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Characterization of Inadequate Host Responses to Intracellular Gram-negative Bacterial Pathogens

Gillette, Devyn Dior
http://rave.ohiolink.edu/etdc/view?acc_num=osu1385465357

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
The innate immune system is notoriously known for protecting the host against invading pathogens, especially those inhaled through the lung. The robust production of cytokines and other immune modulating proteins from innate immune cells contribute to bacterial clearance. Given the significance of this system in overall defense, we hypothesize that the most effective Gram-negative pathogens manipulate the immune response in favor of their own survival. This thesis focuses on the inability of host cells to respond effectively to Gram-negative bacteria. Two Gram-negative bacteria, Burkholderia cenocepacia and Francisella tularensis, are utilized in this study to explore this hypothesis. The first part of this thesis investigates the interactions between Burkholderia and airway epithelial cells, frequently overlooked participants in the immune system. Previously work from our lab detailed how monocytes were able to generate an efficient immune response that is driven by by NF-KB following following B. cenocepacia infections. Pro-inflammatory cytokine responses of airway epithelial cells after B. cenocepacia infection had not been previously explored. We demonstrated the ability of airway epithelial cells to produce pro-inflammatory cytokines after stimulation, yet IL-1b was not secreted despite increased transcript levels. Further examination showed that IL-1b failed to be secreted but instead was confined within the cytosol of epithelial cells. This occurred not only in cell lines but also in primary human bronchial epithelial cells. Caspase-1, the enzyme responsible for IL-1b processing, was extremely diminished in epithelial cells but restoration of this enzyme lead to proper IL-1b release. In the second portion of this thesis, we approached the host’s inability to mount an effective response by investigating monocytes and Francisella interactions. Prior reports from our lab detailed that monocytes infected with virulent F. tularensis exhibit a muted pro-inflammatory response. Active suppression of the host immune system has been speculated, but not thoroughly investigated to date. In this thesis, we showed how virulent F. tularensis is able to suppress the cytokine immune response in monocytes. Mixed infections with F. novicida confirmed that this was not due to F. tularensis's stealth nature, but rather attributed to the active suppressive ability of the pathogen. Additional examination revealed that this active cytokine suppression occurs in a dose and viability dependent manner. Cytokine suppression was documented as early as 4 hours into infection and could also transpire in monocytes with ongoing prior stimulation. Overall, the studies described in this thesis address an important concept concerning immune response. These studies demonstrate a deficiency in cytokine response of both traditional and non-traditional immune cells following intracellular Gram-negative bacterial exposure. These studies are of significance as decreased efficiency of host immune response correlates with increased pathogenesis.
Susheela Tridandapani (Advisor)
Larry Schlesinger (Committee Chair)
Mark Wewers (Committee Member)
Prosper Boyaka (Committee Member)
132 p.
Immunology
Epithelial cells; Monocytes; Cytokines; IL-1b; Immunosuppression; Burkholderia cenocepacia; Francisella tularensis

Recommended Citations

Citations

  • Gillette, D. D. (2013). Characterization of Inadequate Host Responses to Intracellular Gram-negative Bacterial Pathogens [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385465357

    APA Style (7th edition)

  • Gillette, Devyn. Characterization of Inadequate Host Responses to Intracellular Gram-negative Bacterial Pathogens. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1385465357.

    MLA Style (8th edition)

  • Gillette, Devyn. "Characterization of Inadequate Host Responses to Intracellular Gram-negative Bacterial Pathogens." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385465357

    Chicago Manual of Style (17th edition)

osu1385465357
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This open access ETD is published by The Ohio State University and OhioLINK.
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