Abl tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages

The mechanisms that regulate the acidification of intracellular compartments are key to host defense pathways against intracellular pathogens. Here we demonstrate that Abl tyrosine kinase, a master switch for cell growth, cell survival and trafficking of organelles, controls the acidification of lysosomes and phagosomes. Inhibition of Abl tyrosine kinase by imatinib, a molecular targeted therapy used as standard treatment for chronic myeloid leukemia reduced the lysosomal pH in macrophages. This pH-shift was functionally relevant because imatinib increased the activity of the proteolytic enzyme cathepsin D and limited the growth of the major human pathogen Mycobacterium tuberculosis. These effects were active in vivo because acidic monocytes were more readily detectable in the blood of imatinib-treated leukaemia patients than in healthy controls. Given that inhibition of Abl tyrosine kinase enhances macrophage antimycobacterial activity, imatinib or similar antagonists have the potential to complement conventional drug therapy of multidrug- or extremely drug resistant tuberculosis.