The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

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) nonreceptor 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-cellactive agents such as kinase inhibitors.

Leishmaniasis: a review

“…Wetzel et al . demonstrated that a tyrosine kinase non-receptor known as Abl2 facilitates L. amazonensis amastigote uptake by macrophages 34 . Once inside the phagolysosomes, promastigotes differentiate into amastigotes and proliferate extensively by binary fission, evading the immune response.…”

Phagocytic Integrins: Activation and Signaling

“…SFKs appear to be exclusively involved in "outside-in" signaling, as SFK-deficient cells produced reduced ROS after integrin clustering (113), whereas ICAM-1 adhesion and complement-dependent phagocytosis were normal in preactivated SFK-deficient cells (114,115).…”

Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

“…Bosutinib (Figure ), an Abl and Src kinase inhibitor, is an antineoplastic drug approved for CML and other cancers . Bosutinib inhibited L. amazonensis promastigote and amastigote uptake by bone marrow‐derived macrophages (BMDMs) of 49 and 46 %, respectively . In the same work, it has been shown that bosutinib reduces the lesion size in a mouse model of CL.…”