Date of Award

4-1-2008

Degree Type

Restricted Access Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Microbiology and Immunology

Department

Graduate School of Biomedical Sciences

First Advisor

Jerry W. Simecka

Second Advisor

Duncan C. Krause

Third Advisor

Stephen R. Grant

Abstract

Love, Wees J., The role of Toll-like receptor 2 in mediating the host’s defenses toward mycoplasma infection in the upper and lower respiratory tracts. Doctor of Philosophy (Microbiology and Immunology), April, 2008, 88 pp., 7 illustrations, bibliography, 144 titles. The purpose of these studies was to investigate the toll-like receptors (TLR) responsible for the recognition of invading mycoplasmas. They were also meant to evaluate the role of Toll-like receptors in the generation of immune responses and disease progression in mycoplasma respiratory disease. To determine the role of TLRs in recognizing viable Mycoplasma pulmonis, we utilized human embryonic kidney (HEK) cell lines that are known to have low basal expression of TLRs. The HEK cell lines used were stably transfected to express various combinations of TLRs. The HEK cell lines used were stably transfected to express various combinations of TLRs including TLR1, 2 and 6. The current paradigm of TLR recognition of mycoplasma is that TLR2 dimerizes with either TLR1 or TLR6 to recognize different subclasses of mycoplasma lipoproteins. However, the recognition of viable M. pulmonis organisms remains unclear. When stimulated with viable M. pulmonis, it was discovered that TLR2 was pivotal in mediating the host’s pro-inflammatory cytokine production and that the co-expression of TLR1 or TLR6 enhanced the response. To study their role in mycoplasma recognition and disease progression, we utilized TLR2 knockout (KO) mice. Bone-marrow derived dendritic cells (BMDC) from TLR2 KO mice showed an impaired ability to produce pro-inflammatory cytokines such as IL-12p40 in response to viable M. pulmonis. In addition, the host’s ability to clear the infection was also impaired in TLR2 KO animals. There were higher numbers of cfu in the lower respiratory tract where alveolar macrophages are known to mediate the host’s intrapulmonary clearance of organism. In the upper respiratory tract, where alveolar macrophages (AM) are absent, the production of anti-microbial peptides (e.g. β defensing) in response to TLR2 agonists has been demonstrated. Thus, TLR2 does mediate the host’s immune response to mycoplasma infection, by interfering with the host’s ability to clear the infection and be interfering with the host’s ability to mount an effective inflammatory response. These results also suggest that the TLR2 mediated anti-mycoplasma effects vary and are compartmentalized along the respiratory tract. These studies demonstrated diverse and novel roles of TLRs in respiratory infections and will serve as a platform for future studies investigating mycoplasma respiratory infections.

Comments

Love, Wees J., The role of Toll-like receptor 2 in mediating the host’s defenses toward mycoplasma infection in the upper and lower respiratory tracts. Doctor of Philosophy (Microbiology and Immunology), April, 2008, 88 pp., 7 illustrations, bibliography, 144 titles. W 4 L897R 2008

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