ArticlePLoS pathogens2017
A novel genetic technique in Plasmodium berghei allows liver stage analysis of genes required for mosquito stage development and demonstrates that de novo heme synthesis is essential for liver stage development in the malaria parasite.
Article in PLoS pathogens, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 45 citations in OpenAlex.
- Potent acridone antimalarial against all three life stages of Plasmodium.Nature communications · 2026Article
- Heterogeneous constraint and adaptation across the malaria parasite life cycle.Proceedings. Biological sciences · 2025Article
- Identifying antimalarials that disrupt malaria parasite transmission when fed to the mosquito.International journal for parasitology · 2025Article
- Biogenesis of CytochromesACS infectious diseases · 2025Article
- Biogenesis of cytochromesbioRxiv : the preprint server for biology · 2024Article
- Host cell CRISPR genomics and modelling reveal shared metabolic vulnerabilities in the intracellular development of Plasmodium falciparum and related hemoparasites.Nature communications · 2024Article
- Aryl amino acetamides prevent Plasmodium falciparum ring development via targeting the lipid-transfer protein PfSTART1.Nature communications · 2024Article
- Probing the Antiplasmodial Properties of Plakortinic Acids C and D: An Uncommon Pair of Marine Peroxide-Polyketides Isolated from a Two-Sponge Association ofLife (Basel, Switzerland) · 2024Article
- Let it glow: genetically encoded fluorescent reporters in Plasmodium.Malaria journal · 2024Review
- Two Gracilioethers Containing a [2(5H)-Furanylidene]ethanoate Moiety and 9,10-Dihydroplakortone G: New Polyketides from the Caribbean Marine SpongeApplied sciences (Basel, Switzerland) · 2024Article
- Roles of the apicoplast across the life cycles of rodent and human malaria parasites.The Journal of eukaryotic microbiology · 2022Review
- The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Substrate-mediated regulation of the arginine transporter of Toxoplasma gondii.PLoS pathogens · 2021Article
- An integrated platform for genome engineering and gene expression perturbation in Plasmodium falciparum.Scientific reports · 2021Article
- Plasmodium-a brief introduction to the parasites causing human malaria and their basic biology.Journal of physiological anthropology · 2021Review
- An apicoplast-resident folate transporter is essential for sporogony of malaria parasites.Cellular microbiology · 2021Article
- Phytochemical Constituents, Antimalarial Efficacy, and Protective Effect ofPreventive nutrition and food science · 2020Article
- Characterization of the apicoplast-localized enzymeThe Journal of biological chemistry · 2020Article
- Host Porphobilinogen Deaminase Deficiency Confers Malaria Resistance inFrontiers in cellular and infection microbiology · 2020Article
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3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The combination of drug resistance, lack of an effective vaccine, and ongoing conflict and poverty means that malaria remains a major global health crisis. Understanding metabolic pathways at all parasite life stages is important in prioritising and targeting novel anti-parasitic compounds. The unusual heme synthesis pathway of the rodent malaria parasite, Plasmodium berghei, requires eight enzymes distributed across the mitochondrion, apicoplast and cytoplasm. Deletion of the ferrochelatase (FC) gene, the final enzyme in the pathway, confirms that heme synthesis is not essential in the red blood cell stages of the life cycle but is required to complete oocyst development in mosquitoes. The lethality of FC deletions in the mosquito stage makes it difficult to study the impact of these mutations in the subsequent liver stage. To overcome this, we combined locus-specific fluorophore expression with a genetic complementation approach to generate viable, heterozygous oocysts able to produce a mix of FC expressing and FC deficient sporozoites. These sporozoites show normal motility and can invade liver cells, where FC deficient parasites can be distinguished by fluorescence and phenotyped. Parasites lacking FC exhibit a severe growth defect within liver cells, with development failure detectable in the early to mid stages of liver development in vitro. FC deficient parasites could not complete liver stage development in vitro nor infect naïve mice, confirming liver stage arrest. These results validate the heme pathway as a potential target for prophylactic drugs targeting liver stage parasites. In addition, we demonstrate that our simple genetic approach can extend the phenotyping window beyond the insect stages, opening considerable scope for straightforward reverse genetic analysis of genes that are dispensable in blood stages but essential for completing mosquito development.
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