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Background  We have previously reported that ATP treatment of  M bovis -BCG infected human macrophages induces P2X 7  receptor-dependent killing of intracellular mycobacteria. The mechanism mediating this bactericidal effect has not been full characterized but is known to be Ca 2+ -dependent and to promote the maturation and acidification of mycobacteria-containing phagosomes. In this study we demonstrate that the ATP/P2X 7 -mediated, mycobactericidal effect also involves the induction of cell autophagy.    Results  We report that 3 mM ATP induces rapid cell autophagy in THP1 cells and monocyte-derived macrophages within 30 minutes post-treatment, as revealed by the expression of LC3-II bands on western blot analysis. Using Ca 2+ -free media and selective P2X 7  agonists and antagonists, ATP-induced cell autophagy was shown to be Ca 2+  and P2X 7  receptor-dependent. Electron microscopy of ATP-treated, BCG-infected MDMs revealed the presence of the bacteria within characteristic double-membraned autophagosomes. Confocal analysis further confirmed that pharmacological inhibition of autophagy by wortmannin or pre-treatment of macrophages with anti-P2X 7  antibody blocked ATP-induced phago-lysosomal fusion. Induction of cell autophagy with ATP was also temporally associated with a fall in intracellular mycobacterial viability, which was suppressed by treatment with wortmannin or the selective P2X 7  antagonist, oxidized ATP (oATP).    Conclusion  We provide the first evidence that ATP/P2X 7 -mediated killing of intracellular mycobacteria involves the induction of cell autophagy. The findings support the hypothesis that autophagy plays a key role in the control of mycobacterial infections.

ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages