A new model for hemoglobin ingestion and transport by the human malaria parasite <i>Plasmodium falciparum</i>

Lazarus, Michelle D.; Schneider, Timothy; Taraschi, Theodore F.

doi:10.1242/jcs.023150

Cited by 91 publications

(118 citation statements)

References 68 publications

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“…Two recent studies of DV genesis and haemoglobin uptake processes used serial thin section electron microscopy Lazarus et al, 2008). However, because of the huge amount of work involved in this very challenging technique, these studies were restricted to reconstruction of a limited cell depth or of a few whole cells.…”

Section: Haemoglobin Uptake and Degradation Is Initiated In Early Stamentioning

confidence: 99%

“…Another study examined the ultrastructure of the endocytic apparatus and concluded that haemoglobin uptake occurs by a vesicle-independent process (Lazarus et al, 2008). These authors reported that cytostomal invaginations elongate to form tubes that appose the DV but remain connected to the parasite surface and open to the RBC cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

“…These authors reported that cytostomal invaginations elongate to form tubes that appose the DV but remain connected to the parasite surface and open to the RBC cytoplasm. They suggested that the tubules pinch off from the parasite surface and simultaneously undergo fusion with the DV to release their contents into the DV lumen (Lazarus et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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

Bakar

Klonis

Hanssen

et al. 2010

Journal of Cell Science

170

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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Section: Haemoglobin Uptake and Degradation Is Initiated In Early Stamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bakar

Klonis

Hanssen

et al. 2010

Journal of Cell Science

170

209

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“…18,26 Similarly, tumor cell lysosomes degrade damaged organelles or bulk proteins for amino acid and energy recycling via the autophagy pathway. 8 Quinoline-based antimalarial compounds, such as CQ, hydroxychloroquine (HCQ), quinine (QN), mefloquine (MFQ), and quinacrine (QNX), are mainstay therapies that effectively kill P. falciparum parasites.…”

mentioning

confidence: 99%

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Golden

Cho²,

Hofman³

et al. 2015

FOC

150

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OBJECT Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells. METHODS Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death. RESULTS All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis. CONCLUSIONS Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas.

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“…The second phase, the 'trophozoite stage' , is characterized by rapid parasite growth and the appearance of haemozoin (remnant of digested haemoglobin) in the food vacuole (FV). The mode of haemoglobin internalization is still debated and might include several distinct processes [7][8][9] . Finally, the parasite enters the 'schizont stage' during which it generates up to 32 daughter merozoites that, after rupture of the host cell, invade new erythrocytes.…”

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confidence: 99%

Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions

et al. 2011

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Blood stages of Plasmodium falciparum cause the pathology of malaria; however, the progression of the parasite through this complex part of the life cycle has never been visualized. In this study, we use four-dimensional imaging to show for the first time the development of individual parasites in erythrocytes and the concomitant host cell modifications. our data visualize an unexpectedly dynamic parasite, provide a reference for this life cycle stage and challenge the model that protein export in P. falciparum is linked to the biogenesis of host cell modifications termed maurer's clefts. our results provide a novel view of the blood-stage development, maurer's cleft development and protein export in malaria parasites, and open the door to study dynamic processes, drug effects and the phenotype of mutants.

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A new model for hemoglobin ingestion and transport by the human malaria parasite Plasmodium falciparum

Cited by 91 publications

References 68 publications

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

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

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors

Development and host cell modifications of Plasmodium falciparum blood stages in four dimensions

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