Abstract
In regions of high rates of malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites to individuals who already have blood-stage parasitemia1. 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 parasitemias2. Superinfection presents an increased risk of hyperparasitemia and death in less immune individuals but counterintuitively is not frequently observed in the young3,4. 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 hepcidin5, 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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Acknowledgements
We would like to thank L. Renia (Agency for Science, Technology and Research, Singapore) for helpful comments and S-methylthiourea and N-acetylcysteine, as well as R. Appelberg (Instituto de Biologia Molecular e Celular (IBMC), Portugal), J. Di Santo (Institut Pasteur) and J. Rivera (US National Institutes of Arthritis and Musculoskeletal and Skin Diseases) for IFN-γ–, RAG2γc- and Mcpt4-deficient mice, respectively, S. Rivella (Weill Cornell Medical College) for GFP- and HAMP.GFP-expressing adenoviruses, and P. Arosio (Faculty of Medicine, University of Brescia) for antibodies against mouse heavy and light ferritin chains. P. berghei ANKA, P. berghei NK65, P. yoelii 17X NL and P. chabaudi chabaudi AS were obtained from C. Jansen (Leiden University), A. Rodriguez (New York University), D. Walliker (Edinburgh University) and W. Jarra (UK National Institute for Medical Research), respectively. This work was supported by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095 (M.M.M.), Fundação para a Ciência e Tecnologia, European Science Foundation (European Young Investigator Award to M.M.M.), Howard Hughes Medical Institute (to M.M.M.) and the Medical Research Council UK (grant ID 92044). H.D. is a Beit Memorial Fellow for Medical Research and a Medical Research Council New Investigator. S.P. and C.C. were supported by Fundação para a Ciência e a Tecnologia fellowships (SFRH/BD/31523/2006 and SFRH/BPD/40965/2007, respectively). M.R. is supported by a Royal Society University Research Fellowship.
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S.P. performed the majority of the experimental work. C.C. performed the microarray analysis, and M.R. and C.I.N. initiated and tested the mathematical model. L.A.G. produced mouse primary hepatocytes. S.E., D.S. and C.R. provided intellectual input, and C.R. provided HAMP-transgenic mice. M.M.M. conceived of and supervised the study. S.P., A.E.A., C.I.N., H.D. and M.M.M. designed the experimental procedures and wrote the manuscript. All authors read and approved of the manuscript.
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Portugal, S., Carret, C., Recker, M. et al. Host-mediated regulation of superinfection in malaria. Nat Med 17, 732–737 (2011). https://doi.org/10.1038/nm.2368
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DOI: https://doi.org/10.1038/nm.2368
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