Grant: Operating Grant

Malaria remains a major global human health threat. The high prevalence of malaria infections in endemic areas in the developing world is due to several factors, including the lack of an effective vaccine, resistance of the parasite to anti-malarial drugs, and insecticide resistance among mosquito vectors. Plasmodium falciparum is the most virulent and deadly human parasite especially in sub-Saharan Africa, where it is responsible for high morbidity and mortality. In this region, children under the age of 5 and pregnant women have the highest risk for severe malarial anemia (SMA) and cerebral malaria, which are severe complications of P. falciparum infection. The goal of our studies is to provide a better understanding of the etiology of SMA. Observations in P. falciparum infected humans and experimental malaria models in monkeys and mice indicate that suppressed erythropoiesis or red blood cell (RBC) production plays a major role in SMA. Iron is an essential element of life in vertebrates and their microbial invaders. Importantly, iron is critical for erythropoiesis to replace RBC lost or destroyed during episodes of anemia. We propose that iron homeostasis may be disrupted or abnormal during malaria and contribute to suppressed erythropoiesis underlying malarial anemia. The proposed studies will utilize multidisciplinary approaches including hematology, immunology, cell biology, and molecular biology. The proposed experiments will be conducted using a well-characterized mouse malaria model and in serum samples obtained from Kenyan children with malaria. Our studies will lead to a comprehensive understanding of iron homeostasis during malaria and will identify potential molecules and mechanisms that will be useful for the development of urgently needed novel therapy to treat SMA, a severe and often fatal complication of P. falciparum infection.