Tuberculosis is a major cause of mortality worldwide. Elucidation of the host resistance against Mycobacterium tuberculosis infection and the pathogenesis of tuberculosis is a priority. The host response to M. tuberculosis in the lungs includes the formation of granulomas, focal accumulations of mononuclear cells coming together to fight infection. The signals required for the migration of cells into the lungs and those required for the formation of granulomas have not been well defined. In this thesis, we will describe the advances we have made in understanding chemokine expression and cell migration to the lungs in response to M. tuberculosis. We have determined that Tumor Necrosis Factor (TNF) partially controls cell migration by modulating chemokine expression by macrophages in vitro and CD11b+ cells in vivo. In addition, we have taken the subset of chemokines that are affected by TNF and addressed their functions in vivo through knockout and neutralization models. Specifically, we have used an aerosol model of tuberculosis in the mouse to address the roles of CXCL9 (MIG), CXCL10 (IP-10), chemokine receptor5 (CCR5) and chemokine receptor2 (CCR2). In our studies, there was no apparent, strong phenotype in mice without functional CXCL9 or CXCL10. CCR5-/- mice had altered pathology and increased inflammation in response to M. tuberculosis infection, but they were able to control the infection. The CCR5 -/- mice may be hyper-responsive due to higher antigen load in the lymph nodes in conjunction with increased dendritic cell migration and more primed lymphocytes. CCR2-/- mice had a clear defect in macrophage migration and a delay in T cell migration, and the course of the disease was governed by the initial dose. Specifically, when a low dose aerosol infection route was used, CCR2-/- mice were able to control infection with the reduced number of cells migrating into the lungs; however with a higher dose, the mice succumbed to infection. Our findings are relevant to understanding the immune response and granuloma formation during aerosol M. tuberculosis infection, and will contribute to an appreciation of the potential effects of anti-inflammatory or anti-chemokine therapies on infections.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12162003-100614 |
| Date | 17 December 2003 |
| Creators | Scott, Holly Marie |
| Contributors | Paul "Kip" Kinchington, JoAnne L. Flynn, Ph.D., Per Basse, M.D., Ph.D.., Robert Hendricks, Ph.D., Todd Reinhart, Sc.D. |
| 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-12162003-100614/ |
| Rights | unrestricted, 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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