Host-mediated regulation of superinfection in malaria
Open accessAbstract
In regions of high rates of malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites to individuals who already have blood-stage parasitemia. This manifests itself in semi-immune children (who have been exposed since birth to Plasmodium infection and as such show low levels of peripheral parasitemia but can still be infected) older than 5 years of age by concurrent carriage of different parasite genotypes at low asymptomatic parasitemias. Superinfection presents an increased risk of hyperparasitemia and death in less immune individuals but counterintuitively is not frequently observed in the young. Here we show in a mouse model that ongoing blood-stage infections, above a minimum threshold, impair the growth of subsequently inoculated sporozoites such that they become growth arrested in liver hepatocytes and fail to develop into blood-stage parasites. Inhibition of the liver-stage infection is mediated by the host iron regulatory hormone hepcidin, whose synthesis we found to be stimulated by blood-stage parasites in a density-dependent manner. We mathematically modeled this phenomenon and show how density-dependent protection against liver-stage malaria can shape the epidemiological patterns of age-related risk and the complexity of malaria infections seen in young children. The interaction between these two Plasmodium stages and host iron metabolism has relevance for the global efforts to reduce malaria transmission and for evaluation of iron supplementation programs in malaria-endemic regions.
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This mechanism may prevent superinfection by additional malaria parasites during subsequent exposures and provides innate immune protection in infants and children without adaptive immunity.
“This mechanism may function to prevent superinfection by additional malaria parasites during subsequent exposures to malaria-bearing mosquitoes, and it provides a form of innate immune protection in infants and children who have not yet developed an adaptive immune response to malarial parasites31.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [31]
Pathogens adapted to survive intracellularly might have a survival advantage by increased iron availability.
“However, this implies that pathogens adapted to survive intracellularly might have a survival advantage by increased iron availability [156,157].”
From Iron in immune cell function and host defense (2021) · cites this paper as [156]
Humans and mice infected with malaria have elevated plasma hepcidin levels, which correlate positively with parasitemia and plasma IL-6.
“As expected, humans and mice infected with malaria have elevated plasma hepcidin levels, which correlate positively with parasitemia and plasma IL-6 [75–78], but patients with the most severe anemia in the context of P. falciparum infection have reduced hepcidin levels, perhaps suggesting negative feedback, such as the effect of compensatory erythropoiesis, on hepcidin expression [75].”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [77]
Hepcidin protects against malaria by reducing iron availability to parasites.
“These data suggest that hepcidin protects against malaria by reducing iron availability to parasites.”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [77]
Adverse effects of hepcidin inactivation in mouse models of malaria infection or microbial sepsis suggest a therapeutic potential of hepcidin agonists in the context of these pathologies.
“Finally, the adverse effects of hepcidin inactivation in mouse models of malaria infection (Portugal et al., 2011) or microbial sepsis suggest a therapeutic potential of hepcidin agonists in the context of these pathologies (Zeng et al., 2015).”
From Pharmacological Targeting of the Hepcidin/Ferroportin Axis (2016) · cites this paper as Portugal et al., 2011
Malaria induces hepcidin, suggesting that iron sequestration is a major contributing factor to malarial anemia.
“In addition, malaria induces HAMP, suggesting that iron sequestration is a major contributing factor to malarial anemia [100, 101].”
From Iron deficiency or anemia of inflammation?: Differential diagnosis and mechanisms of anemia of inflammation (2016) · cites this paper as [101]
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References 35 · Cited by 232
- Authors
- Portugal, S., Carret, C., Recker, M., Armitage, A. E., Gonçalves, L. A., Epiphanio, S., Sullivan, D., Roy, C., Newbold, C. I., Drakesmith, H., & Mota, M. M.
- Affiliations
- University of Lisbon (PT)
- University of Oxford (GB)
- John Radcliffe Hospital (GB)
- Instituto Gulbenkian de Ciência (PT)
- Johns Hopkins University (US)
- Corresponding author
- Mota, Maria M
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-05-15
- Volume
- 17
- Issue
- 6
- Pages
- 732-737
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4200394
- OpenAlex
- W1976484400
- Cited by
- 232
- References
- 35
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 9 · 2023: 11 · 2022: 8 · 2021: 13 · 2020: 17 · 2019: 13 · 2018: 13 · 2017: 16 · 2016: 16 · 2015: 21 · 2014: 20 · 2013: 22 · 2012: 30
- FWCI
- 27.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082722)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD061241)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Immunology and Microbiology › Parasitology › Bird parasitology and diseases
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- Plasmodium, hepcidin, iron sequestration, liver stage infection, sporozoite infection, density dependence, hyperparasitemia, mathematical modeling, iron supplementation
- MeSH terms
- Animals, Host-Parasite Interactions, Humans, Liver, Malaria, Mice, Inbred BALB C, Mice, Inbred C57BL, Plasmodium, Superinfection, Disease Progression, Antimicrobial Cationic Peptides, Sporozoites, Mice, Hepcidins
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