Cell-Autonomous Defense against Tuberculosis

Our ability to cope with Mycobacterium tuberculosis (Mtb) infection requires activated macrophages to help confer host defense. The extent to which these cells directly eliminate or restrain Mtb varies not only within different human populations but also within a given individual at different times following infection and in different lesions. Genetic studies of susceptible people reveal macrophage-activating cytokines like interferon (IFN)-γ and tumor necrosis factor (TNF) are key determinants of protective immunity against tuberculosis. Both cytokines mobilize macrophage effector programs to kill or restrict the bacterium. Among the downstream agents responsible for this inhibition are reactive nitrogen species (RNS) and reactive oxygen species (ROS); lysosomal and autophagic defense; and antimicrobial peptides, metabolites, and metal ion-binding proteins. Together these cell-autonomous effector pathways furnish toxic products or withhold essential micronutrients. It is a testament to the evolutionary fitness of Mtb that immune sterilization is often incomplete, although sufficient to ensure that most people infected with this airborne pathogen remain disease-free.