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Open Access Research article

Perturbation of copper homeostasis is instrumental in early developmental arrest of intraerythrocytic Plasmodium falciparum

Hiroko Asahi1*, Mohammed Essa Marghany Tolba123, Masanobu Tanabe4, Sumio Sugano2, Kazumi Abe2 and Fumihiko Kawamoto5

Author Affiliations

1 Department of Parasitology, National Institute of Infectious Diseases, 23-1 Toyama 1-chome, Shinjuku-ku, Tokyo 162-8640, Japan

2 Department of Medical Genomics, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

3 Department of Parasitology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt

4 Department of Infectious Diseases, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

5 Institute of Tropical Disease, Campus C, Airlangga University, JL. Mulyorejo Surabaya 160115, Indonesia

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BMC Microbiology 2014, 14:167  doi:10.1186/1471-2180-14-167

Published: 24 June 2014

Abstract

Background

Malaria continues to be a devastating disease. The elucidation of factors inducing asexual growth versus arrest of Plasmodium falciparum can provide information about the development of the parasite, and may help in the search for novel malaria medication. Based on information from genome-wide transcriptome profiling of different developmental stages of P. falciparum, we investigated the critical importance of copper homeostasis in the developmental succession of P. falciparum with regard to three aspects of copper function. These were:1) inhibition of copper-binding proteins, 2) copper-ion chelation, and 3) down-regulated expression of genes encoding copper-binding proteins associated with a specific growth-promoting factor.

Results

Inhibition of copper-binding proteins with tetrathiomolybdate (TTM) caused cessation of growth of the parasite. TTM arrested the parasite irreversibly during the trophozoite to schizont stage progression. Target molecules for TTM may be present in P. falciparum. The involvement of copper ions in developmental arrest was also investigated by copper-ion chelating methods, which indicated a critical function of reduced copper ions (Cu1+) in the parasite during the early developmental stage. Copper ions, not only in the parasite but also in host cells, were targets of the chelators. Chelation of Cu1+caused blockage of trophozoite progression from the ring stage. Profound growth arrest was detected in parasites cultured in a chemically defined medium containing hexadecanoic acid alone as a growth-promoting factor. This developmental arrest was associated with down-regulated expression of genes encoding copper-binding proteins. Cis-9-octadecenoic acid completely prevented the down-regulation of gene expression and developmental arrest that were observed with the use of hexadecanoic acid.

Conclusions

The critical importance of copper homeostasis in early developmental stages of P. falciparum was confirmed. Perturbation of copper homeostasis induced profound and early developmental arrest of P. falciparum. These findings should help to elucidate the mechanisms behind the development of P. falciparum, and may be applied in the development of effective antimalarial strategies.

Keywords:
Plasmodium falciparum; Intraerythrocytic growth; Copper homeostasis; Copper-binding protein; Copper ion; Developmental arrest