CHARACTERIZATION OF MACROPHAGE RESPONSES TO ZINC-LIMITED MYCOBACTERIUM TUBERCULOSIS
Date
2024
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Abstract
Mycobacterium tuberculosis is the causative agent of tuberculosis in humans and one ofthe most successful human pathogens. Tuberculosis killed 1,300,000 million people in 2022 and
has killed more than seventy million people over the last 50 years. Despite M. tuberculosis being
actively studied since its discovery by Dr. Robert Koch in 1882, there is no effective vaccine to
prevent tuberculosis and treatment remains complex. An understudied area that could provide
novel insights into anti-tubercular therapy is the host interactions with zinc-limited M.
tuberculosis bacteria (Mtb). The host immune system attempts to eradicate Mtb by limiting zinc
availability via nutritional immunity, but it is unsuccessful. It has been previously demonstrated
that zinc-limited Mtb are physiologically distinct from the standard zinc-replete Mtb used in
most research. It is hypothesized that zinc-limited Mtb modulate host responses differently
compared to zinc-replete Mtb. In this dissertation, this hypothesis was tested by evaluating the
host responses in macrophages, which is one of the main cell types infected with Mtb, when
infected with zinc-limited Mtb and zinc-replete Mtb. To determine if zinc-limited Mtb modulate
the host response differently, functional assays were undertaken to evaluate macrophages
functions and in-depth characterization of macrophage responses was done using
transcriptomics. Compared to zinc-replete Mtb, it was found that zinc-limited Mtb are more
readily phagocytized by macrophages, increase the production of reactive oxygen species by
macrophages, trigger increased macrophage death, and stimulate increased pro-inflammatory
responses in macrophages. This dissertation highlights that the distinct physiology of zinclimited
Mtb more readily promotes macrophage responses that can be detrimental to the host
compared to zinc-replete Mtb.
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Microbiology, pathogenesis, tuberculosis, zinc
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705 pages
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