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Theses and Dissertations

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Browsing Theses and Dissertations by Author "Ackart, David, author"

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    Metabolic interventions in the treatment of Mycobacterium tuberculosis infection
    (Colorado State University. Libraries, 2023) Ackart, David, author; Basaraba, Randall, advisor; Podell, Brendan, committee member; Chicco, Adam, committee member
    Tuberculosis remains a global threat. For the first time in over a decade, there was an increase in deaths in 2021. Current antimicrobial treatments are lengthy and costly, which leads to non-compliance. Host-directed therapies have emerged as a possible adjuvant to antimicrobial treatment. It has become clear that immune cell function and metabolic pathways are intertwined and a target for therapy. Previously, metformin, a partial inhibitor of complex I, was associated with decreased disease burden in the guinea pig model. Based on these findings, we hypothesized that limiting glycolysis would reduce lesion burden and bacterial viability. To test our hypothesis, we infected guinea pigs for thirty days and then administered metformin or 2-deoxy-glucose alone, and in combination. After 90 days of infection, histological analysis revealed increased healing in the combination treatment. To determine the effect of treatment on cellular metabolism, we evaluated treatments in guinea pig bone marrow-derived macrophages. We found that the combination treatment reduced bacterial viability, prevented mitochondrial damage, and increased apoptosis, which helps support in vivo findings. These findings suggest that the metabolic switch of immune cells to glycolysis alone is insufficient to control Mycobacterium tuberculosis infection; it is essential, as is oxidative phosphorylation.