Host mediated regulation of superinfection in malaria

摘要

In regions of high malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites into individuals who already have blood-stage parasitaemia. This manifests itself in older semi-immune children by concurrent carriage of different parasite genotypes at low asymptomatic parasitaemias. Superinfection presents an increased risk of hyperparasitaemia and death in less immune individuals, but counter-intuitively is not frequently observed in the young^,. Here, we show in a rodent 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 can be mediated by the host iron regulatory hormone hepcidin, the synthesis of which is stimulated by blood-stage parasites in a density-dependent manner. We model this phenomenon and show how density-dependent protection against liver-stage malaria can shape the epidemiological patterns of age-related risk and 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 nutritional programmes of iron supplementation in malaria-endemic regions.