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Dissertation (Nan Zhang).pdf (4.2 MB)

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Identification of Receptors and Signaling Pathways Involved in Borrelia burgdorferi-Elicited IL-10 and Potential Therapies for Lyme disease

Zhang, Nan
http://rave.ohiolink.edu/etdc/view?acc_num=mco1405591577

Abstract Details

2014, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Infection, Immunity, and Transplantation).
B. burgdorferi (Bb) is an extracellular spirochetal bacterium that causes Lyme disease, a significant vector-borne illness in North America and Eurasia. Bb is transmitted into the skin by an infected-Ixodes tick bite. Despite eliciting strong immune responses, Bb persists within host tissues for extensive times and periodically re-emerges to cause disease. One of the important mechanisms by which Bb evades host immune clearance is its rapid elicitation of high levels of IL-10, an anti-inflammatory cytokine, which suppresses the host immune responses critical for efficient Bb clearance. To date, the IL-10-/- mouse line is the only reported animal model that shows enhanced clearance of Bb. However, the mechanism of how B. burgdorferi elicits this dysregulated IL-10 response is largely unknown. Macrophages (MØs) reside in skin tissues where Bb is initially transmitted into the host, and these cells rapidly secrete high levels of IL-10 upon Bb stimulation. The initial studies of my dissertation project were to elucidate signaling pathways that are critical for the dysregulated IL-10 production by Bb-stimulated MØs, with the ultimate goal of identifying potential Lyme disease-therapeutic targets by blocking those signaling pathways more specific to IL-10 production. Early experiments indicated that Bb-induced IL-10 in MØs did not require phagocytosis. TLR2 signaling was necessary for Bb-induced IL-10 in MØs, as well as pro-inflammatory cytokines (TNF-a, IL-6), nitric oxide and chemokines (KC, MIP-2a, MIP-1a, MIP-1ß). Bb activated intracellular protein kinase pathways in MØs, including PI3K, MAPK pathways (p38, ERK, JNK) and the NF-¿B pathway. Blockade of JNK and NF-¿B pathways not only reduced Bb-induced IL-10, but also other cytokines and chemokines assessed. However, blockade of either PI3K or p38 or ERK pathway was more specific to diminished IL-10 induced by Bb, as levels of most pro-inflammatory mediators were not affected. In addition, the secretion profiles of cytokines and chemokines were similar in experiments where MØs were stimulated with Bb lipoprotein OspA, suggesting lipoproteins on intact Bb are major stimulants. Experiments were then focused on the p38 MAPK signaling as a pathway that might be blocked to provide direct suppression of IL-10, while allowing production of pro-inflammatory mediators capable of controlling Bb infection. p38 MAPK signaling was substantially decreased in TLR2-/- MØs compared to wild-type MØs. Mice treated with the specific p38 inhibitor SB203580 during Bb infection demonstrated decreased IL-10 production, similar levels of pro-inflammatory cytokines, increased levels of neutrophil-recruiting chemokines, and reduced Bb numbers compared to vehicle-treated skin tissues at day 1 post-infection. The reduced Bb numbers were also noted through day 4 post-infection. Linear regression analyses showed that reduced Bb numbers correlated with low IL-10 transcript levels in skin. Intravital confocal microscopy on ear tissues showed that neutrophil numbers were elevated when p38 MAPK pathway was blocked, which corresponded to enhanced Bb clearance. Immunoblot analyses on skin tissues indicated that increased MPO levels also correlated with enhanced Bb clearance, suggesting enhanced neutrophil recruitment and activity. These findings indicate that TLR2-mediated p38 MAPK signaling is critical for Bb-elicited IL-10, and subsequently suppresses neutrophil recruitment and activity, resulting in enhanced immune evasion by Bb.
R. Mark Wooten (Advisor)
Z. Kevin Pan (Committee Chair)
Robert Blumenthal (Committee Member)
Stanislaw Stepkowski (Committee Member)
Deborah Vestal (Committee Member)
163 p.
Biomedical Research; Immunology
Borrelia burgdorferi, IL-10, p38 MAPK, neutrophil

Recommended Citations

Citations

  • Zhang, N. (2014). Identification of Receptors and Signaling Pathways Involved in Borrelia burgdorferi-Elicited IL-10 and Potential Therapies for Lyme disease [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1405591577

    APA Style (7th edition)

  • Zhang, Nan. Identification of Receptors and Signaling Pathways Involved in Borrelia burgdorferi-Elicited IL-10 and Potential Therapies for Lyme disease. 2014. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1405591577.

    MLA Style (8th edition)

  • Zhang, Nan. "Identification of Receptors and Signaling Pathways Involved in Borrelia burgdorferi-Elicited IL-10 and Potential Therapies for Lyme disease." Doctoral dissertation, University of Toledo, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=mco1405591577

    Chicago Manual of Style (17th edition)

mco1405591577
444
© 2014, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.