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Immunoregulation of host macrophage responses by Mycobacterium tuberculosis

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2014, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
One-third of the world population is infected with Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, which leads to 1.3 million deaths annually. M.tb is a host-adapted intracellular pathogen of macrophages. A complex, evolutionally adaptive relationship exists between M.tb and the host during which the pathogen evades and subverts the immune response mounted by the macrophage. Understanding the interactions during primary infection between the macrophage and M.tb are important as they determine outcomes of infection and course of disease. In this dissertation we examined the roles of microRNAs (miRNA) and MAPK pathways in M.tb infection of primary human macrophages and identified two mechanisms through which M.tb can down-regulate macrophage immune responses and promote its intracellular survival. We determined the miRNA expression profile of M.tb-infected monocyte-derived macrophages (MDM) by the NanoString nCounter miRNA Expression Assay and identified a number of miRNAs that were differentially expressed relative to the non-infected controls 24 h and 72 h after M.tb infection. Among the up-regulated macrophage miRNAs at 72 h after M.tb infection were miR-132 and miR-26a, which we show down-regulates expression of the transcriptional activator p300, a component of the IFN-gamma signaling pathway that mediates transcriptional responses to IFN-gamma in macrophages. Our data suggest that during human M.tb infection there is decreased capacity for macrophages to be activated by IFN-gamma and perform microbicidal functions. In addition, we show that the expression of the MAP3K Tpl-2, which was previously identified as a host defense molecule against M.tb in a murine knockout model, is down-regulated during M.tb infection in human primary macrophages. Concurrently, we observed increased mRNA levels of Tpl-2, suggesting a role for miRNAs in targeting Tpl-2 mRNA or other post-translational regulatory mechanisms such as loss of stabilization by p105 in suppression of Tpl-2 protein expression. We also reported on the downstream signaling effects of M.tb-induced suppression of Tpl-2 by studying ERK and MEK activation after stimulation with toll-like receptor (TLR) ligands. Our data suggest that M.tb has the capacity to suppress Tpl-2 and alter MAPK signaling to promote a survival advantage within the macrophage Rise in rates of multidrug-resistant and extensively drug-resistant tuberculosis indicate a dire need for new lines of therapies against novel targets. The results of these studies indicate that miRNAs, especially miR-132 and miR-26a, as well as MAPK pathways, including Tpl-2, may be excellent targets of host-directed therapies for tuberculosis and the knowledge gained here will benefit future studies to these ends.
Larry Schlesinger, MD (Advisor)
Amal Amer, MD, PhD (Committee Member)
Clay Marsh, MD (Committee Member)
Stephanie Seveau, PhD (Committee Member)
153 p.

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Citations

  • Ni, B. (2014). Immunoregulation of host macrophage responses by Mycobacterium tuberculosis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1398946253

    APA Style (7th edition)

  • Ni, Bin. Immunoregulation of host macrophage responses by Mycobacterium tuberculosis. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1398946253.

    MLA Style (8th edition)

  • Ni, Bin. "Immunoregulation of host macrophage responses by Mycobacterium tuberculosis." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1398946253

    Chicago Manual of Style (17th edition)