Abstract
The malaria parasite, Plasmodium, requires iron for growth, but how it imports iron remains unknown. We characterize here a protein that belongs to the ZIP (Zrt-, Irt-like Protein) family of metal ion transport proteins and have named ZIP domain-containing protein (ZIPCO). Inactivation of the ZIPCO-encoding gene in Plasmodium berghei, while not affecting the parasite's ability to multiply in mouse blood and to infect mosquitoes, greatly impairs its capacity to develop inside hepatocytes. Iron/zinc supplementation and depletion experiments suggest that ZIPCO is required for parasite utilization of iron and possibly zinc, consistent with its predicted function as a metal transporter. This is the first report of a ZIP protein having a crucial role in Plasmodium liver-stage development, as well as the first metal ion transporter identified in Plasmodium pre-erythrocytic stages. Because of the drastic dependence on iron of Plasmodium growth, ZIPCO and related proteins might constitute attractive drug targets to fight against malaria.
Highlights
Iron is essential for the growth of organisms ranging from bacteria to mammals
The genomes of P. falciparum, P. chabaudi, P. knowlesi, P. vivax, Saccharomyces cerevisiae and Arabidopsis thaliana were screened with the Pfam02535 profile, and a phylogenetic tree was generated (Fig 1B) that indicated the presence of two paralogs of the ZIP family in the screened Plasmodium species
We characterized here a P. berghei protein belonging to the ZIP family, called ZIP domain-containing protein (ZIPCO)
Summary
Iron is essential for the growth of organisms ranging from bacteria to mammals. Pathogen and host compete for iron and the outcome impacts disease severity. Pathogens have evolved efficient tools to scavenge iron, and iron uptake ability is linked to virulence in a broad range of bacteria, protozoa and fungi (Schaible & Kaufmann, 2004; Schrettl et al, 2004; Crouch et al, 2008; Seifert et al, 2008). A master regulator of iron metabolism and redistribution is the peptide hormone hepcidin. Induced upon infection or inflammation, hepcidin depletes iron from the plasma by binding to ferroportin thereby decreasing absorption from the intestine, recycling from macrophages and release of iron stored in hepatocytes (Ganz, 2011; Drakesmith & Prentice, 2012)
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