Mechanisms of iron acquisition by malaria parasites in the red blood cell

Severe malaria (SM) manifests when Plasmodium falciparum parasites invade and replicate within red blood cells (RBCs). It is estimated that SM kills over 600,000 people annually. SM causes significant cardiovascular, pulmonary, neurologic, and hematologic morbidities that undermine the health of millions of people in malaria-endemic regions. Elucidating the fundamental biological processes used by blood-stage parasites provides critical insights that can be used to prevent the cardiopulmonary and neurologic complications of SM. Like all cells, P. falciparum requires iron for essential cellular pathways such as the mitochondrial electron transport chain (ETC). P. falciparum is particularly susceptible to metal chelators, but the mechanisms of iron uptake from the RBC are unknown. The most abundant iron source in RBCs is hemoglobin. P. falciparum internalizes RBC hemoglobin into an acidic food vacuole (FV), where labile iron is expected to be produced from non-enzymatic heme degradation. It is hypothesized that P. falciparum uses this labile iron pool to meet its cellular nutritional needs. In support of this hypothesis, a homolog of the human iron transporter divalent metal transporter 1 (DMT1) was identified and localized to the FV membrane. The project used an inducible knock-down (KD) system to show that PfDMT1 is essential for blood-stage parasite growth. Loss of PfDMT1 impaired the mitochondrial ETC and biogenesis of the apicoplast organelle, processes that depend on iron. It is proposed that the essential function of PfDMT1 is to export iron out of the FV to support iron-dependent metabolism throughout the parasite. This study will test this hypothesis with the following aims: 1: to determine if labile iron pools in the cytoplasm, mitochondrion, apicoplast, and nucleus rely on PfDMT1 function. We will also evaluate changes in the concentration of iron and other metals in the FV upon PfDMT1 KD. 2: to identify the protein interactors of PfDMT1 to unveil proteins that are critical for parasite iron metabolism. Tagged PfDMT1 will be used to determine protein interaction partners using immunoprecipitation and mass spectrometry. These experiments will unveil the first known mechanism for iron acquisition in malaria parasites and identify proteins that can be used to develop novel therapeutics to reduce the cardiopulmonary and neurological complications of SM.

Basic Science

Jan 2024 — Dec 2025

$67,388

United States