Chronicle of a death foretold:<i>Plasmodium</i>liver stage parasites decide on the fate of the host cell

Graewe, Stefanie; Stanway, Rebecca R.; Rennenberg, Annika; Heussler, Volker

doi:10.1111/j.1574-6976.2011.00297.x

Cited by 42 publications

(41 citation statements)

References 129 publications

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“…Maturation of liver stage parasites is characterized by cytomere formation; cytomeres are invaginations of the parasite plasma membrane that greatly increase the membrane surface area and enable rapid formation of exoerythrocytic merozoites by individuation throughout the exoerythrocytic schizont (33). To determine whether cytomere and merozoite formation were occurring in P. yoelii plasmei2 -liver stages, we analyzed expression of merozoite surface protein 1 (MSP1), which is expressed on the parasite plasma membranes of the cytomeres and individual merozoites.…”

Section: Resultsmentioning

confidence: 99%

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

et al. 2016

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bPlasmodium parasites employ posttranscriptional regulatory mechanisms as their life cycle transitions between host cell invasion and replication within both the mosquito vector and mammalian host. RNA binding proteins (RBPs) provide one mechanism for modulation of RNA function. To explore the role of Plasmodium RBPs during parasite replication, we searched for RBPs that might play a role during liver stage development, the parasite stage that exhibits the most extensive growth and replication. We identified a parasite ortholog of the Mei2 (Meiosis inhibited 2) RBP that is conserved among Plasmodium species (PlasMei2) and exclusively transcribed in liver stage parasites. Epitope-tagged Plasmodium yoelii PlasMei2 was expressed only during liver stage schizogony and showed an apparent granular cytoplasmic location. Knockout of PlasMei2 (plasmei2 ؊ ) in P. yoelii only affected late liver stage development. The P. yoelii plasmei2 ؊ liver stage size increased progressively until late in development, similar to wild-type parasite development. However, P. yoelii plasmei2 ؊ liver stage schizonts exhibited an abnormal DNA segregation phenotype and failed to form exoerythrocytic merozoites. Consequently the cellular integrity of P. yoelii plasmei2 ؊ liver stages became increasingly compromised late in development and the majority of P. yoelii plasmei2 ؊ underwent cell death by the time wild-type liver stages mature and release merozoites. This resulted in a complete block of P. yoelii plasmei2 Malaria is caused by unicellular eukaryotic parasites of the genus Plasmodium. The life cycles of the Plasmodium parasites that cause human disease (including the major human parasite Plasmodium falciparum) and other mammalian parasites such as rodent malaria parasites (including P. berghei and P. yoelii) are similar. The parasites progress through an elaborate life cycle, part within an anopheline mosquito vector and part within the mammalian host. Within the host, the sporozoite stage first infects hepatocytes, within which the parasite then develops as a liver stage (also known as an exoerythrocytic form), an acyclic process that occurs once during a malaria infection. Intrahepatocytic parasite development progresses in a cellular process known as schizogony, an endomitotic process characterized by an enormous increase in cell mass with concomitant DNA replication and organelle replication but without cytokinesis. It is only in the final hours of liver stage schizogony that organelles and DNA completely segregate and are apportioned into tens of thousands of rapidly differentiating exoerythrocytic invasive merozoites. These are released and initiate the infection of erythrocytes. Erythrocytic schizogony is cyclic and generates approximately 20 to 30 new merozoites in each cycle. Parasite schizogony and merozoite formation in both hepatocytes and erythrocytes likely employ shared gene regulatory networks and cell regulatory mechanisms, but it is possible that because exoerythrocytic schizogony exceeds erythrocytic schizogony by m...

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Section: Resultsmentioning

confidence: 99%

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

et al. 2016

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“…The GEM iPfa should be further developed to keep it up-to-date, and the detailed description of the reconstruction process provided in the S1 Methods serves as a reference for this purpose. Modifications of iPfa will allow the study of context-specific cases, i.e., modeling of the blood stage or liver stage metabolism [59] (S1 Methods). …”

Section: Discussionmentioning

confidence: 99%

Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks

et al. 2017

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Novel antimalarial therapies are urgently needed for the fight against drug-resistant parasites. The metabolism of malaria parasites in infected cells is an attractive source of drug targets but is rather complex. Computational methods can handle this complexity and allow integrative analyses of cell metabolism. In this study, we present a genome-scale metabolic model (iPfa) of the deadliest malaria parasite, Plasmodium falciparum, and its thermodynamics-based flux analysis (TFA). Using previous absolute concentration data of the intraerythrocytic parasite, we applied TFA to iPfa and predicted up to 63 essential genes and 26 essential pairs of genes. Of the 63 genes, 35 have been experimentally validated and reported in the literature, and 28 have not been experimentally tested and include previously hypothesized or novel predictions of essential metabolic capabilities. Without metabolomics data, four of the genes would have been incorrectly predicted to be non-essential. TFA also indicated that substrate channeling should exist in two metabolic pathways to ensure the thermodynamic feasibility of the flux. Finally, analysis of the metabolic capabilities of P. falciparum led to the identification of both the minimal nutritional requirements and the genes that can become indispensable upon substrate inaccessibility. This model provides novel insight into the metabolic needs and capabilities of the malaria parasite and highlights metabolites and pathways that should be measured and characterized to identify potential thermodynamic bottlenecks and substrate channeling. The hypotheses presented seek to guide experimental studies to facilitate a better understanding of the parasite metabolism and the identification of targets for more efficient intervention.

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“…After sporozoite invasion of the host liver, merozoites are formed by the thousands in infected hepatocytes, and these were long thought to get into the bloodstream by simple rupture of the hepatocyte, although it was not clear how they could cross the endothelium to reach the bloodstream [52][53][54]. Active migration was one possibility, because merozoites possess the necessary gliding machinery; however, it was discovered that small bags of merozoites bud off as merosomes from the infected cells [55].…”

Section: Sporozoite Movements In the Mosquitomentioning

confidence: 97%

Active migration and passive transport of malaria parasites

Douglas

Amino

Sinnis

et al. 2015

Trends in Parasitology

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Chronicle of a death foretold:Plasmodiumliver stage parasites decide on the fate of the host cell

Cited by 42 publications

References 129 publications

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

A Plasmodium yoelii Mei2-Like RNA Binding Protein Is Essential for Completion of Liver Stage Schizogony

Bioenergetics-based modeling of Plasmodium falciparum metabolism reveals its essential genes, nutritional requirements, and thermodynamic bottlenecks

Active migration and passive transport of malaria parasites

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