | Schnettger, L. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1532039/ |
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