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Helicobacter pylori VacA as a mitochondrial targeted pathogenic effector
Holland, Robin L.
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https://hdl.handle.net/2142/101790
Description
- Title
- Helicobacter pylori VacA as a mitochondrial targeted pathogenic effector
- Author(s)
- Holland, Robin L.
- Issue Date
- 2018-07-12
- Director of Research (if dissertation) or Advisor (if thesis)
- Blanke, Steven R.
- Doctoral Committee Chair(s)
- Blanke, Steven R.
- Committee Member(s)
- Kuhlenschmidt, Mark S.
- Yoo, Dongwan
- Lau, Gee
- Department of Study
- Pathobiology
- Discipline
- VMS - Pathobiology
- Degree Granting Institution
- University of Illinois at Urbana-Champaign
- Degree Name
- Ph.D.
- Degree Level
- Dissertation
- Keyword(s)
- Helicobacter pylori
- mitochondria
- toxin
- Abstract
- Mitochondria play a central role in life and death. Although mitochondrial dysfunction is at the core of many diseases, the mechanisms and consequences of mitochondrial targeting and dysfunction induced by pathogenic microbes is poorly understood. The vacuolating cytotoxin (VacA) of the human gastric pathogen Helicobacter pylori localizes to and disrupts mitochondrial function. In order to evaluate mitochondrial targeting of VacA, VacA associated cellular compartments were isolated by magnetic based fractionation for proteomic analysis. Several proteins were identified to be important for VacA activity, including 14-3-3-G, VPS4B, Rab35, and Stx18, with Rab53 being important for VacA localization to mitochondria. Furthermore, all constituents of TIM23 and TOM complex were identified, suggesting a potential mechanism of VacA import into mitochondria. In order to evaluate the host cellular response to VacA mediated mitochondrial dysfunction, cells were treated with VacA, where a robust induction of mitochondria dysfunction was observed, then upon removal of VacA, mitochondria dysfunction was observed to recover over time, indicating an induction of quality control. Further studies suggest the mechanism of recovery is independent of mitophagy. Fluorescence microscopy and in vitro assays of purified mitochondria with VacA, revealed VacA to associate with mitochondrial derived, VacA containing vesicles, as a means to repair VacA mediated mitochondrial dysfunction. Finally, in order to evaluate the effects of VacA in vivo, an intragastric toxin infusion model was established and verified, whereby infusion of VacA into the stomachs of mice revealed perturbations in gastric mucosal structure, a decrease in gastric mucus production, parietal cell vacuolation, and induction of a humoral response to VacA. Altogether, these studies illustrate a model that VacA traffics to mitochondria by endosomes, and upon associating with the mitochondria and inducing dysfunction, a quality control response is activated. Furthermore, by disrupting mitochondrial function, the ability of gastric mucous and parietal cells to function properly is inhibited, thus facilitating H. pylori colonization and persistence within a human host.
- Graduation Semester
- 2018-08
- Type of Resource
- text
- Permalink
- http://hdl.handle.net/2142/101790
- Copyright and License Information
- Copyright 2018 Robin Holland
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Graduate Dissertations and Theses at Illinois PRIMARY
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