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

Smith, Clare M.; Jerkovic, Ante; Puy, Hervé; Winship, Ingrid; Deybach, Jean Charles; Gouya, Laurent; Dooren, Giel G. van; Goodman, Christopher D.; Sturm, Angelika; Manceau, Hana; McFadden, Geoffrey I.; David, Peter H.; Mercereau‐Puijalon, Odile; Burgio, Gaétan; McMorran, Brendan J.; Foote, Simon J.

doi:10.1182/blood-2014-04-567149

Cited by 34 publications

(44 citation statements)

References 41 publications

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“…Strikingly, heme scavenging from host erythrocytes is important for parasite growth, as shown by refractoriness to P. falciparum growth within ferrochelatase (FECH)-deficient erythrocytes from individuals with erythropoietic protoporphyria (28). In good agreement with these natural genetics data, vestigial heme synthesis in host erythrocytes can be exploited for host-directed therapy of malaria (29).…”

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confidence: 60%

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

2016

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Malarial parasites have evolved complex regulation of heme supply and disposal to adjust to heme-rich and -deprived host environments. In addition to its own pathway for heme biosynthesis, Plasmodium likely harbors mechanisms for heme scavenging from host erythrocytes. Elaborate compartmentalization of de novo heme synthesis into three subcellular locations, including the vestigial plastid organelle, indicates critical roles in life cycle progression. In this study, we systematically profile the essentiality of heme biosynthesis by targeted gene deletion of enzymes in early steps of this pathway. We show that disruption of endogenous heme biosynthesis leads to a first detectable defect in oocyst maturation and sporogony in the Anopheles vector, whereas blood stage propagation, colonization of mosquito midguts, or initiation of oocyst development occurs indistinguishably from that of wild-type parasites. Although sporozoites are produced by parasites lacking an intact pathway for heme biosynthesis, they are absent from mosquito salivary glands, indicative of a vital role for heme biosynthesis only in sporozoite maturation. Rescue of the first defect in sporogony permitted analysis of potential roles in liver stages. We show that liver stage parasites benefit from but do not strictly depend upon their own aminolevulinic acid synthase and that they can scavenge aminolevulinic acid from the host environment. Together, our experimental genetics analysis of Plasmodium enzymes for heme biosynthesis exemplifies remarkable shifts between the use of endogenous and host resources during life cycle progression. Heme is a ubiquitous iron-porphyrin complex that serves as a cofactor of hemoproteins, such as globins, catalases, and cytochromes (1). The iron component of heme permits the binding of diatomic gases, as well as unique enzymatic redox reactions based on its reduction potential from the oxidized ferric (Fe 3ϩ ) to the reduced ferrous (Fe 2ϩ ) state (1). Thus, heme mediates fundamental biological processes, including oxygen transport, antioxidant responses, and cellular respiration, and is, therefore, indispensable for virtually all living organisms. Exceptions, like the parasitic kinetoplastid flagellate Phytomonas serpens that can survive in the complete absence of heme (2), are rare. As a result of this nearly universal dependence on heme, two complementary strategies for heme acquisition have evolved; heme scavenging and de novo heme biosynthesis.Plasmodium parasites are the causative agents of malaria and have adapted to an intraerythrocytic lifestyle during blood infection, the exclusive pathogenic phase of the parasite life cycle. Erythrocytes make up the largest pool of heme in the human body, as they are rich in hemoglobin. In turn, hemoglobin constitutes the major source of amino acids for developing blood stage parasites, which import and digest almost all host hemoglobin, liberating large amounts of heme (3). Free heme acts as a biological Fenton reagent and can thus damage organic molecules by oxidation...

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Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

2016

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“…Following the revelation that apicoplast FASII is dispensable in three species of blood stage malaria parasites, it was also revealed that apicoplast-localised steps of the multi compartment haem biosynthesis pathway (Ralph et al, 2004) were similarly dispensable during the blood stage (Nagaraj et al, 2013; Ke et al, 2014; Sigala and Goldberg, 2014; Smith et al, 2014). In rodent and human malaria parasites the final enzyme for haem biosynthesis is essential for oocysts (Nagaraj et al, 2013; Ke et al, 2014; Sigala and Goldberg, 2014).…”

Section: The Apicoplast As a Drug Targetmentioning

confidence: 99%

The apicoplast: now you see it, now you don’t

McFadden

Yeh

2017

International Journal for Parasitology

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112

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Parasites such as Plasmodium and Toxoplasma possess a vestigial plastid homologous to the chloroplasts of algae and plants. The plastid (known as the apicoplast; for apicomplexan plastid) is non-photosynthetic and very much reduced, but has clear endosymbiotic ancestry including a circular genome that encodes RNAs and proteins and a suite of bacterial biosynthetic pathways. Here we review the initial discovery of the apicoplast, and recount the major new insights into apicoplast origin, biogenesis and function. We conclude by examining how the apicoplast can be removed from malaria parasites in vitro, ultimately completing its reduction by chemical supplementation.

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“…As such our findings suggest that FECH may have a role extending beyond heme synthesis. Indeed, it was recently shown that FECH ‐deficient red blood cells are resistant to the growth of Plasmodium falciparum causing malaria . It is intriguing to conjecture that EPP may be a risk factor for colon cancer warranting screening in the manner similar to that clinically observed in individuals with familial adenomatous polyposis and Lynch syndromes.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer

et al. 2017

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Erythropoietic protoporphyria (EPP) is a rare cutaneous and systemic disease caused by mutations in the ferrochelatase gene (FECH). The molecular underpinnings of EPP in Middle Eastern populations and relative to other ethnic groups secondary to increased consanguinity are unknown. To understand the molecular pathogenesis of Middle Eastern EPP, we surveyed clinicopathological and molecular features in 6 large consanguineous families from Lebanon and Syria presenting with cutaneous and systemic features consistent with EPP. We observed 30% increased liver disease and 20% elevated end-stage liver complications in our EPP cohort compared to EPP patients previously reported elsewhere. In addition, Middle Eastern EPP patients in our cohort exhibited uniquely an increased incidence of colon cancer. Sequence analysis revealed 2 novel non-synonymous FECH mutations in the studied families designated p.M294T and p.I230M. In addition, FECH activity was significantly decreased (6%) in fibroblasts obtained from sun-exposed sites in a patient with p.M294T mutation, whereas in sharp contrast, protected sites from the same patient exhibited 54% activity for the gene. We also found that sun-exposed fibroblasts, relative to sun-protected and control fibroblasts, exhibited suppressed growth and atypical morphology in vitro, and that these effects were alleviated when the cells were co-cultured with sun-protected fibroblasts. Our findings on the increased incidence of colon cancer in EPP patients prompted us to survey FECH expression patterns in cancer. Using publicly available microarray datasets we found that FECH mRNA was largely significantly decreased in colon adenocarcinomas relative to normal colon tissues. Our findings suggest that families with autosomal recessive EPP should be screened more extensively for systemic involvement including liver diseases and colon cancer, and point to a previously unknown yet plausible tumor suppressor role for FECH in colon malignancy.

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

Cited by 34 publications

References 41 publications

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

Distinct Prominent Roles for Enzymes of Plasmodium berghei Heme Biosynthesis in Sporozoite and Liver Stage Maturation

The apicoplast: now you see it, now you don’t

Erythropoietic protoporphyria a clinical and molecular study from Lebanon: Ferrochelatase a potential tumor suppressor gene in colon cancer

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