Iron and iron-containing heme are essential cofactors in reactions that perform critical biological functions, but are toxic in excess. Hence, the availability of these nutrients is tightly controlled. Leishmania parasites replicate intracellulary and can't synthesize heme, so must acquire iron and heme from the host cell. Until recently, it was not known how this was achieved. Work from the previous grant cycle identified three membrane proteins involved in iron and heme uptake that are essential for the intracellular growth and virulence of L. amazonensis: The ferric iron reductase LFR1, the ferrous iron transporter LIT1, and the long- sought heme transporter, LHR1. The availability of parasite strains deficient in these molecules and powerful tools to interrogate host cell heme-iron metabolism will now allow us to take this work to the next level: An investigation of the functiona interrelationship between parasite and host cell pathways for heme-iron homeostasis. Understanding this process is critical because Leishmania parasitizes macrophages, cells that perform a key role in the maintenance of organismal heme-iron metabolism. Reticuloendothelial macrophages recycle iron from phagocytosed senescent red blood cells at a staggering rate. In mammals, about 5x106 red blood cells or 5x1015 heme molecules are degraded each second inside macrophage phagolysosomes, releasing iron for body redistribution through a tightly regulated membrane transporter, ferroportin. We will take advantage of exciting recent advances in the field of heme- iron traffic in macrophages to: (1) Elucidate how the iron export machinery of macrophages impacts the ability of Leishmania amazonensis to acquire iron and replicate intracellularly;(2) Determine how the dynamics of heme traffic in macrophages affects intracellular heme uptake by L. amazonensis;and (3) Elucidate the importance of heme as a source of iron for L. amazonensis. Our results will facilitate future drug development by defining where L. amazonensis intercepts the elaborate heme-iron traffic machinery of macrophages, and by revealing whether heme reaching parasitophorous vacuoles represents a major source of iron for the parasites. Importantly, this project will also propel forward our understanding of human susceptibility to leishmaniasis. Iron deficiency is the most prevalent nutritional disorder, and identification of novel host factors that counteract the parasite's machinery for heme-iron acquisition can have a significant impact in the assessment of infection risk.
of this research to public health: Iron and heme uptake are critical for the survival and intracellular growth of Leishmania amazonensis. Access to these essential co-factors requires that the parasites compete effectively with highly developed pathways for iron and heme traffic that are present in their host cell, the macrophage. A detailed understanding of the interface between host and parasite iron and heme transport mechanisms will have a strong impact on the future development of new treatments for this serious infectious agent, and in the assessment of human risk for Leishmania infections.
|de Menezes, Juliana Perrone Bezerra; Koushik, Amrita; Das, Satarupa et al. (2017) Leishmania infection inhibits macrophage motility by altering F-actin dynamics and the expression of adhesion complex proteins. Cell Microbiol 19:|
|Mittra, Bidyottam; Laranjeira-Silva, Maria Fernanda; Miguel, Danilo Ciccone et al. (2017) The iron-dependent mitochondrial superoxide dismutase SODA promotes Leishmania virulence. J Biol Chem 292:12324-12338|
|Mittra, Bidyottam; Laranjeira-Silva, Maria Fernanda; Perrone Bezerra de Menezes, Juliana et al. (2016) A Trypanosomatid Iron Transporter that Regulates Mitochondrial Function Is Required for Leishmania amazonensis Virulence. PLoS Pathog 12:e1005340|
|Soares, Miguel P; Hamza, Iqbal (2016) Macrophages and Iron Metabolism. Immunity 44:492-504|
|Renberg, Rebecca L; Yuan, Xiaojing; Samuel, Tamika K et al. (2015) The Heme Transport Capacity of LHR1 Determines the Extent of Virulence in Leishmania amazonensis. PLoS Negl Trop Dis 9:e0003804|
|Ben-Othman, Rym; Flannery, Andrew R; Miguel, Danilo C et al. (2014) Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLoS Pathog 10:e1003901|
|Miguel, Danilo C; Flannery, Andrew R; Mittra, Bidyottam et al. (2013) Heme uptake mediated by LHR1 is essential for Leishmania amazonensis virulence. Infect Immun 81:3620-6|
|Mittra, Bidyottam; Cortez, Mauro; Haydock, Andrew et al. (2013) Iron uptake controls the generation of Leishmania infective forms through regulation of ROS levels. J Exp Med 210:401-16|
|Flannery, Andrew R; Renberg, Rebecca L; Andrews, Norma W (2013) Pathways of iron acquisition and utilization in Leishmania. Curr Opin Microbiol 16:716-21|
|Mittra, Bidyottam; Andrews, Norma W (2013) IRONy OF FATE: role of iron-mediated ROS in Leishmania differentiation. Trends Parasitol 29:489-96|
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