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CHARACTERIZING THE ROLES FOR HOST-DERIVED LIPIDS DURING MYCOBACTERIUM TUBERCULOSIS INFECTION

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Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a proficient bacterial pathogen capable of establishing long-term infection in humans. An important factor contributing to the long-term survival of Mtb is its ability to utilize host-derived lipids both as an energy source and as precursors for biosynthesis of cell envelope lipids that act as essential virulence factors. To take advantage of host nutrients, Mtb employs importers, Mce1 and Mce4, to facilitate uptake of fatty acids and cholesterol, respectively. These multiprotein complexes are hypothesized to utilize the same ATPase, MceG, to enable translocation of lipid substrates into the cytosol. Key shared subunits have been identified as essential for stabilizing the two transporters, therefore we investigated the role of MceG in stabilizing the Mce1 and Mce4 complexes. We show enzymatic activity of MceG is required for Mce1- and Mce4-mediated transport of fatty acids and cholesterol and that loss of lipid uptake in mutants lacking MceG is due to degradation of the complexes. Lastly, we show that MceG is required for full fitness in mice indicating that MceG may be a bottleneck that could be exploited by novel therapeutics. Once imported, host lipids can be assimilated into Mtb lipid biosynthetic pathways to produce virulence factors that influence the host immune response and aid in the establishment of infection. One such immune response is dependent on prostaglandin E2 (PGE2), which regulates both cell death pathways and macrophage type I interferon (IFN) responses, yet how Mtb induces PGE2 production remains poorly understood. Here, we demonstrate that the cell wall lipid, phthiocerol dimycocerosate (PDIM), is required to stimulate PGE2 synthesis during Mtb infection in mice and in macrophages ex vivo. Additionally, PDIM-dependent stimulation of PGE2 production occurs independent of signaling through IL-1β but requires export of the ESX-1 secretory protein, ESAT-6. Overall, this work reveals a new aspect of Mtb sensing in the cytosol of macrophages and provides a more complete understanding of critical events in lipid homeostasis during Mtb infection.

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118 pages

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2023-08

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Union Local

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VanderVen, Brian

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Doerr, Tobias
Peters, Joseph

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Microbiology

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Ph. D., Microbiology

Degree Level

Doctor of Philosophy

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Government Document

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dissertation or thesis

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