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

Citation

Smith, CM and Jerkovic, A and Puy, H and Winship, I and Deybach, JC and Gouya, L and van Dooren, G and Goodman, CD and Sturm, A and Manceau, H and McFadden, GI and David, P and Mercereau-Puijalon, O and Burgio, G and McMorran, BJ and Foote, SJ, Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites, Blood, 125, (3) pp. 534-541. ISSN 1528-0020 (2015) [Refereed Article]

Copyright Statement

Copyright 2015 by The American Society of Hematology

DOI: doi:10.1182/blood-2014-04-567149

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.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Clinical Sciences
Research Field:Infectious Diseases
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Infectious Diseases
Author:Smith, CM (Dr Clare Smith)
ID Code:98170
Year Published:2015 (online first 2014)
Web of Science® Times Cited:13
Deposited By:Menzies Institute for Medical Research
Deposited On:2015-02-04
Last Modified:2015-04-27
Downloads:0

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