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The Lung Mucosa and its Impact on Mycobacterium tuberculosis Pathogenesis and Bacillus Calmette-Guerin Vaccine Efficacy

Moliva, Juan Ignacio
http://rave.ohiolink.edu/etdc/view?acc_num=osu1497602977755499

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is the current leading cause of death due to a single infectious organism. Although curable, the broad emergence of drug resistant M.tb strains has hindered eradication efforts. Furthermore, computational models predict a quarter of the world's population is infected with M.tb in a latent state, effectively serving as the largest reservoir of any human pathogen with the ability to cause significant global morbidity and mortality. Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the only vaccine approved for use to prevent TB. In humans, BCG is highly efficacious against disseminated forms of TB, but fails to fully protect against the development of pulmonary TB. Thus, new vaccination strategies are urgently needed if we are to eradicate this pathogen. The World Health Organization has prioritized research and development of novel TB vaccines, however our incomplete understanding on the requirements for protective immunity to M.tb has made it difficult to develop new successful vaccines. In this collective work, we explore how manipulation of the mycobacterial cell wall can further advance our knowledge of M.tb pathogenesis and the development of effective protective immunity. The microenvironment of the lung has emerged as an important contributor to antimicrobial immunity, especially in the context of M.tb. Homeostatic components within the alveolar lining fluid (ALF) of the lung mucosa have been shown to play a significant role in the pathogenesis of M.tb via modulation of host immunity. Previous studies demonstrated that exposure of M.tb to human ALF can modify the M.tb cell wall, stripping virulent lipids, glycolipids, and lipoglycans used by M.tb to subvert host immunity. This interaction renders M.tb more susceptible to killing by host immune cells. We demonstrate that human ALF can affect the development of mycobacterial-specific immunity by BCG in the lung, increasing its efficacy against M.tb pathogenesis and virulence. These results led us to hypothesize that effective pulmonary immunity against M.tb brought forth by BCG can be improved by taking into consideration the influence of cell wall lipids, glycolipids, and lipoglycans on the development of immunological responses. We uncovered that chemical treatment of BCG with the aliphatic hydrocarbon solvent petroleum ether accomplishes similar effects as human ALF; it reduces the presence of virulent lipids and glycolipids (but not lipoglycans) from the cell wall of BCG with high reproducibility. Pulmonary vaccination with 'delipidated' BCG was superior to conventional BCG against M.tb morbidity in mice. Lastly, we evaluated whether the co-morbidity of aging had any effects on human ALF physiology and if 'age-related' changes to ALF could impact M.tb pathogenesis. We show that increases in age are associated with decreases in the innate antimicrobial properties of ALF, and that M.tb may benefit from the declining host defense functions of the human lung mucosa in the elderly. Overall, this collective work expands upon our understanding on how the human lung mucosa can have a significant impact on the pathogenesis of M.tb, and how understanding the mycobacterial cell wall can lead to new efficacious vaccination strategies.
Jordi Torrelles, PhD (Advisor)
Stefan Niewiesk, DVM, PhD (Committee Chair)
Susheela Tridandapani, PhD (Committee Member)
Daniel Wozniak, PhD (Committee Member)
289 p.
Biochemistry; Biomedical Research; Cellular Biology; Immunology; Microbiology
Tuberculosis, Mycobacterium tuberculosis, Mycobacterium bovis BCG, Bacillus Calmette-Guerin, CD8, petroleum ether, IL-17, alveolar lining fluid, lung mucosa, trehalose dimycolate, mycobacteria cell wall, alveolar hydrolases, surfactant

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Citations

  • Moliva, J. I. (2017). The Lung Mucosa and its Impact on Mycobacterium tuberculosis Pathogenesis and Bacillus Calmette-Guerin Vaccine Efficacy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1497602977755499

    APA Style (7th edition)

  • Moliva, Juan. The Lung Mucosa and its Impact on Mycobacterium tuberculosis Pathogenesis and Bacillus Calmette-Guerin Vaccine Efficacy. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1497602977755499.

    MLA Style (8th edition)

  • Moliva, Juan. "The Lung Mucosa and its Impact on Mycobacterium tuberculosis Pathogenesis and Bacillus Calmette-Guerin Vaccine Efficacy." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1497602977755499

    Chicago Manual of Style (17th edition)

osu1497602977755499
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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.