Iron metabolism and malarial pathogenesis

It is estimated two fifths of the world?s population is at risk from malaria. Malaria is a disease caused by infection with the parasite Plasmodium. The parasite has a complicated life-cycle, and lives in cells in the liver, and in red blood cells. Although several treatments to combat malaria exist, we still need to know more about how the parasite lives in humans in order to effectively control the disease. Plasmodium needs iron to survive, and obtains its iron from its human host. Investigating how this happens, and how iron influences the growth and life-cycle of the parasite, are the aims of this project. A better understanding of these issues may allow regulation of iron transport to inhibit Plasmodium, and benefit infected humans.

Malaria, caused by infections of the protozoan parasite Plasmodium, causes significant morbidity and mortality, particularly in the developing world. In 2006 the results of a clinical trial involving iron supplementation to infants in Tanzania revealed an increased incidence of malaria-related events. The life-cycle of Plasmodium includes a liver-stage and an erythrocyte stage. The liver controls host iron homeostasis by making hepcidin, and most iron in the body resides within red cells. There are likely to be crucial links between Plasmodium biology and host iron transport, and the Tanzania trial re-emphasized this. The mechanisms by which iron metabolism and Plasmodium interact are important for at least two reasons; iron availability controls the growth the pathogen, and anaemia associated with malaria is a major cause of disease. However the molecular interactions between iron transport and Plasmodium are poorly understood.
In this grant application we address this issue in two ways. First we will examine the effect of the liver- and the red-cell stages of infection on synthesis of the peptide hormone hepcidin. Hepcidin is the master regulator of host iron homeostasis, and reduces iron supply to the erythron by inhibiting dietary iron absorption and iron recycling by macrophages. Changes in hepatocyte hepcidin levels during liver infection would influence the erythrocyte population that are the targets for next stage of Plasmodium infection. For the red cell stage, we have found that hepcidin mRNA expression is stimulated by parasitized erythrocytes in vitro. High hepcidin levels cause anaemia, so exploring the basis of Plasmodium-induced hepcidin may allow a better understanding of malarial anaemia and suggest new interventions. The molecular mechanisms controlling hepcidin synthesis are quite well understood, but how malaria affects these pathways has not been explored. Our second line of work will investigate the effects of iron availability on Plasmodium growth and commitment to gametocytogenesis. Using recently developed methods we will test whether adding iron to parasite cultures promotes Plasmodium asexual replication. These experiments have some specific value in the context of the results of the Tanzania trial mentioned above. Instead of dividing asexually, Plasmodium can decide to commit to making gametocytes, the form that is transmittable from human to mosquito. Because gametocyte levels correlate with anaemia, we propose that reduced intraerythrocytic iron levels provoke gametocytogenesis. We describe experiments aimed at testing this hypothesis.