Characterization of Iron and Heme Acquisition between the Intracellular Parasite Leishmania and its Host, the Macrophage

利什曼原虫感染损害了全世界数百万人的健康。该项目旨在确定细胞内寄生虫利什曼原虫及其宿主细胞巨噬细胞之间铁和血红素摄取的竞争机制，这对于从衰老红细胞中回收血红素铁至关重要。在哺乳动物中，这种原生动物寄生虫居住在巨噬细胞内的寄生虫空泡中并在其中增殖。到目前为止，很少有人知道铁和血红素收购机制利什曼原虫，血红素营养缺陷型，缺乏血红素合成的酶，必须依靠宿主血红素生存。近年来，随着三种直接参与铁和血红素摄取的寄生虫蛋白的鉴定，对其中一些过程的认识已经得到阐明。然而，利什曼原虫如何操纵宿主巨噬细胞血红素和铁稳态途径仍不清楚。从寄生虫和宿主的角度来看，这些问题的答案是重要的，本提案中的多维目标旨在填补我们对宿主-寄生虫相互作用这一关键因素的理解中的重大知识空白。使用骨髓源性巨噬细胞和小鼠模型的体外、离体和体内研究的组合将能够分析感染对宿主铁和血红素代谢的影响，并将有助于确定利什曼原虫调节宿主血红素和铁稳态的过程。我们的最终目标是提供更深入的了解利什曼原虫如何克服宿主机制，限制血红素和铁的可用性。

Infection with Leishmania impairs the health of millions throughout the world. This project aims to define the competing mechanisms for iron and heme uptake between the intracellular parasite Leishmania and its host cell, the macrophage, which are essential for recycling of heme-iron from senescent red blood cells. In mammals, this protozoan parasite resides and proliferates in parasitophorous vacuoles inside macrophages. To date, very little is known about the iron and heme acquisition mechanisms of Leishmania, a heme auxotroph that lacks most enzymes for heme synthesis and must rely upon host heme for survival. Insights into some of these processes have been elucidated in recent years with the identification of three parasite proteins directly involved in iron and heme uptake. However, how Leishmania manipulates the host macrophages heme and iron homeostasis pathways remains unclear. Answers to these questions are significant from the perspective of both parasite and host, and the multi-dimensional aims in this proposal are designed to fill significant knowledge gaps in our understanding of this crucial element of host-parasite interaction. A combination of in vitro, ex vivo and in vivo studies using bone-marrow derived macrophages and the mouse model will enable analyzing the impact of infection upon host iron and heme metabolism, and will help determine the processes by which Leishmania modulates host heme and iron homeostasis. Our ultimate goal is to provide deeper insights into how Leishmania overcomes the host mechanisms that restrain availability of heme and iron.