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Exploitation of a newly-identified entry pathway into the malaria parasite-infected erythrocyte to inhibit parasite egress.

ABSTRACT: While many parasites develop within host cells to avoid antibody responses and to utilize host cytoplasmic resources, elaborate egress processes have evolved to minimize the time between escaping and invading the next cell. In human erythrocytes, malaria parasites perforate their enclosing erythrocyte membrane shortly before egress. Here, we show that these pores clearly function as an entry pathway into infected erythrocytes for compounds that inhibit parasite egress. The natural glycosaminoglycan heparin surprisingly inhibited malaria parasite egress, trapping merozoites within infected erythrocytes. Labeled heparin neither bound to nor translocated through the intact erythrocyte membrane during parasite development, but fluxed into erythrocytes at the last minute of the parasite lifecycle. This short encounter was sufficient to significantly inhibit parasite egress and dispersion. Heparin blocks egress by interacting with both the surface of intra-erythrocytic merozoites and the inner aspect of erythrocyte membranes, preventing the rupture of infected erythrocytes but not parasitophorous vacuoles, and independently interfering with merozoite disaggregation. Since this action of heparin recapitulates that of neutralizing antibodies, membrane perforation presents a brief opportunity for a new strategy to inhibit parasite egress and replication.

SUBMITTER: Glushakova S

PROVIDER: S-EPMC5612957 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Exploitation of a newly-identified entry pathway into the malaria parasite-infected erythrocyte to inhibit parasite egress.

Glushakova Svetlana S Busse Brad L BL Garten Matthias M Beck Josh R JR Fairhurst Rick M RM Goldberg Daniel E DE Zimmerberg Joshua J

Scientific reports 20170925 1

While many parasites develop within host cells to avoid antibody responses and to utilize host cytoplasmic resources, elaborate egress processes have evolved to minimize the time between escaping and invading the next cell. In human erythrocytes, malaria parasites perforate their enclosing erythrocyte membrane shortly before egress. Here, we show that these pores clearly function as an entry pathway into infected erythrocytes for compounds that inhibit parasite egress. The natural glycosaminogly ...[more]

PMID: 28947749

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Project description:Malaria parasites modify their host erythrocyte in multiple ways, leading to changes in the deformability, adhesiveness, and permeability of the host erythrocyte. Most of these changes are mediated by proteins exported from the parasite to the host erythrocyte, where these proteins interact with the host cell cytoskeleton or form complexes in the plasma membrane of the infected erythrocyte. In addition, malaria parasites induce the formation of membranous compartments-the parasitophorous vacuole, the tubovesicular network (TVN), the Maurer's clefts and small vesicles-within the infected erythrocyte, a cell that is normally devoid of internal membranes. After infection, changes also occur in the composition and asymmetry of the erythrocyte plasma membrane. Although many aspects of the mechanism of export of parasite proteins have become clear, the mechanism by which these membranous compartments are formed and expanded is almost entirely unknown. To determine whether parasite-derived phospholipids play a part in these processes, we applied a metabolic labeling technique that allows phosphatidylcholine to be labeled with a fluorophore. As the host erythrocyte cannot synthesize phospholipids, within infected erythrocytes, only parasite-derived phosphatidylcholine will be labeled with this technique. The results revealed that phosphatidylcholine produced by the parasite is distributed throughout the infected erythrocyte, including the TVN and the erythrocyte plasma membrane, but not Maurer's clefts. Interestingly, labeled phospholipids were also detected in the erythrocyte plasma membrane very soon after invasion of the parasites, indicating that the parasite may add phospholipids to the host erythrocyte during invasion. IMPORTANCE Here, we describe a previously unappreciated way in which the malaria parasite interacts with the host erythrocyte, namely, by the transfer of parasite phospholipids to the erythrocyte plasma membrane. This likely has important consequences for the survival of the parasite in the host cell and the host organism. We show that parasite-derived phospholipids are transferred from the parasite to the host erythrocyte plasma membrane and that other internal membranes that are produced after the parasite has invaded the cell are produced, at least in part, using parasite-derived phospholipids. The one exception to this is the Maurer's cleft, a membranous organelle that is involved in the transport of parasite proteins to the surface of the erythrocyte. This reveals that the Maurer's cleft is produced in a different manner than the other parasite-induced membranes. Overall, these findings provide a platform for the study of a new aspect of the host-parasite interaction.

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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Exploitation of a newly-identified entry pathway into the malaria parasite-infected erythrocyte to inhibit parasite egress.

Publications

Exploitation of a newly-identified entry pathway into the malaria parasite-infected erythrocyte to inhibit parasite egress.

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