title: 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.affiliation: Menzies Research Institute Tasmania and School of Medicine, University of Tasmania, Hobart, TAS, Australia;
authors.forename: Clare M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, North Ryde, NSW, Australia;
authors.forename: Ante
authors.initials: A
authors.lastname: Jerkovic
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France; Centre de Recherche sur l'Inflammation, INSERM U1149, Paris, France; Groupe d'Excellence, Pôle de Recherche et d'Enseignement Supérieur, Sorbonne Paris-Cité, Paris, France;
authors.forename: Hervé
authors.initials: H
authors.lastname: Puy
authors.affiliation: Department of Medicine, University of Melbourne, Melbourne, VIC, Australia; Office of Research, Royal Melbourne Hospital, Parkville, VIC, Australia;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France; Centre de Recherche sur l'Inflammation, INSERM U1149, Paris, France;
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Deybach
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM U1149, Paris, France; Groupe d'Excellence, Pôle de Recherche et d'Enseignement Supérieur, Sorbonne Paris-Cité, Paris, France;
authors.forename: Laurent
authors.initials: L
authors.lastname: Gouya
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT, Australia;
authors.forename: Giel
authors.initials: G
authors.lastname: van Dooren
authors.affiliation: School of Botany, University of Melbourne, Parkville, VIC, Australia;
authors.forename: Christopher Dean
authors.initials: CD
authors.lastname: Goodman
authors.affiliation: School of Botany, University of Melbourne, Parkville, VIC, Australia;
authors.forename: Angelika
authors.initials: A
authors.lastname: Sturm
authors.affiliation: Centre Français des Porphyries, Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France; Centre de Recherche sur l'Inflammation, INSERM U1149, Paris, France;
authors.forename: Hana
authors.initials: H
authors.lastname: Manceau
authors.affiliation: School of Botany, University of Melbourne, Parkville, VIC, Australia;
authors.forename: Geoffrey Ian
authors.initials: GI
authors.lastname: McFadden
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Centre Nationale de la Recherche Scientifique, Unite de Recherche Associé 2581, Paris, France; and.
authors.forename: Peter
authors.initials: P
authors.lastname: David
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, Centre Nationale de la Recherche Scientifique, Unite de Recherche Associé 2581, Paris, France; and.
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, North Ryde, NSW, Australia;
authors.forename: Gaétan
authors.initials: G
authors.lastname: Burgio
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, North Ryde, NSW, Australia;
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: McMorran
authors.affiliation: Australian School of Advanced Medicine, Macquarie University, North Ryde, NSW, Australia; The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Foote
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000201:enzymology / Q000469:parasitology*; D005260:Female; D005294:Ferrochelatase / Q000037:antagonists & inhibitors / Q000502:physiology*; D006418:Heme / Q000378:metabolism; D006801:Humans; D016778:Malaria, Falciparum / Q000201:enzymology / Q000469:parasitology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010962:Plasmodium berghei / Q000254:growth & development*; D046351:Protoporphyria, Erythropoietic / Q000201:enzymology / Q000469:parasitology / Q000517:prevention & control*; D011524:Protoporphyrins / Q000494:pharmacology
chemical_list: D011524:Protoporphyrins; D006418:Heme; C028842:N-methylprotoporphyrin IX; D005294:Ferrochelatase