Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects one third of the world’s population and causes two million deaths worldwide each year. TB is spread by the inhalation of droplets from the cough of infected patients. In the upper respiratory tract, M. tuberculosis is taken up by macrophages. Once inside a macrophage, mycobacteria reside in phagosomes, within which they are subjected to an arsenal of destructive mechanisms. However, mycobacteria have developed resistance mechanisms to the antibacterial activities of the macrophage. A better understanding of the host defense against M. tuberculosis is needed to enhance treatment and prevention strategies for tuberculosis.
Iron is an essential element needed for the growth and survival of most organisms. Mycobacteria require this element to establish infection, during which they compete with macrophages for iron. In mammals, iron homeostasis is regulated by a peptide, hepcidin, produced by liver hepatocytes in response to inflammatory stimuli and iron overload. Hepcidin negatively regulates iron absorption by the duodenum and inhibits the release of recycled iron by macrophages.
The goal of this dissertation was to determine the role of hepcidin during an infection with mycobacteria, and the molecular mechanisms that regulate the production of hepcidin in activated macrophages. The present data are the first to show that infection of mice with the intracellular pathogen Mycobacterium avium induces the acute phase synthesis of hepcidin within the liver, lung and spleen. We also show that macrophages activated by M. avium or M. tuberculosis, and by the inflammatory cytokine IFN-γ synergistically produce hepcidin. We show that hepcidin protein partially colocalizes with Lamp1, that it is present in the mycobacteria-containing phagosomes, and that it possesses antimycobacterial activity.
We propose a model that hepcidin is a nonspecific effector molecule of the innate immune system, whose role is to complement other macrophage defense mechanisms against intracellular pathogens. Our studies suggest that the production by infected macrophages is an IFN-gamma induced host defense mechanism against mycobacteria.