Pathogenesis of Tuberculosis
Approximately eight million people develop active tuberculosis (TB) each year with two million dying from the disease. In addition, it is estimated that one third of the world’s population is chronically infected with Mycobacterium tuberculosis (Mtb). Most individuals respond to infection with Mtb by mounting a strong cellular immune response that prevents active disease but does not sterilize the infection. Mtb has developed strategies to persist within macrophages, its major host cells, even in the face of fully developed T cell immunity. Thus, there is a fine balance between the host immune response that controls infection and the pathogen’s ability to evade and manipulate this response.
To better understand the molecular basis for Mtb’s ability to resist host defense mechanisms we characterize Mtb mutants that are susceptible to stresses encountered by the bacterium during persistence within the host. In an infected host, Mtb primarily resides within the phagosomes of macrophages and is able to arrest phagosome maturation. However, after cytokine activation of the macrophage, the phagosome matures along the endosomal-lysosomal pathway. Mtbpersists within mature phagosomes, indicating that the bacterium possesses resistance mechanisms against defenses of activated macrophages, such as low pH, nitric oxide and others. We have identified Mtb mutants that are hyper susceptible to such stress conditions. Some of these mutants are also attenuated in the mouse model of TB. The identification and characterization of the molecular mechanisms underlying the loss of stress resistance and loss of virulence of these mutants will help better understand the intracellular environment encountered by Mtb and how the pathogen resists host defense mechanisms.
We are also interested in the metabolic environment Mtb faces within its host. Metabolic adaptation to the host niche is a defining feature of the pathogenicity of Mtb, yet Mtb’s central carbon metabolism remains remain incompletely defined. We are investigating the metabolic pathways Mtb requires to establish and maintain chronic infections.
In collaboration with Dr. Schnappinger’s laboratory (Department of Microbiology, Weill Medical College of Cornell University) we developed controlled expression systems that allow silencing of mycobacterial genes in vitro and in vivo. We apply these systems to create conditional knock-downs of mycobacterial genes that are important for growth and persistence within the host. These conditional knock-downs allow us to investigate if a mycobacterial gene is required at all or only at specific stages of an infection. They also are also used for drug target evaluation and studies of essential mycobacterial genes.