Francisella tularensis: host-pathogen responses to infection and drug target identification
| dc.contributor.author | Kingry, Luke Charles, author | |
| dc.contributor.author | Slayden, Richard A., advisor | |
| dc.contributor.author | Bowen, Richard A., committee member | |
| dc.contributor.author | Dow, Steven W., committee member | |
| dc.contributor.author | Schenkel, Alan R., committee member | |
| dc.contributor.author | Hanneman, William H., committee member | |
| dc.date.accessioned | 2007-01-03T05:49:28Z | |
| dc.date.available | 2007-01-03T05:49:28Z | |
| dc.date.issued | 2011 | |
| dc.description.abstract | The pathobiology of the host and pathogen responses to Francisella tularensis infection and disease progression were poorly understood when I started my graduate career. To address this, we have employed an integrative biological approach consisting of monitoring of the host transcriptional response to infection and dissemination, and determining the transcriptionally active and essential genes required for F. tularensis infection and disease progression. Drug therapies for F. tularensis that control the dissemination of the bacterium from the lungs to the spleen, liver, and kidneys are associated with positive clinical outcome. Therefore the studies focused on the host response were designed to address the hypothesis that host responses to F. tularensis strains of varying virulence will differ and the differences will shed light on why the host is unable to contain infection with highly virulent strains of Francisella in the lungs. We utilized the F. tularensis mouse model of pulmonary infection, the highly virulent Type A F. tularensis strain Schu4, and the less virulent Type B live vaccine strain (LVS) to study the host response to infection and identification of essential bacterial genes. This model and these strains provide a means for comparative analysis of virulence in a defined and rapidly adaptable model of disease progression. Bacterial burden and organ pathology was used to monitor disease progression, and the host transcriptional response to F. tularensis infection was used as a guide for the bacterial studies. We found that dissemination and pathology in the spleen was significantly greater in mice infected with F. tularensis Schu4 compared to F. tularensis LVS and there was altered apoptosis, antigen presentation, and production of inflammatory mediators that explain the differences in pathogenicity of F. tularensis Schu4 and LVS. We then designed experiments to address the hypothesis that genes actively transcribed during infection could be used to define the genes essential for the bacteria to cause disease. We identified active metabolic pathways utilized by F. tularensis during the infection, and the essential genes necessary for the bacteria to cause infection including those encoding components in isoprenoid biosynthesis, fatty acid biosynthesis, and aromatic amino acid biosynthesis. Together, these studies allowed for the identification of host diagnostic markers and F. tularensis therapeutic targets required for the establishment of infection in the lungs and dissemination to secondary sites of infection. Importantly, this information promises to guide the development of diagnostics, chemotherapeutics and therapeutic vaccines that are relevant to clinical stages of disease. | |
| dc.format.medium | born digital | |
| dc.format.medium | doctoral dissertations | |
| dc.identifier | Kingry_colostate_0053A_10676.pdf | |
| dc.identifier.uri | http://hdl.handle.net/10217/52064 | |
| dc.language | English | |
| dc.language.iso | eng | |
| dc.publisher | Colorado State University. Libraries | |
| dc.relation.ispartof | 2000-2019 | |
| dc.rights | Copyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright. | |
| dc.subject | next gen sequencing | |
| dc.subject | intracellular pathogen | |
| dc.subject | host-pathogen | |
| dc.subject | host response | |
| dc.subject | bacterial transcriptome | |
| dc.subject.lcsh | Francisella tularensis | |
| dc.title | Francisella tularensis: host-pathogen responses to infection and drug target identification | |
| dc.type | Text | |
| dcterms.rights.dpla | This Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). | |
| thesis.degree.discipline | Cell and Molecular Biology | |
| thesis.degree.grantor | Colorado State University | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) |
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