Plasmodium falciparum: sacrificing membrane to grow crystals?

Hempelmann, Ernst; Motta, María Cristina M.; Hughes, Ruth H; Ward, Stephen A.; Bray, Patrick G.

doi:10.1016/s1471-4922(02)00011-9

Cited by 57 publications

(54 citation statements)

References 19 publications

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“…This scenario is consistent with the fact that the inner membranes of hemoglobin-laden endocytic vesicles disappear when the vesicles are incorporated into digestive vacuoles (13)(14)(15)(16). Since the inner membranes are derived from the parasitophorous vacuolar membrane, this scenario also is consistent with the recent hypothesis that the parasitophorous vacuolar membrane is somehow involved in the formation of hemozoin crystals (17). As the inner membranes disappear, their constituents presumably are released, thus making a lipid, probably linoleate (9), accessible to promote FP dimerization.…”

Section: Discussionsupporting

confidence: 89%

Chloroquine-induced Masking of a Lipid That Promotes Ferriprotoporphyrin IX Dimerization in Malaria

Fitch

Chen

Cai

2003

Journal of Biological Chemistry

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Mice infected with the NYU-2 strain of Plasmodium berghei were used to study the effect of chloroquine on masking of a lipid that promotes ferriprotoporphyrin IX dimerization. More than 40% of this lipid was masked and unable to promote dimerization in membrane ghosts from erythrocytes of untreated, infected mice. Thus, preparations of membrane ghosts dimerized 57 ؎ 6 nmol of ferriprotoporphyrin IX during a 2-h incubation, whereas the lipids extracted from these preparations dimerized 101 ؎ 11 nmol of ferriprotoporphyrin IX (means ؎ S.D. for four experiments). Exposure of membrane ghosts to sonication or cold significantly increased the extent of masking. In addition, chloroquine treatment of infected mice increased the extent of masking to ϳ90%. The lipid could be unmasked by extracting it into acetone or by aging erythrocyte membrane ghosts from untreated or chloroquine-treated, infected mice for 24 h at pH 7.4 and 25°C. These findings indicate that masking and unmasking of a lipid is central to the regulation of ferriprotoporphyrin IX dimerization in malaria parasites. They also indicate that chloroquine impairs the function of this regulatory process.When mice infected with Plasmodium berghei are treated with chloroquine, the parasites lose 80% or more of their ability to produce ␤-hematin (1), a dimer of ferriprotoporphyrin IX (FP) 1 (2). Consequently, undimerized, toxic FP accumulates (3) and, presumably, kills the parasites (4, 5). The biochemical basis for the effect of chloroquine on the production of betahematin in vivo presently is unknown. It is true that chloroquine and other quinoline derivatives, including quinine and mefloquine, bind to FP and inhibit dimerization in vitro (3, 6), but something else occurs in vivo. In fact, inhibition of FP dimerization by chloroquine is antagonized by quinine and mefloquine in vivo (3). These and other observations indicate that chloroquine acts by affecting a regulatory process rather than by directly inhibiting FP dimerization (7). To understand the biochemical basis for the antimalarial action of chloroquine, therefore, it is desirable to know more about the process that regulates FP dimerization.Current knowledge of FP dimerization in malaria parasites can be briefly summarized as follows. The process is promoted only by the lipid fraction of parasitized erythrocytes (8). Apparently, the lipid serves to concentrate monomeric FP and keep it in a state favorable for dimerization (8). Once formed, FP dimers spontaneously aggregate in an acidic milieu (2) such as occurs in the digestive vacuoles of malaria parasites. These aggregates are insoluble at physiologic pH or lower (5), and, in contrast to undimerized FP, they appear to be nontoxic for malaria parasites.Since malaria parasites are enriched with linoleic acid, it is likely that linoleate or a linoleate derivative is the lipid that promotes FP dimerization (9). The linoleate probably is released from the inner membranes of hemoglobin-laden endocytic vesicles as they are processed into digestive vacuoles (...

