The Src kinases Hck, Fgr and Lyn activate Arg to facilitate IgG-mediated phagocytosis and Leishmania infection.
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.
['Wetzel|Dawn M|DM|0000-0002-3990-7043', 'Rhodes|Emma L|EL|', 'Li|Shaoguang|S|', 'McMahon-Pratt|Diane|D|', 'Koleske|Anthony J|AJ|']
D000814:Aniline Compounds D000818:Animals D016207:Cytokines D004195:Disease Models, Animal D000068877:Imatinib Mesylate D007074:Immunoglobulin G D007891:Leishmania D007896:Leishmaniasis D008264:Macrophages D051379:Mice D008954:Models, Biological D009570:Nitriles D010271:Parasites D010587:Phagocytosis D010766:Phosphorylation D011505:Protein-Tyrosine Kinases D011518:Proto-Oncogene Proteins D051572:Proto-Oncogene Proteins c-hck D011743:Pyrimidines D011804:Quinolines D000067996:RAW 264.7 Cells D015398:Signal Transduction D019061:src-Family Kinases
Src Kinase Phagocytosis Leishmania Macrophage Abl