Abelson Tyrosine Kinase Controls Phagosomal Acidification Required for Killing of Mycobacterium tuberculosis in Human Macrophages

Abstract

The mechanisms that regulate the acidification of intracellular compartments are key to host defense against pathogens. In this paper, we demonstrate that Abl tyrosine kinase, a master switch for cell growth and trafficking of intracellular organelles, controls the acidification of lysosomes in human macrophages. Pharmacological inhibition by imatinib and gene silencing of Abelson (Abl) tyrosine kinase reduced the lysosomal pH in human macrophages by increasing the transcription and expression of the proton pumping enzyme vacuolar-type H+-adenosine triphosphatase. Because lysosomal acidification is required for antimicrobial activity against intracellular bacteria, we determined the effect of imatinib on the growth of the major human pathogen Mycobacterium tuberculosis. Imatinib limited the multiplication of M. tuberculosis. and growth restriction was dependent on acidification of the mycobacterial compartment. The effects of imatinib were also active in vivo because circulating monocytes from imatinibtreated leukemia patients were more acidic than monocytes from control donors. Importantly, sera from imatinib-treated patients triggered acidification and growth restriction of M. tuberculosis in macrophages. In summary, our results identify the control of phagosomal acidification as a novel function of Abl tyrosine kinase and provide evidence that the regulation occurs on the level of the vacuolar-type H+-adenosine triphosphatase. Given the efficacy of imatinib in a mouse model of tuberculosis and our finding that orally administered imatinib increased the ability of human serum to trigger growth reduction of intracellular M. tuberculosis, clinical evaluation of imatinib as a complementary therapy of tuberculosis, in particular multidrug or extremely drugresistant disease, is warranted.

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…Several protein kinase inhibitors are available for clinical use. 129 Imatinib, a tyrosine kinase inhibitor, reduces bacterial load and lung pathology, likely by enhancing autophagy, phagosomal acidification and myeloid cell mobilization, [130][131] and is currently being tested for its safety and immunogenicity as repurposed TB treatment. Adenosine monophosphate-activated protein kinase (AMPK) regulates cellular energy levels, T-cell differentiation and development of memory.…”

Multifunctional Abl kinases in health and disease

“…Subsequent reports showed that Abl kinases are also required for infection by several bacteria (e.g. Helicobacter pylori, EPEC, Salmonella enterica, Anaplasma phagocytophilum, Pseudomonas aeruginosa, Chlamydia trachomatis, Mycobacterium tuberculosis) (Bauer et al, 2009;Bruns et al, 2012;Elwell et al, 2008;Jayaswal et al, 2010;Lin et al, 2007;Ly and Casanova, 2009;Muller, 2012;Napier et al, 2011;Pielage et al, 2008;Poppe et al, 2007;Swimm et al, 2004;Tammer et al, 2007) and viruses [vaccinia virus,coxsackievirus,enterovirus 71 (EV71), HIV, hepatitis C virus (HCV) and Ebola virus] (Chen et al, 2007;Coyne and Bergelson, 2006;Garcia et al, 2012;Harmon et al, 2010;Newsome et al, 2006;Reeves et al, 2005;Yamauchi et al, 2015). Microbial pathogens exploit the ability of Abl kinases to regulate cytoskeletal processes in order to achieve efficient internalization, intracellular motility, pedestal formation, cell-to-cell spread, membrane modeling and release (egress).…”

The Lung Immune Niche in Tuberculosis: Insights from Studies on Human Alveolar Macrophages

“…Mtb is a highly successful pathogen that is able to manipulate and prevent phagosome acidification and maturation of this compartment [43]. This phenomenon was recently demonstrated to be controlled by Abl tyrosine kinases and could be reversed by the Abl tyrosine kinase inhibitor imatinib [44]. Mtb can also impair phagolysosomal fusion.…”