Invasion of Erythrocytes by Malaria Merozoites

Dvorak, James A.; Miller, Louis H.; Whitehouse, Willard C.; Shiroishi, Tsugiye

doi:10.1126/science.803712

Cited by 401 publications

(334 citation statements)

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“…Although the process by which the parasite enters erythrocytes is complex and not well understood, invasion of erythrocytes by Plasmodium can be divided into multiple steps. Initial attachment of the parasite to the erythrocyte is followed by reorientation to bring the apical end of the parasite into close contact with the surface of the erythrocyte (1). The parasite forms a junction between its apical end and the erythrocyte surface.…”

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confidence: 99%

Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity

Mayer

Kaneko

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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107

138

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The malaria parasite lives within erythrocytes and depends on the binding of parasite ligands to host cell surface receptors for invasion. The most virulent human malaria parasite, Plasmodium falciparum, uses multiple ligands, including EBA-175, BAEBL, and JESEBL of the Duffy-binding-like (DBL) family of erythrocytebinding proteins, for invasion of human erythrocytes. Region II of these parasite ligands is the erythrocyte-binding domain. Previously, we had shown that polymorphism in region II of BAEBL leads to different erythrocyte-binding specificities. We have now identified and characterized the binding specificity of six JESEBL variants. We sequenced region II of JESEBL from 20 P. falciparum clones collected from various parts of the world where malaria is endemic. We observed eight JESEBL variants that contained amino acid polymorphisms at five positions among all clones. Seven of the eight variants could be connected by a single base change that led to an amino acid change. We investigated the functional significance of these polymorphisms by transiently expressing region II from six of JESEBL variants on the surface of Chinese hamster ovary cells. We observed four erythrocyte-binding patterns to enzymetreated erythrocytes. Thus, P. falciparum DBL ligands JESEBL and BAEBL can recognize multiple receptors on the erythrocyte surface. In contrast to Plasmodium vivax, which has disappeared from West Africa because of the Duffy-negative blood group, P. falciparum may have been successful in endemic areas because it has mutated the ligands of the DBL family to create multiple pathways of invasion, thus making selection of refractory erythrocytes unlikely.parasite polymorphism A ll of the clinical manifestations associated with human malaria infection are due to the asexual erythrocytic phase of the Plasmodium life cycle. Although the process by which the parasite enters erythrocytes is complex and not well understood, invasion of erythrocytes by Plasmodium can be divided into multiple steps. Initial attachment of the parasite to the erythrocyte is followed by reorientation to bring the apical end of the parasite into close contact with the surface of the erythrocyte (1). The parasite forms a junction between its apical end and the erythrocyte surface. Junction formation is irreversible and is followed by entry through invagination of the erythrocyte membrane (2). The process of junction formation is mediated by interaction between specific erythrocyte receptors and specific parasite ligands, as indicated by the inability of Plasmodium knowlesi, a simian malaria parasite that can infect humans, to form a junction with human erythrocytes lacking the Duffy blood group antigen and Plasmodium vivax to invade erythrocytes and infect Duffy-negative individuals (3-5).Unlike P. vivax, which is restricted to the erythrocytes expressing the Duffy blood group antigen and to reticulocytes, invasion of human erythrocytes by Plasmodium falciparum involves a number of apparently redundant receptor-ligand interactions between th...

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confidence: 99%

Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity

Mayer

Kaneko

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

107

138

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“…This species has a 24-h erythrocytic life cycle and large, long-lived invasive merozoites, facilitating the use of electron and video microscopy to dissect the dynamics of erythrocyte invasion (6)(7)(8). P. knowlesi can be cultured in vitro in rhesus monkey (Macaca mulata) RBC with rhesus or human serum (9,10).…”

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Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes

Moon

Hall

Rangkuti

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

259

393

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Research into the aetiological agent of the most widespread form of severe malaria, Plasmodium falciparum, has benefitted enormously from the ability to culture and genetically manipulate blood-stage forms of the parasite in vitro. However, most malaria outside Africa is caused by a distinct Plasmodium species, Plasmodium vivax, and it has become increasingly apparent that zoonotic infection by the closely related simian parasite Plasmodium knowlesi is a frequent cause of life-threatening malaria in regions of southeast Asia. Neither of these important malarial species can be cultured in human cells in vitro, requiring access to primates with the associated ethical and practical constraints. We report the successful adaptation of P. knowlesi to continuous culture in human erythrocytes. Humanadapted P. knowlesi clones maintain their capacity to replicate in monkey erythrocytes and can be genetically modified with unprecedented efficiency, providing an important and unique model for studying conserved aspects of malarial biology as well as speciesspecific features of an emerging pathogen.invasion | transfection T he development of a continuous culture system for asexual blood stages of the most deadly human malaria parasite, Plasmodium falciparum (1, 2), proved a milestone in malaria research, enabling genetic modification of the parasite (3), high-throughput drug screening (4), and other fundamental advances in parasite biology. Adaptation of other human malaria parasite species to in vitro culture has proved more challenging, and none of the additional four parasite species that cause human malaria can be continuously maintained in human RBC. This difficulty is a significant obstacle to studying these pathogens, which differ from P. falciparum in important aspects of biology and the pathology they cause. Furthermore, although considerable progress has been made in the development of transgenic technologies for Plasmodium, P. falciparum remains poorly amenable to genetic manipulation, with a typical transfection efficiency of only ∼10 −6 (5). Additional in vitro human malaria parasite models that are genetically tractable and that complement the P. falciparum system have tremendous potential.Much of the early work on the mechanics of RBC invasion by the malaria parasite used the simian parasite Plasmodium knowlesi. This species has a 24-h erythrocytic life cycle and large, long-lived invasive merozoites, facilitating the use of electron and video microscopy to dissect the dynamics of erythrocyte invasion (6-8). P. knowlesi can be cultured in vitro in rhesus monkey (Macaca mulata) RBC with rhesus or human serum (9, 10). Importantly, P. knowlesi is amenable to genetic manipulation, with reported transfection efficiencies similar to those achieved with the rodent malaria model Plasmodium berghei and far surpassing those attained in P. falciparum (10, 11). P. knowlesi is phylogenetically closely related to Plasmodium vivax, the most important cause of malaria outside of Africa (12), so its study can provide insights ...

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“…Malaria blood stage biology was studied in fixed parasites, in live parasites removed from culture or by very short term analyses under culture conditions such as two dimensional (2D) time lapse to investigate parasite invasion [27][28][29] . This limits the perception of the complex development in erythrocytes and ham pers the recognition and study of dynamic processes in these stages.…”

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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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Invasion of Erythrocytes by Malaria Merozoites

Cited by 401 publications

References 8 publications

Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity

Polymorphism in the Plasmodium falciparum erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity

Adaptation of the genetically tractable malaria pathogen Plasmodium knowlesi to continuous culture in human erythrocytes

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

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