Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages.
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.
Gutierrez
Maximiliano G
MG
Instituto de Histologia y Embriologia, Facultad de Ciencias Medicas, Universidad Nacional de Cuyo-CONICET, Mendoza 5500, Argentina.
Master
Sharon S
SS
Singh
Sudha B
SB
Taylor
Gregory A
GA
Colombo
Maria I
MI
Deretic
Vojo
V
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects / Q000276:immunology*; D000071186:Beclin-1; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000648:ultrastructure; D002478:Cells, Cultured; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology*; D008247:Lysosomes / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology* / Q000382:microbiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C096000:Ifi1 protein, mouse; D011506:Proteins; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins; D020123:Sirolimus