This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.
Date of Award
Doctor of Philosophy (PhD)
Tuberculosis is a significant global health threat, with one quarter of the world’s population infected with its causative agent, Mycobacterium tuberculosis (Mtb). Additionally, approximately 3.5% of new and 18% of previously treated tuberculosis cases are rifampicin or multidrug resistant (MDR), which require treatment with less effective and toxic second-line drugs. However, the specific host-pathogen interactions that mediate the host immune response to MDR Mtb strains are poorly understood. Using a collection of MDR Mtb strains, we demonstrate that a single nucleotide polymorphism (SNP) in the gene rpoB (rpoB-H445Y), conferring rifampicin resistance, leads to overexpression of the Mtb cell wall lipids, phthiocerol dimycocerosates (PDIMs), driving enhanced interferon-beta (IFN-) production and IFN--dependent downregulation of interleukin(IL)-1 production in murine and human monocyte-derived macrophages. Production of IL-1 by macrophages coincides with a metabolic shift to aerobic glycolysis, a process that mediates protection against drug susceptible Mtb. However, we show that rpoB-H445Y carrying MDR Mtb strains do not require the IL-1 receptor type I (IL1R1) signaling pathway to drive aerobic glycolysis in macrophages, instead utilizing type I IFN signaling to drive less effective aerobic glycolysis. The presence of the rpoB-H445Y SNP in Mtb is sufficient to modulate host metabolic macrophage reprogramming. Other common rifampicin resistance SNPs, such as rpoB-S450L, may also mediate differential macrophage metabolic activation and alter the course of infection. These findings transform our understanding of how emerging MDR Mtb strains can acquire drug resistance SNPs which alter Mtb surface lipid expression, and modulate host metabolic macrophage reprogramming to benefit MDR Mtb pathogenesis.
Chair and Committee
Shabaana A. Khader
Gaya K. Amarasinghe, Maxim N. Artyomov, Michael S. Diamond, Jennifer A. Philips,
Howard, Nicole Christine, "The Role of Rifampicin Resistance Mutations in Host Immune Modulation by Mycobacterium tuberculosis" (2019). Arts & Sciences Electronic Theses and Dissertations. 2003.
Available for download on Friday, December 15, 2119