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New stages in the program of malaria parasite egress imaged in normal and sickle erythrocytes.

ABSTRACT: The apicomplexan parasite Plasmodium falciparum causes malignant malaria. The mechanism of parasite egress from infected erythrocytes that disseminate parasites in the host at the end of each asexual cycle is unknown. Two new stages of the egress program are revealed: (1) swelling of the parasitophorous vacuole accompanied by shrinkage of the erythrocyte compartment, and (2) poration of the host cell membrane seconds before erythrocyte rupture because of egress. Egress was inhibited in dehydrated cells from patients with sickle cell disease in accord with experimental dehydration of normal cells, suggesting that vacuole swelling involves intake of water from the erythrocyte compartment. Erythrocyte membrane poration occurs in relaxed cells, thus excluding involvement of osmotic pressure in this process. Poration does not depend on cysteine protease activity, because protease inhibition blocks egress but not poration, and poration is required for the parasite cycle because the membrane sealant P1107 interferes with egress. We suggest the following egress program: parasites initiate water influx into the vacuole from the erythrocyte cytosol to expand the vacuole for parasite separation and vacuole rupture upon its critical swelling. Separated parasites leave the erythrocyte by breaching its membrane, weakened by putative digestion of erythrocyte cytoskeleton and membrane poration.

SUBMITTER: Glushakova S

PROVIDER: S-EPMC3541015 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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New stages in the program of malaria parasite egress imaged in normal and sickle erythrocytes.

Glushakova Svetlana S Humphrey Glen G Leikina Evgenia E Balaban Amanda A Miller Jeffrey J Zimmerberg Joshua J

Current biology : CB 20100527 12

The apicomplexan parasite Plasmodium falciparum causes malignant malaria. The mechanism of parasite egress from infected erythrocytes that disseminate parasites in the host at the end of each asexual cycle is unknown. Two new stages of the egress program are revealed: (1) swelling of the parasitophorous vacuole accompanied by shrinkage of the erythrocyte compartment, and (2) poration of the host cell membrane seconds before erythrocyte rupture because of egress. Egress was inhibited in dehydrate ...[more]

PMID: 20537541

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Project description:BackgroundEgress of Plasmodium falciparum, from erythrocytes at the end of its asexual cycle and subsequent parasite invasion into new host cells, is responsible for parasite dissemination in the human body. The egress pathway is emerging as a coordinated multistep programme that extends in time for tens of minutes, ending with rapid parasite extrusion from erythrocytes. While the Ca2+ regulation of the invasion of P. falciparum in erythrocytes is well established, the role of Ca2+ in parasite egress is poorly understood. This study analysed the involvement of cytoplasmic free Ca2+ in infected erythrocytes during the multistep egress programme of malaria parasites.MethodsLive-cell fluorescence microscopy was used to image parasite egress from infected erythrocytes, assessing the effect of drugs modulating Ca2+ homeostasis on the egress programme.ResultsA steady increase in cytoplasmic free Ca2+ is found to precede parasite egress. This increase is independent of extracellular Ca2+ for at least the last two hours of the cycle, but is dependent upon Ca2+ release from internal stores. Intracellular BAPTA chelation of Ca2+ within the last 45 minutes of the cycle inhibits egress prior to parasitophorous vacuole swelling and erythrocyte membrane poration, two characteristic morphological transformations preceding parasite egress. Inhibitors of the parasite endoplasmic reticulum (ER) Ca2+-ATPase accelerate parasite egress, indicating that Ca2+ stores within the ER are sufficient in supporting egress. Markedly accelerated egress of apparently viable parasites was achieved in mature schizonts using Ca2+ ionophore A23187. Ionophore treatment overcomes the BAPTA-induced block of parasite egress, confirming that free Ca2+ is essential in egress initiation. Ionophore treatment of immature schizonts had an adverse effect inducing parasitophorous vacuole swelling and killing the parasites within the host cell.ConclusionsThe parasite egress programme requires intracellular free Ca2+ for egress initiation, vacuole swelling, and host cell cytoskeleton digestion. The evidence that parasitophorous vacuole swelling, a stage of unaffected egress, is dependent upon a rise in intracellular Ca2+ suggests a mechanism for ionophore-inducible egress and a new target for Ca2+ in the programme liberating parasites from the host cell. A regulatory pathway for egress that depends upon increases in intracellular free Ca2+ is proposed.

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New stages in the program of malaria parasite egress imaged in normal and sickle erythrocytes.

Publications

New stages in the program of malaria parasite egress imaged in normal and sickle erythrocytes.

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