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Bioinformatics approaches to studying immune processes associated with immunity to Mycobacterium tuberculosis infection in the lung and blood

Thiel, Bonnie Arlene
http://rave.ohiolink.edu/etdc/view?acc_num=case1627247387242562

Abstract Details

2021, Doctor of Philosophy, Case Western Reserve University, Systems Biology and Bioinformatics.
Strategies to find an effective TB vaccine have relied on enhancing the natural immunity that occurs in a subset of the population in response to primary exposure or reinfection with Mycobacterium tuberculosis (Mtb). Although still controversial, there is good evidence that some people exposed to Mtb show early clearance of the infection and do not exhibit a specific T-cell response that is the hallmark of Mtb infection. At the same time, the majority of people who do become infected, never progress to an active TB state and remain healthy without symptoms for many years. New vaccine candidates will require better targeting of these natural mechanisms through increased knowledge of immune functions. The biological processes contributing to early clearance of infection can be investigated by comparing individuals who resist infection to those with stable latent infection. We compared lung and blood cell subsets in a Ugandan cohort and found subtle differences that may contribute to resistance. In addition, we were able to quantify lymphocyte memory cell populations in the lung and blood and found a greater percentage of effector memory cells in the lung. Recent vaccine candidates have induced a robust T-cell response to Mtb antigens as measured in the blood, and yet provide no significant protection against progression from infection to disease. One hypothesis is that measurement of vaccine biomarkers in the blood do not correlate with markers in the lung where infection occurs. In this study, proteomic profiles in alveolar macrophages and blood monocytes were measured to answer the question of whether there is a differential IFN-γ cytokine response in these compartments. We found greater overall protein expression in monocytes that was not explained by differences in proximal signal transduction. In order to further interrogate IFN-γ transcriptional processes, we performed a meta-analysis with MDM transcriptomic datasets and combined the results with STAT1 transcriptional targets to map out primary and secondary waves of transcription. Further investigation of T-cell – macrophage interactions through IFN-γ signaling is critical to understanding how LTBI is maintained and may lead to new vaccine candidates.
William Henry Boom, MD (Committee Member)
Catherine Stein, PhD (Advisor)
Gurken Bebek, PhD (Committee Member)
Richard Silver, MD (Committee Member)
Mark Cameron, PhD (Committee Chair)
113 p.
Bioinformatics; Biology; Biomedical Research; Biostatistics; Epidemiology; Immunology
Mycobacterium tuberculosis; vaccine; interferon gamma; IFN-gamma; macrophage; monocyte; resistance to infection; latent Mtb infection; LTBI; bronchoscopy; TB; TB immunology

Recommended Citations

Citations

  • Thiel, B. A. (2021). Bioinformatics approaches to studying immune processes associated with immunity to Mycobacterium tuberculosis infection in the lung and blood [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1627247387242562

    APA Style (7th edition)

  • Thiel, Bonnie. Bioinformatics approaches to studying immune processes associated with immunity to Mycobacterium tuberculosis infection in the lung and blood. 2021. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1627247387242562.

    MLA Style (8th edition)

  • Thiel, Bonnie. "Bioinformatics approaches to studying immune processes associated with immunity to Mycobacterium tuberculosis infection in the lung and blood." Doctoral dissertation, Case Western Reserve University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1627247387242562

    Chicago Manual of Style (17th edition)

case1627247387242562
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.