Malaria parasite-synthesized heme is essential in the mosquito and liver stages and complements host heme in the blood stages of infection
Open accessAbstract
Heme metabolism is central to malaria parasite biology. The parasite acquires heme from host hemoglobin in the intraerythrocytic stages and stores it as hemozoin to prevent free heme toxicity. The parasite can also synthesize heme de novo, and all the enzymes in the pathway are characterized. To study the role of the dual heme sources in malaria parasite growth and development, we knocked out the first enzyme, δ-aminolevulinate synthase (ALAS), and the last enzyme, ferrochelatase (FC), in the heme-biosynthetic pathway of Plasmodium berghei (Pb). The wild-type and knockout (KO) parasites had similar intraerythrocytic growth patterns in mice. We carried out in vitro radiolabeling of heme in Pb-infected mouse reticulocytes and Plasmodium falciparum-infected human RBCs using [4-(14)C] aminolevulinic acid (ALA). We found that the parasites incorporated both host hemoglobin-heme and parasite-synthesized heme into hemozoin and mitochondrial cytochromes. The similar fates of the two heme sources suggest that they may serve as backup mechanisms to provide heme in the intraerythrocytic stages. Nevertheless, the de novo pathway is absolutely essential for parasite development in the mosquito and liver stages. PbKO parasites formed drastically reduced oocysts and did not form sporozoites in the salivary glands. Oocyst production in PbALASKO parasites recovered when mosquitoes received an ALA supplement. PbALASKO sporozoites could infect mice only when the mice received an ALA supplement. Our results indicate the potential for new therapeutic interventions targeting the heme-biosynthetic pathway in the parasite during the mosquito and liver stages.
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Plasmodium may be able to take up TBI via its own TFR.
“In addition, Plasmodium may also be able to take up TBI via its own TFR (Ke et al., 2014;Nagaraj et al., 2013;Pollack and Fleming, 1984;Rodriguez and Jungery, 1986).”
From Iron in infection and immunity (2020) · cites this paper as Nagaraj et al., 2013
The Introduction and Results discuss Plasmodium acquiring heme from host hemoglobin, but those passages do not address transferrin-bound iron (TBI) uptake through a parasite transferrin receptor (TFR). Searches for transferrin, TFR, and iron uptake found no passage in our copy supporting that proposed route; page numbers were unavailable. (LLM, conf=0.77)
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- Authors
- Nagaraj, V. A., Sundaram, B., Varadarajan, N. M., Subramani, P. A., Kalappa, D. M., Ghosh, S. K., & Padmanaban, G.
- Affiliations
- Indian Institute of Science Bangalore (IN)
- National Institute of Malaria Research (IN)
- Corresponding author
- Nagaraj, Viswanathan Arun
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-08-01
- Volume
- 9
- Issue
- 8
- Pages
- e1003522
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC3731253
- OpenAlex
- W2080661532
- Cited by
- 159
- References
- 59
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 13 · 2023: 9 · 2022: 11 · 2021: 16 · 2020: 22 · 2019: 11 · 2018: 9 · 2017: 16 · 2016: 12 · 2015: 13 · 2014: 13 · 2013: 2
- FWCI
- 13.63
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- NOT FOUND REPOSITORY (Indian Institute of Science Bangalore) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Indian National Science Academy
- Department of Science and Technology, Ministry of Science and Technology, India
- Indian Council of Medical Research
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- heme biosynthesis, Plasmodium berghei, Plasmodium falciparum, delta-aminolevulinic acid synthase, ferrochelatase, hemozoin, liver stage development, 5-aminolevulinic acid, antimalarial drug targets
- MeSH terms
- 5-Aminolevulinate Synthetase, Animals, Anopheles, Ferrochelatase, Heme, Hemeproteins, Humans, Liver, Plasmodium berghei, Plasmodium falciparum, Malaria, Falciparum, Oocysts, Sporozoites, Mice
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