Iron metabolism in trypanosomatids, and its crucial role in infection

Abstract

Iron is almost ubiquitous in living organisms due to the utility of its redox chemistry. It is also dangerous as it can catalyse the formation of reactive free radicals -a classical double-edged sword. In this review, we examine the uptake and usage of iron by trypanosomatids and discuss how modulation of host iron metabolism plays an important role in the protective response. Trypanosomatids require iron for crucial processes including DNA replication, antioxidant defence, mitochondrial respiration, synthesis of the modified base J and, in African trypanosomes, the alternative oxidase. The source of iron varies between species. Bloodstream-form African trypanosomes acquire iron from their host by uptake of transferrin, and Leishmania amazonensis expresses a ZIP family cation transporter in the plasma membrane. In other trypanosomatids, iron uptake has been poorly characterized. Iron-withholding responses by the host can be a major determinant of disease outcome. Their role in trypanosomatid infections is becoming apparent. For example, the cytosolic sequestration properties of NRAMP1, confer resistance against leishmaniasis. Conversely, cytoplasmic sequestration of iron may be favourable rather than detrimental to Trypanosoma cruzi. The central role of iron in both parasite metabolism and the host response is attracting interest as a possible point of therapeutic intervention.

Transferrin Binding Proteins as a Means to Obtain Iron in Parasitic Protozoa

“…In mammals, T. brucei lives as a trypomastigote in the bloodstream and tissue fluids [Bitter et al, 1998;Subramanya, 2009;Taylor and Kelly, 2010;Johnson and Wessling-Resnick, 2012]. As an extracellular parasite, it depends on endocytosis to take up nutrients from the host blood [Subramanya, 2009].…”

“…brucei binds TF through a transferrin receptor, TbTFR. Although TbTFR and human transferrin receptor (HsTFR) bind the same iron transport protein (TF), they have no detectable amino acid homology [Borst, 1991;Schell et al, 1991;Taylor and Kelly, 2010]. TbTFR is present in only bloodstream forms and not in insect forms of the T. brucei life cycle.…”

“…Antigenic variation prevents receptors from being recognized by the immune system and allows parasites to use TF from different mammalian hosts [Borst, 1991;Bitter et al, 1998]. The surface of the parasite bloodstream form is covered with VSG protein, which is required for nutrient uptake; its variability provides protection from the mammalian immune system [Schell et al, 1991;Taylor and Kelly, 2010]. When some parasites in the population switch VSG gene expression, they produce resistant phenotypes.…”

“…TbTFR is a heterodimer consisting of ESAG7, a 42 kDa soluble protein attached to the membrane by the 50-60 kDa ESAG6 protein through a glycosyl-phosphatidylinositol (GPI) residue in the C-terminal tail [Borst, 1991;Schell et al, 1991;Ligtenberg et al, 1994;Salmon et al, 1994;Steverding et al, 1995;Salmon et al, 1997;Steverding, 2000;Maier and Steverding, 2008;Taylor and Kelly, 2010]. ESAG6 and ESAG7 can homodimerize, but only heterodimers bind TF; thus, each subunit provides a necessary component for the specific ligand-binding site [Salmon et al, 1994;Salmon et al, 1997].…”

“…Ferric iron solubility is low at physiological pH, and in aerobic environments, ferrous iron is highly toxic. Thus, iron is not free but bound to proteins [Clarke et al, 2001;Taylor and Kelly, 2010]. In complex organisms, the majority of iron is intracellularly sequestered within heme-compounds or iron-containing proteins or is stored in ferritin.…”