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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Smith, CM; Jerkovic, A; Puy, H; Winship, I; Deybach, J-C; Gouya, L; van Dooren, G; Goodman, CD; Sturm, A; Manceau, H; McFadden, GI; David, P; Mercereau-Puijalon, O; Burgio, G; McMorran, BJ; Foote, SJ

Published Date

  • January 15, 2015

Published In

Volume / Issue

  • 125 / 3

Start / End Page

  • 534 - 541

PubMed ID

  • 25414439

Pubmed Central ID

  • 25414439

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2014-04-567149

Language

  • eng

Conference Location

  • United States