title: The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection.
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.
authors.affiliation: Department of Pediatrics, Yale University, New Haven, CT 06520, USA dawn.wetzel@utsouthwestern.edu.
authors.forename: Dawn M
authors.identifier: 0000-0002-3990-7043
authors.initials: DM
authors.lastname: Wetzel
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Rhodes
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Shaoguang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Epidemiology of Microbial Disease, Yale School of Public Health, New Haven, CT 06520, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
authors.affiliation: Department of Molecular Biochemistry and Biophysics, Yale University, CT 06520, USA Department of Neuroscience, Yale University, New Haven, CT 06520, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Koleske
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007074:Immunoglobulin G / Q000378:metabolism*; D007891:Leishmania / Q000187:drug effects / Q000472:pathogenicity*; D007896:Leishmaniasis / Q000201:enzymology / Q000469:parasitology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology; D051379:Mice; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D010271:Parasites / Q000187:drug effects / Q000469:parasitology; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C412373:AG 1879; D000814:Aniline Compounds; D016207:Cytokines; D007074:Immunoglobulin G; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases
keywords: Abl; Kinase; Leishmania; Macrophage; Phagocytosis; Src