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Section: Discussionsupporting

confidence: 89%

Chloroquine-induced Masking of a Lipid That Promotes Ferriprotoporphyrin IX Dimerization in Malaria

Fitch

Chen

Cai

2003

Journal of Biological Chemistry

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“…An alternative, or perhaps additional, explanation for the apparent lack of effect of marked variations in pH DV on parasite growth might lie in a proposal made previously (Hempelmann et al, 2003;Spiller et al, 2002), that much of the haemoglobin degradation actually occurs in the vesicles in which the haemoglobin is trafficked from the parasite surface to the digestive vacuole (i.e. before they fuse with the digestive vacuole).…”

Section: Discussionmentioning

confidence: 98%

The pH of the digestive vacuole ofPlasmodium falciparumis not associated with chloroquine resistance

Hayward

Saliba

Kirk

2006

Journal of Cell Science

127

134

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noted that this hypothesis is Chloroquine resistance in the human malaria parasite, Plasmodium falciparum, arises from decreased accumulation of the drug in the 'digestive vacuole' of the parasite, an acidic compartment in which chloroquine exerts its primary toxic effect. It has been proposed that changes in the pH of the digestive vacuole might underlie the decreased accumulation of chloroquine by chloroquineresistant parasites. In this study we have investigated the digestive vacuole pH of a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, using a range of dextran-linked pH-sensitive fluorescent dyes. The estimated digestive vacuole pH varied with the concentration and pK a of the dye, ranging from ~3.7-6.5. However, at low dye concentrations the estimated digestive vacuole pH of both the chloroquine-resistant and chloroquine-sensitive strains converged in the range 4.5-4.9. The results suggest that there is no significant difference in digestive vacuole pH of chloroquine-sensitive and chloroquine-resistant parasites, and that digestive vacuole pH does not play a primary role in chloroquine resistance.

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“…Some authors have argued that haemoglobin digestion commences only after cytostomal vesicles fuse with the DV (Olliaro and Goldberg, 1995;Slomianny and Prensier, 1990). Others suggest that haemoglobin digestion is initiated en route to the DV, and that the DV is merely a dumping site for haemozoin crystals (Hempelmann et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum

Bakar

Klonis

Hanssen

et al. 2010

Journal of Cell Science

173

209

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SummaryThe digestive vacuole of the malaria parasite Plasmodium falciparum is the site of haemoglobin digestion and haem detoxification, and is the target of chloroquine and other antimalarials. The mechanisms for genesis of the digestive vacuole and transfer of haemoglobin from the host cytoplasm are still debated. Here, we use live-cell imaging and photobleaching to monitor the uptake of the pH-sensitive fluorescent tracer SNARF-1-dextran from the erythrocyte cytoplasm in ring-stage and trophozoite-stage parasites. We compare these results with electron tomography of serial sections of parasites at different stages of growth. We show that uptake of erythrocyte cytoplasm is initiated in mid-ring-stage parasites. The host cytoplasm is internalised via cytostome-derived invaginations and concentrated into several acidified peripheral structures. Haemoglobin digestion and haemozoin formation take place in these vesicles. The ringstage parasites can adopt a deeply invaginated cup shape but do not take up haemoglobin via macropinocytosis. As the parasite matures, the haemozoin-containing compartments coalesce to form a single acidic digestive vacuole that is fed by haemoglobin-containing vesicles. There is also evidence for haemoglobin degradation in compartments outside the digestive vacuole. The work has implications for the stage specificity of quinoline and endoperoxide antimalarials.

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Plasmodium falciparum: sacrificing membrane to grow crystals?

Cited by 57 publications

References 19 publications

Chloroquine-induced Masking of a Lipid That Promotes Ferriprotoporphyrin IX Dimerization in Malaria

Chloroquine-induced Masking of a Lipid That Promotes Ferriprotoporphyrin IX Dimerization in Malaria

The pH of the digestive vacuole ofPlasmodium falciparumis not associated with chloroquine resistance

Digestive-vacuole genesis and endocytic processes in the early intraerythrocytic stages of Plasmodium falciparum

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