Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
J Cell Sci. 2023 Jul 15;136(14). doi: 10.1242/jcs.260809. Epub 2023 Jul 28.
Leishmania spp. are obligate intracellular parasites that must be internalized by phagocytic cells to evade immune responses and cause disease. The uptake of both Leishmania promastigotes (insect-stage parasites) and amastigotes (proliferative-stage parasites in humans and mice) by phagocytes is thought to be mainly host cell driven, not parasite driven. Our previous work indicates that host Src- and Abl-family kinases facilitate Leishmania entry into macrophages and pathogenesis in murine cutaneous leishmaniasis. Here, we demonstrate that host spleen tyrosine kinase (SYK) is required for efficient uptake of Leishmania promastigotes and amastigotes. A Src-family kinase-Abl-family kinase-SYK signaling cascade induces Leishmania amastigote internalization. Finally, lesion size and parasite burden during Leishmania infection is significantly decreased in mice lacking SYK in monocytes or by treatment with the SYK inhibitor entospletinib. In summary, SYK is required for maximal Leishmania uptake by macrophages and disease in mice. Our results suggest potential for treating leishmaniasis using host cell-directed agents.
利什曼原虫属是专性细胞内寄生虫，必须被吞噬细胞内化才能逃避免疫反应并引起疾病。吞噬细胞对利什曼前鞭毛体（昆虫期寄生虫）和无鞭毛体（人类和小鼠中的增殖期寄生虫）的摄取被认为主要是宿主细胞驱动的，而不是寄生虫驱动的。我们之前的工作表明，宿主Src 和 Abl 激酶家族促进利什曼原虫进入巨噬细胞并在小鼠皮肤利什曼病发病机制中发挥作用。在这里，我们证明宿主脾酪氨酸激酶（SYK）是有效摄取利什曼前鞭毛体和无鞭毛体所必需的。Src 激酶家族-Abl 激酶家族-SYK 信号级联诱导利什曼无鞭毛体的内化。最后，在缺乏单核细胞中的 SYK 或用 SYK 抑制剂 entospletinib 治疗的小鼠中，利什曼原虫感染期间的病变大小和寄生虫负荷显著降低。总之，SYK 是巨噬细胞摄取利什曼原虫和小鼠疾病的最大必需。我们的结果表明，使用宿主细胞定向药物治疗利什曼病具有潜力。
