Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability

ABSTRACTTo ensure the transport of nutrients necessary for their survival, Plasmodium falciparum parasites increase erythrocyte permeability to diverse solutes. These New Permeation Pathways (NPP) have been extensively characterized in the pathogenic asexual parasite stages, however the existence of NPP has never been investigated in gametocytes, the sexual stages responsible for transmission to mosquitoes. Here, we show that NPP are still active in erythrocytes infected with immature gametocytes and that this activity declines along gametocyte maturation. Our results indicate that NPP are regulated by cyclic AMP (cAMP) signaling cascade during sexual parasite stages, and that the decrease in cAMP levels in mature stages results in a slowdown of NPP activity. We also show that NPP facilitate the uptake of artemisinin derivatives and that phosphodiesterase (PDE) inhibitors can reactivate NPP and increase drug uptake in mature gametocyte-infected erythrocytes. These processes are predicted to play a key role in P. falciparum gametocyte biology and susceptibility to antimalarials.

Download Full-text

Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability

Communications Biology ◽

10.1038/s42003-020-01454-7 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Guillaume Bouyer ◽

Daniela Barbieri ◽

Florian Dupuy ◽

Anthony Marteau ◽

Abdoulaye Sissoko ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Infected Erythrocyte ◽

Drug Uptake ◽

Camp Signaling ◽

Signaling Cascade ◽

Asexual Parasite ◽

Artemisinin Derivatives ◽

Pde Inhibitors ◽

Sexual Stages ◽

Camp Levels

AbstractTo ensure the transport of nutrients necessary for their survival, Plasmodium falciparum parasites increase erythrocyte permeability to diverse solutes. These new permeation pathways (NPPs) have been extensively characterized in the pathogenic asexual parasite stages, however the existence of NPPs has never been investigated in gametocytes, the sexual stages responsible for transmission to mosquitoes. Here, we show that NPPs are still active in erythrocytes infected with immature gametocytes and that this activity declines along gametocyte maturation. Our results indicate that NPPs are regulated by cyclic AMP (cAMP) signaling cascade, and that the decrease in cAMP levels in mature stages results in a slowdown of NPP activity. We also show that NPPs facilitate the uptake of artemisinin derivatives and that phosphodiesterase (PDE) inhibitors can reactivate NPPs and increase drug uptake in mature gametocytes. These processes are predicted to play a key role in P. falciparum gametocyte biology and susceptibility to antimalarials.

Download Full-text

Shifts in P. falciparum genetic structure and gametocyte markers in the transition to elimination

10.21203/rs.3.rs-92978/v1 ◽

2020 ◽

Author(s):

Himanshu Gupta ◽

Beatriz Galatas ◽

Arlindo Chidimatembue ◽

Wilson Simone ◽

Gloria Matambisso ◽

...

Keyword(s):

Genetic Diversity ◽

Plasmodium Falciparum ◽

Genetic Structure ◽

Large Scale ◽

Reverse Transcription Pcr ◽

Mature Gametocyte ◽

Before And After ◽

Sexual Stages ◽

The Impact ◽

Pcr Targeting

Abstract Large-scale programs targeting Plasmodium falciparum (Pf) elimination can exert strong selection pressures on the parasite population. To better understand the impact that elimination initiatives can have on Pf genetic structure and gametocyte carriage, we applied amplicon-based sequencing of two polymorphic Pf genes and quantitative reverse-transcription PCR targeting gametocyte-specific genes to Pf isolates collected in Magude District (Southern Mozambique) before and after an elimination initiative. The 71% reduction of Pf prevalence achieved in 2 years was followed by reductions in Pf genetic diversity and increases in between-infection similarity. These genetic shifts were accompanied by increases in the relative transcript number of the female mature gametocyte marker pfs25, the pfap2g transcription factor that drives gametocytogenesis and the sexual ring marker pfgexp02, suggesting the parasite ability of adapting its sexual investment during elimination initiatives. Reactive interventions that target Pf sexual stages may be required to achieve complete interruption of transmission.

