M. tuberculosis-mediated inhibition of phagosomal maturation is associated with decreased phagosome acidification, which results from mycobacterial disruption of intracellular-trafficking pathways that depend on the phosphatidylinositol 3-kinase VPS34. As VPS34 is also crucial for autophagy, Gutierrez et al. set out to investigate whether inducing autophagy would overcome the block in maturation of mycobacterial phagosomes. Exposure of Mycobacterium bovis bacillus Calmette-Guérin (BCG)-infected macrophages (using the mouse macrophage cell line RAW 264.7) to two autophagy stimuli — starvation conditions or rapamycin (a pharmacological inhibitor of MTOR, the serine/threonine kinase target of rapamycin) — led to increased acidification of mycobacterial phagosomes. Further evidence that mycobacterial phagosomes had matured and were destined for the autophagy pathway was provided by the observation that starvation resulted in co-localization of mycobacterial phagosomes with late-endosomal/lysosomal markers, including cathepsin D and LAMP1, and proteins involved in autophagy, such as LC3 and beclin-1.
The induction of autophagy in RAW 264.7 cells infected with BCG was associated with a decrease in mycobacterial survival. Similar inhibition of mycobacterial survival was observed when primary human and mouse macrophages infected with BCG, or RAW 264.7 cells infected with the virulent M. tuberculosis H37Rv, were induced to undergo autophagy.
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