A perforin-like protein mediates disruption of the erythrocyte membrane during egress of<i>Plasmodium berghei</i>male gametocytes

Deligianni, Elena; Morgan, Rhiannon N.; Bertuccini, Lucia; Wirth, Christine C.; Monerri, Natalie C. Silmon de; Spanos, Lefteris; Blackman, Michael J.; Louis, Christos; Pradel, Gabriele; Sidén‐Kiamos, Inga

doi:10.1111/cmi.12131

Cited by 87 publications

(103 citation statements)

References 44 publications

(67 reference statements)

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“…These egress vesicles contain the plasmodial pore‐forming perforin PPLP2, which is able to perforate the EM. This event occurs approximately 6 min post‐activation of the gametocyte and results in the release of the erythrocyte cytoplasm; hence, the gamete is then contained by the EM only (Deligianni et al ., 2013; Wirth et al ., 2014). Approximately 15 min after uptake by the blood‐feeding mosquito, the EM opens and releases the fertile gamete (Sologub et al ., 2011; Wirth et al ., 2014; reviewed in Wirth and Pradel, 2012).…”

Section: The Formation Of Gametesmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

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167

155

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SummaryThe mosquito midgut stages of malaria parasites are crucial for establishing an infection in the insect vector and to thus ensure further spread of the pathogen. Parasite development in the midgut starts with the activation of the intraerythrocytic gametocytes immediately after take‐up and ends with traversal of the midgut epithelium by the invasive ookinetes less than 24 h later. During this time period, the plasmodia undergo two processes of stage conversion, from gametocytes to gametes and from zygotes to ookinetes, both accompanied by dramatic morphological changes. Further, gamete formation requires parasite egress from the enveloping erythrocytes, rendering them vulnerable to the aggressive factors of the insect gut, like components of the human blood meal. The mosquito midgut stages of malaria parasites are unprecedented objects to study a variety of cell biological aspects, including signal perception, cell conversion, parasite/host co‐adaptation and immune evasion. This review highlights recent insights into the molecules involved in gametocyte activation and gamete formation as well as in zygote‐to‐ookinete conversion and ookinete midgut exit; it further discusses factors that can harm the extracellular midgut stages as well as the measures of the parasites to protect themselves from any damage.

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Section: The Formation Of Gametesmentioning

confidence: 99%

The development of malaria parasites in the mosquito midgut

Bennink

Kiesow

Pradel

2016

Cellular Microbiology

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167

155

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“…PPLP1 plays a role in merozoite release from the schizont during the erythrocytic replication cycle of Plasmodium falciparum, during which it is discharged from the merozoite micronemes in a calcium-dependent manner to mediate membrane rupture [3]. PPLP2 on the other hand supports the liberation of activated Plasmodium berghei or P. falciparum gametocytes from the enveloping erythrocyte at the onset of gametogenesis [4,5], which takes place in the mosquito midgut within a few minutes after the uptake of the gametocytes with the blood meal. Upon gametocyte activation, PPLP2 is calcium-dependently discharged from egress vesicles into the vacuolar space to perforate the erythrocyte membrane.…”

Section: Introductionmentioning

confidence: 99%

Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum

Wirth

Bennink

Scheuermayer

et al. 2015

Molecular and Biochemical Parasitology

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The genomes of Plasmodium parasites encode for five perforin-like proteins, PPLP1-5, and four of them have previously been demonstrated to be involved in disruption of host cell barriers. We now show that the fifth perforin, PPLP4, is crucial for infection of the mosquito vector by Plasmodium falciparum parasites. PPLP4 is expressed in the blood and mosquito midgut stages in granular structures. In gametocytes, PPLP4 expression is specific to the female gender, while ookinetes show a PPLP4 localization at the apical pole. Gene disruption of pplp4 results in no phenotypical change during blood stage replication, gametocyte development or gametogenesis, while mosquitoes fed with PPLP4-deficient gametocytes display a severe reduction in oocyst numbers, and an accumulation of ookinetes in the mosquito midguts was observed. In conclusion, we propose an essential role for PPLP4 in infection of the mosquito midgut, presumably by mediating ookinete traversal through the midgut epithelium.

