Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages.
Bruns H, Stegelmann F, Fabri M, Doehner K, Van Zandbergen G, Wagner M, Skinner M, Modlin RL, Stenger S (2012)
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2012
Journal
Book Volume: 189
Pages Range: 4069-78
Journal Issue: 8
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 imatinib-treated 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 drug-resistant disease, is warranted.
Authors with CRIS profile
Involved external institutions
Universitätsklinikum Ulm
Germany (DE)
University of California Los Angeles (UCLA)
United States (USA) (US)
Klinikum Nürnberg
Germany (DE)
University of Guelph (U of G)
Canada (CA)
Germany (DE)
University of California Los Angeles (UCLA)
United States (USA) (US)
Klinikum Nürnberg
Germany (DE)
University of Guelph (U of G)
Canada (CA)
How to cite
APA:
Bruns, H., Stegelmann, F., Fabri, M., Doehner, K., Van Zandbergen, G., Wagner, M.,... Stenger, S. (2012). Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages. Journal of Immunology, 189(8), 4069-78. https://doi.org/10.4049/jimmunol.1201538
MLA:
Bruns, Heiko, et al. "Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages." Journal of Immunology 189.8 (2012): 4069-78.
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