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Abstract
Mycobacterium tuberculosis is an intracellular pathogen persisting within phagosomes
through interference with phagolysosome biogenesis. Here we show that stimulation
of autophagic pathways in macrophages causes mycobacterial phagosomes to mature into
phagolysosomes. Physiological induction of autophagy or its pharmacological stimulation
by rapamycin resulted in mycobacterial phagosome colocalization with the autophagy
effector LC3, an elongation factor in autophagosome formation. Autophagy stimulation
increased phagosomal colocalization with Beclin-1, a subunit of the phosphatidylinositol
3-kinase hVPS34, necessary for autophagy and a target for mycobacterial phagosome
maturation arrest. Induction of autophagy suppressed intracellular survival of mycobacteria.
IFN-gamma induced autophagy in macrophages, and so did transfection with LRG-47, an
effector of IFN-gamma required for antimycobacterial action. These findings demonstrate
that autophagic pathways can overcome the trafficking block imposed by M. tuberculosis.
Autophagy, which is a hormonally, developmentally, and, as shown here, immunologically
regulated process, represents an underappreciated innate defense mechanism for control
of intracellular pathogens.