Francisella tularensis, the causative agent of tularemia, is a pathogen capable of survival and growth in a vast array of environments ranging from arthropod vectors to over one hundred different mammalian hosts, including humans. An understanding of the mechanisms that this bacterium uses to adapt to these varied environments is vital to fully understanding its pathogenesis. The environmental signals that Francisella responds to include low iron concentrations, oxidative stress, and temperature. The work described in this dissertation constitutes a significant step forward in our understanding of Francisella adaptation specifically to the host intracellular environment. We have shown that bacterial growth conditions have a great impact on bacterial phenotypes, particularly on the ability of Francisella to induce or inhibit macrophage cytokine production. We have identified a specific eukaryotic molecule, spermine, which is abundant in the intracellular environment and leads to significant changes in bacterial phenotypes and gene expression. We also present the first evidence of a role for the abundant Francisella IS elements in the regulation of transcription by functioning as spermine-responsive promoters. The ability of the bacterium to adapt to this signal is vital to its survival and a mutant lacking this sensing mechanism is highly attenuated. A thorough analysis of different culture conditions has lead to the identification of both known and putative virulence factors that may be important for altering host cell responses to F. tularensis. Our results demonstrate a novel mechanism of host-pathogen interaction and could have significant implications for other intracellular pathogens.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04232008-140626 |
| Date | 24 April 2008 |
| Creators | Carlson, Paul Edward |
| Contributors | Gerard Nau, JoAnne Flynn, Russell Salter, Bruce McClane, James Carroll |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04232008-140626/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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