Investigations of Metabolic Pathways in Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis in humans, infects roughly two billion people worldwide. However, less than one percent of infected individuals are symptomatic. Most have a latent infection characterized by dormant, non-replicating bacteria that persist within a mass of immune cells in the lung called the granuloma. The granuloma provides a protective barrier between infected cells and surrounding tissue. When host immunity is compromised, the granuloma can deteriorate and reactivate the disease. In order to mount a latent infection, Mtb must survive in alveolar macrophages, the host's primary line of defense against this intracellular pathogen. By evading typical bactericidal processes, Mtb is able to replicate and stimulate granuloma formation. The mechanisms by which Mtb persists in macrophages are ill defined; thus, elucidating the factors responsible for this hallmark of Mtb pathogenesis is an important area of research.This thesis explores three discrete metabolic pathways in Mtb that are likely to mediate its interactions with host immune cells. The first three chapters examine the sulfate assimilation pathway of Mtb and its regulation by the phosphatase CysQ. Chapter 1 provides a general overview of the transcriptional, biochemical, and molecular levels of sulfur metabolism regulation in Mtb, while Chapters 2 and 3 present a detailed analysis of how CysQ may influence sulfur transactions in the cell. Chapter 4 explores the biosynthesis of the cell wall glycolipid Polyacyltrehalose, which is exclusively synthesized by pathogenic mycobacteria and may mediate host-pathogen interactions. Finally, Chapter 5 describes a novel osmoregulatory pathway in Mtb that affects the pathogen's response to osmotic stress and its production of the well-characterized virulence factor EspA