Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway
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Case Western Reserve University School of Graduate Studies / OhioLINK
2015
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ndltd-OhioLink-oai-etd.ohiolink.edu-case14334464302021-08-03T06:31:40Z Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway Richardson, Edward Thompson, III Immunology Microbiology Tuberculosis Mycobacterium tuberculosis lipoprotein LprG lipoarabinomannan Tpl2 MAP3K8 ERK macrophages <i>Mycobacterium tuberculosis</i>, the cause of tuberculosis, survives for long periods in a latent state in infected individuals, and the immune system is typically able to control but not eliminate the bacteria. Latency is a complex phenomenon but involves, in part, interactions of the bacteria and its unique lipoproteins and lipoglycans with macrophages, the main cells that become infected. The purpose of this dissertation was to expand understanding of how <i>M. tuberculosis</i> engages with macrophages. In the first part, we characterized the lipoglycan binding function of <i>M. tuberculosis</i> lipoprotein LprG. We determined the binding properties of these <i>M. tuberculosis</i> lipoglycans to LprG using surface plasmon resonance. We also verified the presence of a non-acyl chain dependent binding mode to LprG, and determined that LprG also binds mannan. Finally, we determined that one function of LprG is to facilitate exposure of LAM on the bacterial cell surface for interaction with macrophages. LprG-deficient <i>M. tuberculosis</i> had reduced surface-exposed lipoarabinomannan, and had reduced ability to block phagolysosome maturation, a known immune evasion mechanism that requires lipoarabinomannan. These studies contribute to understanding of LprG, and develop increased knowledge of how <i>M. tuberculosis</i> lipoarabinomannan is exposed to macrophages to block phagolysosome fusion, a process involved in bacterial persistence and intracellular survival.In the second part, we studied the TLR2 signaling response of macrophages to <i>M. tuberculosis</i>. We determined that TLR2 was required for <i>M. tuberculosis</i> to trigger NF-κB and ERK, and that TLR2 signaling results in balanced downstream effects. NF-κB is required for expression of pro-inflammatory IL-12, and <i>M. tuberculosis</i>-stimulated Tpl2-ERK signaling suppressed IL-12 while inducing anti-inflammatory IL-10. These effects reduced CD4+ T cell responses against <i>M. tuberculosis</i>. Tpl2-deficient macrophages expressed IL-12 in response to <i>M. tuberculosis</i>, and were more potent at stimulating antigen-specific T cells, upon initial stimulation and recall. These findings contribute to understanding of the signaling triggered by <i>M. tuberculosis</i>, and the role of the macrophage-intrinsic ERK cascade in inhibiting T cell-mediated host defense. Together, these studies expand understanding of the regulation of macrophages by <i>M. tuberculosis</i> in ways that promote long-term survival of the bacteria, and may potentiate latent infection. 2015-09-03 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430 http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
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NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Immunology Microbiology Tuberculosis Mycobacterium tuberculosis lipoprotein LprG lipoarabinomannan Tpl2 MAP3K8 ERK macrophages |
| spellingShingle |
Immunology Microbiology Tuberculosis Mycobacterium tuberculosis lipoprotein LprG lipoarabinomannan Tpl2 MAP3K8 ERK macrophages Richardson, Edward Thompson, III Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway |
| author |
Richardson, Edward Thompson, III |
| author_facet |
Richardson, Edward Thompson, III |
| author_sort |
Richardson, Edward Thompson, III |
| title |
Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway |
| title_short |
Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway |
| title_full |
Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway |
| title_fullStr |
Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway |
| title_full_unstemmed |
Regulation of Macrophages by <i>Mycobacterium tuberculosis</i> and the ERK MAP Kinase Signaling Pathway |
| title_sort |
regulation of macrophages by <i>mycobacterium tuberculosis</i> and the erk map kinase signaling pathway |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2015 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430 |
| work_keys_str_mv |
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