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,
*
Department of Medicine,
Inflammation Program, and
Graduate Program in Immunology, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA 52242
Advances in therapy for tuberculosis will require greater understanding of the molecular mechanisms of pathogenesis and the human immune response in this disease. Exposure of Mycobacterium tuberculosis-infected human macrophages to extracellular ATP (ATPe) results in bacterial killing, but the molecular mechanisms remain incompletely characterized. In this study, we demonstrate that ATPe-induced bactericidal activity toward virulent M. tuberculosis requires an increase in cytosolic Ca2+ in infected macrophages. Based on our previous work with primary infection of human macrophages, we hypothesized that the Ca2+ dependence of ATP-induced killing of intracellular M. tuberculosis was linked to promotion of phagosome-lysosome fusion. Using confocal laser-scanning microscopy, we demonstrate that ATPe induces fusion of the M. tuberculosis-containing phagosome with lysosomes, defined by accumulation of three lysosomal proteins and an acidophilic dye. Stimulation of phagosome-lysosome fusion by ATPe exhibited distinct requirements for both Ca2+ and phospholipase D and was highly correlated with killing of intracellular bacilli. Thus, key signal transduction pathways are conserved between two distinct models of human macrophage antituberculous activity: primary infection of naive macrophages and physiologic stimulation of macrophages stably infected with M. tuberculosis.
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