The Abl and Arg kinases mediate distinct modes of phagocytosis and are required for maximal Leishmania infection.
Leishmania, an obligate intracellular parasite, binds several receptors to trigger engulfment by phagocytes, leading to cutaneous or visceral disease. These receptors include complement receptor 3 (CR3), used by promastigotes, and the Fc receptor (FcR), used by amastigotes. The mechanisms mediating uptake are not well understood. Here we show that Abl family kinases mediate both phagocytosis and the uptake of Leishmania amazonensis by macrophages (Ms). Imatinib, an Abl/Arg kinase inhibitor, decreases opsonized polystyrene bead phagocytosis and Leishmania uptake. Interestingly, phagocytosis of IgG-coated beads is decreased in Arg-deficient Ms, while that of C3bi-coated beads is unaffected. Conversely, uptake of C3bi-coated beads is decreased in Abl-deficient Ms, but that of IgG-coated beads is unaffected. Consistent with these results, Abl-deficient Ms are inefficient at C3bi-opsonized promastigote uptake, and Arg-deficient Ms are defective in IgG1-opsonized amastigote uptake. Finally, genetic loss of Abl or Arg reduces infection severity in murine cutaneous leishmaniasis, and imatinib treatment results in smaller lesions with fewer parasites than in controls. Our studies are the first to demonstrate that efficient phagocytosis and maximal Leishmania infection require Abl family kinases. These results highlight Abl family kinase-mediated signaling pathways as potential therapeutic targets for leishmaniasis.
Department of Pediatrics, Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
Dawn M
DM
Wetzel
Diane
D
McMahon-Pratt
Anthony J
AJ
Koleske
D000818:Animals; D001549:Benzamides; D002460:Cell Line; D003179:Complement C3b / Q000276:immunology; D000068877:Imatinib Mesylate; D007074:Immunoglobulin G / Q000276:immunology; D007894:Leishmania mexicana / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D007896:Leishmaniasis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D016177:Macrophage-1 Antigen / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008863:Microspheres; D010587:Phagocytosis; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; D007074:Immunoglobulin G; D016177:Macrophage-1 Antigen; D010879:Piperazines; D011743:Pyrimidines; D003179:Complement C3b; D000068877:Imatinib Mesylate; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl