Replication of <i>Plasmodium</i> in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance

Cerebral malaria is a pathology involving inflammation in the brain. There are many immune cell types activated during this process, but there is little information on the response of microglia, in this severe complication. We examined microglia by genome wide transcriptomic analysis in a model of experimental cerebral malaria (ECM), in which C57BL/6 mice are infected with Plasmodium berghei ANKA. Thousands of transcripts were differentially expressed in microglia at two different time points during infection. Proliferation of microglia was a dominant feature before the onset of ECM, and supporting this, we observed an increase in numbers of these cells in the brain. When cerebral malaria symptoms were manifest, genes involved in immune responses and chemokine production were upregulated, which were possibly driven by Type I Interferon. Consistent with this hypothesis, in vitro culture of a microglial cell line with Interferon-β, but not infected red blood cells, resulted in production of several of the chemokines shown to be upregulated in the gene expression analysis. It appears that these responses are associated with ECM, as microglia from mice infected with a mutant P. berghei parasite (ΔDPAP3), which does not cause ECM, did not show the same level of activation or proliferation.

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“…For this we used a gene-deletion mutant for the dipeptidyl peptidase 3 (DPAP3), Δ dpap3 28. Infection with 10 5 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

Capuccini

Lin

Talavera-López

et al. 2016

Sci Rep

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“…have shown that heme is responsible for artemisinins’ activation to react and conjugate with many cellular proteins. Nevertheless, Khan’s group has reported that replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance, but their sensitivity to artesunate, an artemisinin derivative, also thought to be dependent on hemoglobin degradation, is retained36.…”

Section: Discussionmentioning

confidence: 99%

A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities

Sun

Cao

Zhu

et al. 2017

Sci Rep

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The potent anti-malarial drug artemisinins are additionally anti-tumorigenic and inhibitory to yeast growth. The action mechanism of artemisinins, however, is not well understood. Heme and mitochondrial membrane are both suggested to be involved in the action of artemisinins. Because heme is also synthesized in the mitochondrion, mitochondria appear to be a critical organelle for artemisinins’ activities. In this study, we synthesized a mitochondria-targeting artemisinin derivative by conjugating triphenylphosphonium (TPP) to artelinic acid (ARTa). ARTa-TPP displays far more potent anti-tumorigenic activity than its parent compound. In contrast, ARTa-TPP is much less active against yeast respiration growth and malarial parasites. Notably, ARTa-TPP is also associated with increased toxicity to other kinds of control mammalian cells. These results suggest divergent action modes for artemisinins against cancer cells and malaria or yeast cells. We conclude that mitochondrial targeting could substantially elevate the anticancer potency of artemisinins, but the accompanied increased toxicity to normal cells raises an alert. The mechanism regarding the opposing effects of TPP conjugation to ARTa on its anticancer and anti-malarial/anti-yeast potencies is discussed based on our current understandings of artemisinins’ action.

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“…2015). Hemoglobin degradation in the parasite takes place within the digestive vacuole (also referred to as the food vacuole), a lysosome-like organelle containing enzymes that break down hemoglobin and convert heme, a toxic catabolite, into non-toxic hemozoin (Goldberg 2005).…”

Section: The Parasitophorous Vacuole and Parasitophorous Vacuole Membmentioning

confidence: 99%

Host cell remodeling by pathogens: the exomembrane system inPlasmodium-infected erythrocytes

Sherling

Ooij

2016

FEMS Microbiology Reviews

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Malaria is caused by infection of erythrocytes by parasites of the genus Plasmodium. To survive inside erythrocytes, these parasites induce sweeping changes within the host cell, one of the most dramatic of which is the formation of multiple membranous compartments, collectively referred to as the exomembrane system. As an uninfected mammalian erythrocyte is devoid of internal membranes, the parasite must be the force and the source behind the formation of these compartments. Even though the first evidence of the presence these of internal compartments was obtained over a century ago, their functions remain mostly unclear, and in some cases completely unknown, and the mechanisms underlying their formation are still mysterious. In this review, we provide an overview of the different parts of the exomembrane system, describing the parasitophorous vacuole, the tubovesicular network, Maurer's clefts, the caveola-vesicle complex, J dots and other mobile compartments, and the small vesicles that have been observed in Plasmodium-infected cells. Finally, we combine the data into a simplified view of the exomembrane system and its relation to the alterations of the host erythrocyte.

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

Cited by 68 publications

References 34 publications

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

Transcriptomic profiling of microglia reveals signatures of cell activation and immune response, during experimental cerebral malaria

A mitochondria-targeting artemisinin derivative with sharply increased antitumor but depressed anti-yeast and anti-malaria activities

Host cell remodeling by pathogens: the exomembrane system inPlasmodium-infected erythrocytes

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