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

Abstract

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.

Maurer's clefts, the enigma of Plasmodium falciparum

“…Clefts move rapidly in young stages and become fixed before the parasite develops into the trophozoites stage at around 22 hpi (45,81). This arrest is not a limitation of space because clefts stop moving before the parasite grows rapidly, indicating the completion of host cell modification (81). In the third phase, the spatial arrangement of clefts collapses shortly before merozoites egress, suggesting an active process of host cell modification disassembly.…”

“…Taken together, these data indicate a constant flow of cargo from the parasite to the Maurer's clefts, the means by which, however, remains elusive. Although Maurer's clefts are formed very early after invasion, they occur as highly mobile structures (41,45,81). Live imaging over the 48-h life cycle using REX2-GFPexpressing parasites revealed a movement of Maurer's clefts over three phases.…”

“…Live imaging over the 48-h life cycle using REX2-GFPexpressing parasites revealed a movement of Maurer's clefts over three phases. Clefts move rapidly in young stages and become fixed before the parasite develops into the trophozoites stage at around 22 hpi (45,81). This arrest is not a limitation of space because clefts stop moving before the parasite grows rapidly, indicating the completion of host cell modification (81).…”

“…It is also unclear if Maurer's clefts resident proteins are loaded into the clefts because they are formed at the PVM, or if there is continuous transport of cargo to already existing Maurer's clefts. Recent live-imaging studies demonstrated that some proteins arrived at Maurer's clefts after these had been formed (45,81). …”

“…Other Maurer's clefts resident proteins, skeleton binding protein 1 (SBP1) and MAHRP1, appear somewhat later at 4-6 hpi (45,81), and at 6 hpi all three proteins are detected in most of the Maurer's clefts (45). All clefts seem to be formed at the early ring stage because no new clefts were observed after invasion (81) and the number of clefts remained constant as early as 8 hpi (45) 45). Taken together, these data indicate a constant flow of cargo from the parasite to the Maurer's clefts, the means by which, however, remains elusive.…”