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

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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.