Abelson Tyrosine Kinase Controls Phagosomal Acidification Required for Killing of Mycobacterium tuberculosis in Human Macrophages
Open accessAbstract
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.
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Inhibition of Abl tyrosine kinase by imatinib resulted in increased acidification of the lysosome and improved control of M. tuberculosis.
“Inhibition of Abl tyrosine kinase by the clinically used drug imatinib resulted in increased acidification of the lysosome and improved control of M. tuberculosis (39).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [39]
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Self-citation
- Authors
- Bruns, H., Stegelmann, F., Fabri, M., Döhner, K., van Zandbergen, G., Wagner, M., Skinner, M., Modlin, R. L., & Stenger, S.
- Affiliations
- Universität Ulm (DE)
- University Hospital Ulm (DE)
- University of California, Los Angeles (US)
- Institut für Medizinische Mikrobiologie und Hygiene, Universitätsklinikum Ulm , D-89081 Ulm,
- Nuremberg Hospital (DE)
- University of Guelph (CA)
- Corresponding author
- Bruns, Heiko
- Stenger, Steffen
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-10
- Volume
- 189
- Issue
- 8
- Pages
- 4069-4078
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3684563
- OpenAlex
- W2143119706
- Cited by
- 112
- References
- 62
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 11 · 2023: 5 · 2022: 5 · 2021: 13 · 2020: 6 · 2019: 11 · 2018: 13 · 2017: 8 · 2016: 12 · 2015: 12 · 2014: 3 · 2013: 4
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- European Commission
- National Institute of Allergy and Infectious Diseases (R01AI047868)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- c-Abl, phagosome acidification, Mycobacterium tuberculosis, macrophages, lysosomal acidification, vacuolar H+-ATPase, imatinib, intracellular bacterial killing, monocytes, drug-resistant tuberculosis, host defense against mycobacteria
- MeSH terms
- Imatinib Mesylate, Benzamides, Cells, Cultured, Cytoskeletal Proteins, Humans, Hydrogen-Ion Concentration, Mycobacterium tuberculosis, Phagosomes, Piperazines, Pyrimidines, Macrophages, Alveolar, Protein Transport, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing
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