dc.creator | Foegeding, Nora June | |
dc.date.accessioned | 2020-08-22T00:42:37Z | |
dc.date.available | 2021-05-15 | |
dc.date.issued | 2019-05-15 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-05142019-210956 | |
dc.identifier.uri | http://hdl.handle.net/1803/12312 | |
dc.description.abstract | <em>Helicobacter pylori</em> is a Gram-negative bacterium that colonizes the human stomach. More than 50% of the global population is chronically infected with <em>H. pylori</em>, and infection with <em>H. pylori</em> is a leading cause of peptic ulcer disease and gastric cancer. One of the virulence factors associated with an increased risk of gastric disease is vacuolating cytotoxin A (VacA). VacA is a pore-forming toxin that can elicit a range of cellular responses in diverse cell types, yet the precise role of VacA as a virulence factor is not clear. Work detailed in this thesis elucidates the VacA structural features that target the toxin to host cells, the localization and fate of VacA inside host cells, and cellular alterations that occur following VacA intoxication. We show using giant plasma membrane vesicles (GPMVs) that VacA predominantly associates with lipid rafts and that the p55 domain is sufficient for VacA partitioning into lipid rafts. Acid-activation and oligomerization are not required for VacA lipid raft association, and disruptions to the VacA amino-terminal pore-forming region do not abrogate its lipid raft association. We also show that host cells can resist VacA-induced vacuolation and cell death by degrading VacA in lysosomes and that ammonia renders cells more susceptible to VacA by inhibiting VacA degradation. Therefore, VacA toxicity is influenced by the extracellular concentration of ammonia, which is generated <em>in vivo</em> by <em>H. pylori</em> urease and other enzymes. Altogether, this work expands our understanding of VacA toxicity and reveals important factors that modulate VacA activity. | |
dc.format.mimetype | application/pdf | |
dc.subject | Helicobacter pylori | |
dc.subject | VacA | |
dc.subject | toxins | |
dc.subject | pore-forming toxins | |
dc.subject | gastric cancer | |
dc.title | Cellular Responses to the Helicobacter pylori Pore-Forming Toxin, VacA | |
dc.type | dissertation | |
dc.contributor.committeeMember | Melanie D. Ohi | |
dc.contributor.committeeMember | Timothy L. Cover | |
dc.contributor.committeeMember | James R. Goldenring | |
dc.contributor.committeeMember | Jason MacGurn | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Cell and Developmental Biology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2021-05-15 | |
local.embargo.lift | 2021-05-15 | |
dc.contributor.committeeChair | Matthew J. Tyska | |