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J Cell Sci. 2016 Aug 15;129(16):3130-43. doi: 10.1242/jcs.185595. Epub 2016 Jun 29.

The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection.

Author information

1
Department of Pediatrics, Yale University, New Haven, CT 06520, USA dawn.wetzel@utsouthwestern.edu.
2
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Department of Epidemiology of Microbial Disease, Yale School of Public Health, New Haven, CT 06520, USA.
5
Department of Molecular Biochemistry and Biophysics, Yale University, CT 06520, USA Department of Neuroscience, Yale University, New Haven, CT 06520, USA.

Abstract

Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood. We have previously shown that the Arg (also known as Abl2) non-receptor tyrosine kinase facilitates L. amazonensis amastigote uptake by macrophages. Using small-molecule inhibitors and primary macrophages lacking specific Src family kinases, we now demonstrate that the Hck, Fgr and Lyn kinases are also necessary for amastigote uptake by macrophages. Src-mediated Arg activation is required for efficient uptake. Interestingly, the dual Arg and Src kinase inhibitor bosutinib, which is approved to treat cancer, not only decreases amastigote uptake, but also significantly reduces disease severity and parasite burden in Leishmania-infected mice. Our results suggest that leishmaniasis could potentially be treated with host-cell-active agents such as kinase inhibitors.

KEYWORDS:

Abl; Kinase; Leishmania; Macrophage; Phagocytosis; Src

PMID:
27358479
PMCID:
PMC5004897
DOI:
10.1242/jcs.185595
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no competing or financial interests.

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