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Richardson ETD.pdf (13.28 MB)
ETD Abstract Container
Abstract Header
Regulation of Macrophages by
Mycobacterium tuberculosis
and the ERK MAP Kinase Signaling Pathway
Author Info
Richardson, Edward Thompson, III
ORCID® Identifier
http://orcid.org/0000-0002-7576-2603
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430
Abstract Details
Year and Degree
2015, Doctor of Philosophy, Case Western Reserve University, Pathology.
Abstract
Mycobacterium tuberculosis
, 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
M. tuberculosis
engages with macrophages. In the first part, we characterized the lipoglycan binding function of
M. tuberculosis
lipoprotein LprG. We determined the binding properties of these
M. tuberculosis
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
M. tuberculosis
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
M. tuberculosis
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
M. tuberculosis
. We determined that TLR2 was required for
M. tuberculosis
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
M. tuberculosis
-stimulated Tpl2-ERK signaling suppressed IL-12 while inducing anti-inflammatory IL-10. These effects reduced CD4+ T cell responses against
M. tuberculosis
. Tpl2-deficient macrophages expressed IL-12 in response to
M. tuberculosis
, 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
M. tuberculosis
, 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
M. tuberculosis
in ways that promote long-term survival of the bacteria, and may potentiate latent infection.
Committee
Clifford Harding (Advisor)
W Henry Boom (Advisor)
Alex Huang (Committee Chair)
Clive Hamlin (Committee Member)
Liem Nguyen (Committee Member)
Roxana Rojas (Committee Member)
Pamela Wearsch (Committee Member)
Pages
170 p.
Subject Headings
Immunology
;
Microbiology
Keywords
Tuberculosis
;
Mycobacterium tuberculosis
;
lipoprotein
;
LprG
;
lipoarabinomannan
;
Tpl2
;
MAP3K8
;
ERK
;
macrophages
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Richardson, III, E. T. (2015).
Regulation of Macrophages by
Mycobacterium tuberculosis
and the ERK MAP Kinase Signaling Pathway
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430
APA Style (7th edition)
Richardson, III, Edward.
Regulation of Macrophages by
Mycobacterium tuberculosis
and the ERK MAP Kinase Signaling Pathway.
2015. Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430.
MLA Style (8th edition)
Richardson, III, Edward. "Regulation of Macrophages by
Mycobacterium tuberculosis
and the ERK MAP Kinase Signaling Pathway." Doctoral dissertation, Case Western Reserve University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1433446430
Chicago Manual of Style (17th edition)
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Document number:
case1433446430
Download Count:
813
Copyright Info
© 2015, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.