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“…Other effector proteins involved in membrane breakdown are not fully characterized. In the related apicomplexan parasite Toxoplasma gondii, the pore-forming perforin-like protein 1 (PLP1) mediates rupture of vacuole and host cell membranes (37), whereas in Plasmodium the perforin-like proteins PLP2 and PLP1 have been implicated in egress of gametes (38,39) and asexual blood forms, respectively (40).…”

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confidence: 99%

Parasitophorous vacuole poration precedes its rupture and rapid host erythrocyte cytoskeleton collapse in Plasmodium falciparum egress

Hale

Watermeyer

Hackett

et al. 2017

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

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126

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In the asexual blood stages of malarial infection, merozoites invade erythrocytes and replicate within a parasitophorous vacuole to form daughter cells that eventually exit (egress) by sequential rupture of the vacuole and erythrocyte membranes. The current model is that PKG, a malarial cGMP-dependent protein kinase, triggers egress, activating malarial proteases and other effectors. Using selective inhibitors of either PKG or cysteine proteases to separately inhibit the sequential steps in membrane perforation, combined with video microscopy, electron tomography, electron energy loss spectroscopy, and soft X-ray tomography of mature intracellular Plasmodium falciparum parasites, we resolve intermediate steps in egress. We show that the parasitophorous vacuole membrane (PVM) is permeabilized 10-30 min before its PKG-triggered breakdown into multilayered vesicles. Just before PVM breakdown, the host red cell undergoes an abrupt, dramatic shape change due to the sudden breakdown of the erythrocyte cytoskeleton, before permeabilization and eventual rupture of the erythrocyte membrane to release the parasites. In contrast to the previous view of PKG-triggered initiation of egress and a gradual dismantling of the host erythrocyte cytoskeleton over the course of schizont development, our findings identify an initial step in egress and show that host cell cytoskeleton breakdown is restricted to a narrow time window within the final stages of egress. malaria | egress | electron tomography | soft X-ray microscopy | electron energy loss spectroscopy T he major cause of severe human malaria is Plasmodium falciparum, and its asexual blood cycle is the source of all clinical disease (1). Egress is an important step in the blood life cycle, as it allows daughter merozoites produced by intracellular parasite replication to escape and invade new erythrocytes, thereby continuing and amplifying the infection. Merozoites develop within a parasitophorous vacuole (PV), a membrane-bound compartment that forms during invasion (2-4), so the daughter parasites have two compartments to escape (5, 6).Blood-stage malaria parasites replicate by schizogony, in which several rounds of nuclear division form a multinucleated syncytium called a schizont. Individual merozoites are then produced by an unusual form of cytokinesis called budding or segmentation, which involves invagination of the single plasma membrane of the schizont. Minutes before egress, the segmented schizont suddenly transforms from an irregular to a relatively symmetrical structure with the merozoites arranged around the central digestive vacuole (5). This process, referred to as "flower formation" or rounding up, is usually accompanied by noticeable swelling of the PV and apparent shrinkage of the host cell (4, 5, 7-9). The first membrane to rupture at egress is the parasitophorous vacuole membrane (PVM) (5,6,8). When the PV does not occupy the entire infected cell, the individual merozoites can be seen to be expelled into the blood cell cytosol seconds before they escape fr...

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A perforin-like protein mediates disruption of the erythrocyte membrane during egress ofPlasmodium bergheimale gametocytes

Cited by 87 publications

References 44 publications

The development of malaria parasites in the mosquito midgut

The development of malaria parasites in the mosquito midgut

Perforin-like protein PPLP4 is crucial for mosquito midgut infection by Plasmodium falciparum

Parasitophorous vacuole poration precedes its rupture and rapid host erythrocyte cytoskeleton collapse in Plasmodium falciparum egress

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