Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites.

Abstract

Many red cell polymorphisms are a result of selective pressure by the malarial parasite. Here, we add another red cell disease to the panoply of erythrocytic changes that give rise to resistance to malaria. Erythrocytes from individuals with erythropoietic protoporphyria (EPP) have low levels of the final enzyme in the heme biosynthetic pathway, ferrochelatase. Cells from these patients are resistant to the growth of Plasmodium falciparum malarial parasites. This phenomenon is due to the absence of ferrochelatase and not an accumulation of substrate, as demonstrated by the normal growth of P falciparum parasites in the EPP phenocopy, X-linked dominant protoporphyria, which has elevated substrate, and normal ferrochelatase levels. This observation was replicated in a mouse strain with a hypomorphic mutation in the murine ferrochelatase gene. The parasite enzyme is not essential for parasite growth as Plasmodium berghei parasites carrying a complete deletion of the ferrochelatase gene grow normally in erythrocytes, which confirms previous studies. That ferrochelatase is essential to parasite growth was confirmed by showing that inhibition of ferrochelatase using the specific competitive inhibitor, N-methylprotoporphyrin, produced a potent growth inhibition effect against cultures of P falciparum. This raises the possibility of targeting human ferrochelatase in a host-directed antimalarial strategy.

• Authors: Clare M Smith, Ante Jerkovic, Hervé Puy, Ingrid Winship, Jean-Charles Deybach, Laurent Gouya, Giel van Dooren, Christopher Dean Goodman, Angelika Sturm, Hana Manceau, Geoffrey Ian McFadden, Peter David, Odile Mercereau-Puijalon, Gaétan Burgio, Brendan J McMorran, Simon J Foote
• Journal: Blood (Blood) Vol. 125 Issue 3 Pg. 534-41 (Jan 15 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25414439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Protoporphyrins
• Heme
• N-methylprotoporphyrin IX
• Ferrochelatase

Topics

• Animals
• Erythrocytes (enzymology, parasitology)
• Female
• Ferrochelatase (antagonists & inhibitors, physiology)
• Heme (metabolism)
• Humans
• Malaria, Falciparum (enzymology, parasitology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Phenotype
• Plasmodium berghei (growth & development)
• Protoporphyria, Erythropoietic (enzymology, parasitology, prevention & control)
• Protoporphyrins (pharmacology)