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J Exp Med. 2015 Jun 1;212(6):893-903. doi: 10.1084/jem.20141731. Epub 2015 May 4.

Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance.

Author information

1
Leiden Malaria Research Group, Department of Parasitology, Department of Molecular Cell Biology, and Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands Division of Parasitology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
2
Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06132 Perugia, Italy.
3
Department of Oncology, University of Torino, 10124 Torino, Italy.
4
Leiden Malaria Research Group, Department of Parasitology, Department of Molecular Cell Biology, and Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands.
5
Laboratory of Immunobiology, Rega Institute for Medical Research, KU Leuven - University of Leuven, 3000 Leuven, Belgium.
6
Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06132 Perugia, Italy Division of Parasitology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
7
Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, 1007 MB Amsterdam, Netherlands.
8
Department of Experimental Medicine, University of Perugia, Piazzale Gambuli, 06132 Perugia, Italy Department of Biological Sciences, Imperial College London, South Kensington Campus, SAF, London SW7 2AZ, England, UK.
9
Division of Parasitology, MRC National Institute for Medical Research, London NW7 1AA, England, UK.
10
Leiden Malaria Research Group, Department of Parasitology, Department of Molecular Cell Biology, and Department of Pathology, Leiden University Medical Centre, 2333 ZA Leiden, Netherlands s.m.khan@lumc.nl.

Abstract

Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes.

PMID:
25941254
PMCID:
PMC4451122
DOI:
10.1084/jem.20141731
[Indexed for MEDLINE]
Free PMC Article

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