DESCRIBING THE ROLE OF ZINC AND ZINC-INDEPENDENT RIBOSOMAL PROTEINS IN MYCOBACTERIAL PHYSIOLOGY

Date
2021
Authors
Burger, Allexa Dow
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Prisic, Sladjana
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Microbiology
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Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has plagued humanity for millennia and remains the world’s deadliest bacterium today. Bacterial heterogeneity complicates TB treatment, however specific cues from the host leading to development of Mtb subpopulations are not well understood. Access to zinc ion (Zn2+) may be a relevant cue, considering microenvironments developed during TB create a perpetual cycle exposing Mtb to high and low concentrations of Zn2+. In this dissertation I investigate the relevance of Zn2+ as a cue in mycobacterial physiology. I start by describing the role of Zn2+ and Zn2+-independent ribosomal proteins using the model mycobacterium, M. smegmatis (Msm). I found that Msm undergoes a unique morphogenesis in Zn2+-limiting conditions but interestingly the altRP deletion mutant does not, implicating a role for Zn2+-independent ribosomal proteins in mycobacterial physiology. Using a multiomics approach, I demonstrated that Mtb enduring limited Zn2+ employ defensive measures to fight oxidative stress and exhibit increased replication in vivo. The results provide a novel link to the oxidative stress response in Mtb and suggest host-pathogen interactions are influenced by the pre-exposure status of Mtb to Zn2+. Mycobacteria that transit through a Zn2+-depleted microenvironment, a prerequisite for host-to-host transmission, have anticipatory adaptations and are primed to withstand impending oxidative stress upon subsequent contact with immune cells. Considering that standard mycobacterial media recapitulates a Zn2+-replete environment, the Zn2+-dependent phenotype of the pathogen may confound our fundamental understanding of initial interactions between Mtb and the human host.
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Microbiology, Alternative ribosomes, Mycobacteria, Oxidative stress response, Tuberculosis, Zinc
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249 pages
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