The Src and Abl family kinases activate the Spleen Tyrosine Kinase to maximize phagocytosis andLeishmaniainfection

Abstract

ABSTRACTLeishmaniaspp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease.Leishmaniauptake is thought to be mainly host cell-driven, not parasite-driven. Promastigote (insect-stage) parasites primarily bind complement receptors (e.g., CR3) on phagocytes and are internalized through a process analogous to complement-mediated phagocytosis. Amastigote-stage parasites (proliferative forms in humans and mice) primarily bind Fc receptors and are engulfed through a process similar to immunoglobulin-mediated phagocytosis. Our previous work indicates that host Src and Abl family kinases facilitateLeishmaniaentry into macrophages and pathogenesis in murine cutaneous leishmaniasis. Here we demonstrate that host spleen tyrosine kinase (SYK) is required for efficient uptake ofLeishmaniapromastigotes and amastigotes. A Src family kinase-Abl family kinase-SYK signaling cascade inducesLeishmaniaamastigote internalization. Finally, lesion size and parasite burden duringLeishmaniainfection is significantly decreased in mice lacking SYK in monocytes or by treatment with the SYK inhibitor entospletinib. In summary, SYK is required for maximalLeishmaniauptake by macrophages and disease in mice. Our results suggest potential for treating leishmaniasis using host cell-directed agents.SUMMARY STATEMENTActivation of Spleen Tyrosine Kinase by Src and Abl family kinases is required for maximalLeishmaniauptake by macrophages and disease in a mouse model of cutaneous leishmaniasis.