Iron Deficiency Anemia and the Pathogenesis of Falciparum Malaria Public Deposited

Downloadable Content

Download PDF
Last Modified
  • March 20, 2019
Creator
  • Goheen, Morgan
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Anemia, primarily iron deficiency anemia (IDA), affects up to 50% of pregnant women and 40% of preschool children in the developing world, significantly impacting perinatal and developmental health. However, clinical studies have found (1) iron deficiency protects from malaria, and (2) administration of iron to iron deficient individuals may increase the risk of malaria, thus complicating universal iron supplementation recommendations in malaria-endemic areas. Our lab developed an in vitro model, obtaining red blood cells (RBCs) from IDA or healthy donors at UNC, to study mechanisms of malaria-associated IDA protection and iron treatment risk. We demonstrated decreased P.falciparum invasion and growth in IDA RBCs and increased infection susceptibility in young RBCs and reticulocytes. Given iron is essential for the parasite, it was previously thought iron deficiency inhibited malaria through starvation. However, IDA also limits erythropoiesis and induces physiologic RBC changes. Our UNC-based studies thus generated a novel and paradigm-shifting hypothesis – namely that changes in RBC properties and the RBC population structure drive IDA resistance to and iron supplementation risk for malaria. Our next objective was to evaluate this hypothesis in pregnant women and children from a malaria-endemic area, via comprehensive longitudinal examination of P.falciparum pathogenesis in RBCs drawn from iron deficient Gambian children and pregnant women before, during, and after iron supplementation. RBCs were collected from 135 children and 165 pregnant women throughout 12 weeks of iron supplementation and used in flow cytometry-based in vitro assays. Our results demonstrate P.falciparum erythrocytic stage growth in vitro is low at baseline, correlating with hemoglobin levels and mean corpuscular volume. We also determined parasite growth increases during supplementation, using RBCs from both children and pregnant women. Additionally, we found reduced parasite invasion in RBCs from iron deficient Gambian children, which increases during iron supplementation. The elevated growth rates following iron supplementation paralleled increases in circulating reticulocytes and other markers of young RBCs, kinetics of which correlate with overall increased erythropoiesis. We conclude malaria growth in vitro corresponds with elevated erythropoiesis, an inevitable consequence of iron supplementation. Our findings imply iron supplementation in malarious regions should be accompanied by effective preventative measures against falciparum malaria.
Date of publication
Keyword
DOI
Resource type
Rights statement
  • In Copyright
Advisor
  • Cerami, Carla
  • Kasthuri, Raj
  • Kawula, Thomas
  • Meshnick, Steven R.
  • De Paris, Kristina
  • Cohen, Myron
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
Language
Parents:

This work has no parents.

Items