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    The Role of the TNF-alpha Inducing Protein (Tipα) in the Host Immune and Inflammatory Response to Helicobacter pylori Infection

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    Author
    Morningstar-Wright, Lindsay
    0000-0003-1964-4220
    Advisor
    Blanchard, Thomas G.
    Date
    2018
    Type
    dissertation
    
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    Other Titles
    The Role of the TNF-alpha Inducing Protein (Tip alpha) in the Host Immune and Inflammatory Response to Helicobacter Pylori Infection
    Abstract
    Helicobacter pylori (H. pylori) is a Gram-negative bacterium that colonizes the human stomach leading to the development of chronic gastritis, peptic ulcers and gastric cancer. It is estimated that 50% of the world population is infected with the bacterium and approximately 15-20% of those infected will develop gastric disease. It remains impossible to predict which individuals will develop disease, but it appears that host and environmental factors play a role along with bacterial virulence factors. A greater understanding of H. pylori virulence factors and their role in pathogenesis will help determine why over 80% of infected individuals remain unsymptomatic and healthy. The H. pylori Tumor necrosis factor- alpha (TNFα) inducing protein (Tipα) is a virulence factor shown to induce multiple pro-inflammatory cytokines in addition to TNFα, and is believed to contribute to cancer development. We hypothesize that Tipɑ will have a pro-infammatory effect on the host immune response and stimulate additional pro-inflammatory pathways in gastric epithelial cells that promote inflammation and carcinogenesis. Mouse infections with wild-type Sydney strain (SS1) and a Tipα mutant (Δtipα) suggest that Tipα plays a significant role in promoting inflammation by the upregulation of several pro-inflammatory cytokines such as TNFα, Interferon-gamma (IFNγ), Interleukin 17 (IL-17) and chemokine 1 (Cxcl1/KC) in mice and may play a role in the development of hyperplasia. A group of co-infected mice with a 1:1 mix of wild-type SS1: and Δtipα had comparable cytokine expression and inflammation to the wild-type mice. Three out of ten animals were positive for Δtipα in the co-infected group suggesting Δtipα can be outcompeted during co-infection. Examination of N87 gastric epithelial cells co-cultured with Δtipα showed similar gene expression and pathway analysis to N87 cells co-cultured with wild-type SS1 suggesting redundant mechanisms within the bacteria that induce similar responses to those induced by Tipα. The use of recombinant Tipα (rTipα) co-cultured with gastric epithelial cells shows the induction of pro-inflammatory upstream regulators TNFα, IFNγ, IL-6 and IL-1. Overall, we identified some putitive gene targets of Tipɑ for further exploration in addition to previous pathways known to be affected by H. pylori infection.
    Description
    University of Maryland in Baltimore. Human Genetics. Ph.D. 2018
    Keyword
    Helicobacter pylori--pathogenicity
    Tumor Necrosis Factor-alpha
    Virulence Factors
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/7945
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