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Regulation of Granuloma Formation in Mouse Models of Tuberculosis

Scott, Holly Marie (2003) Regulation of Granuloma Formation in Mouse Models of Tuberculosis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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 receptor-5 (CCR5) and chemokine receptor-2 (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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Scott, Holly Mariehmsst21@pitt.eduHMSST21
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFlynn, JoAnne Ljoanne@pitt.eduJOANNE
Committee MemberKinchington, Paul "Kip"
Committee MemberBasse, Per
Committee MemberHendricks, Robert
Committee MemberReinhart, Todd
Date: 17 December 2003
Date Type: Completion
Defense Date: 8 December 2003
Approval Date: 17 December 2003
Submission Date: 16 December 2003
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cell migration; chemokine; inflammation; tuberculosis; tumor necrosis factor
Other ID:, etd-12162003-100614
Date Deposited: 10 Nov 2011 20:11
Last Modified: 15 Nov 2016 13:54


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