Download Full-text

Distinct Trafficking and Localization of STEVOR Proteins in Three Stages of the Plasmodium falciparum Life Cycle

Infection and Immunity ◽

10.1128/iai.72.11.6597-6602.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6597-6602 ◽

Cited By ~ 60

Author(s):

Louisa McRobert ◽

Peter Preiser ◽

Sarah Sharp ◽

William Jarra ◽

Mallika Kaviratne ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Life Cycle ◽

Asexual Parasite ◽

Reading Frame ◽

Trafficking Pathway ◽

Erythrocyte Plasma Membrane ◽

Three Stages ◽

Sexual Stages ◽

Maurer's Clefts ◽

Subtelomeric Regions

ABSTRACT The genome of Plasmodium falciparum harbors three extensive multigene families, var, rif, and stevor (for subtelomeric variable open reading frame), located mainly in the subtelomeric regions of the parasite's 14 chromosomes. STEVOR variants are known to be expressed in asexual parasites, but no function has as yet been ascribed to this protein family. We have examined the expression of STEVOR proteins in intraerythrocytic sexual stages, gametocytes, and extracellular sporozoites isolated from infected Anopheles mosquitoes. In gametocytes, stevor transcripts appear transiently early in development but STEVOR proteins persist for several days and are transported out of the parasite, travel through the host cell cytoplasm, and localize to the erythrocyte plasma membrane. In contrast to asexual parasites, gametocytes move STEVOR to the periphery via a trafficking pathway independent of Maurer's clefts. In sporozoites, STEVOR appear dispersed throughout the cytoplasm in vesicle-like structures. The pattern of STEVOR localization we have observed in gametocytes and sporozoites differs significantly from that in asexual parasite stages. STEVOR variants are therefore likely to perform different functions in each stage of the parasites life cycle in which they occur.

Download Full-text

A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages

Blood ◽

10.1182/blood-2012-03-414557 ◽

2012 ◽

Vol 119 (24) ◽

pp. e172-e180 ◽

Cited By ~ 86

Author(s):

Marta Tibúrcio ◽

Makhtar Niang ◽

Guillaume Deplaine ◽

Sylvie Perrot ◽

Emmanuel Bischoff ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Blood Circulation ◽

Infected Erythrocyte ◽

Erythrocyte Deformability ◽

Mature Stage ◽

Parasite Transmission ◽

Immature Stages ◽

Sexual Stages ◽

Cellular Deformability ◽

Host Tissues

AbstractAchievement of malaria elimination requires development of novel strategies interfering with parasite transmission, including targeting the parasite sexual stages (gametocytes). The formation of Plasmodium falciparum gametocytes in the human host takes several days during which immature gametocyte-infected erythrocytes (GIEs) sequester in host tissues. Only mature stage GIEs circulate in the peripheral blood, available to uptake by the Anopheles vector. Mechanisms underlying GIE sequestration and release in circulation are virtually unknown. We show here that mature GIEs are more deformable than immature stages using ektacytometry and microsphiltration methods, and that a switch in cellular deformability in the transition from immature to mature gametocytes is accompanied by the deassociation of parasite-derived STEVOR proteins from the infected erythrocyte membrane. We hypothesize that mechanical retention contributes to sequestration of immature GIEs and that regained deformability of mature gametocytes is associated with their release in the bloodstream and ability to circulate. These processes are proposed to play a key role in P falciparum gametocyte development in the host and to represent novel and unconventional targets for interfering with parasite transmission.

Download Full-text

Plasmodium falciparumgametocytes: with a view to a kill

Parasitology ◽

10.1017/s0031182013001236 ◽

2013 ◽

Vol 140 (14) ◽

pp. 1718-1734 ◽

Cited By ~ 20

Author(s):

ALICE S. BUTTERWORTH ◽

TINA S. SKINNER-ADAMS ◽

DON L. GARDINER ◽

KATHARINE R. TRENHOLME

Keyword(s):

Plasmodium Falciparum ◽

Drug Discovery ◽

Malaria Control ◽

Asexual Parasite ◽

Malaria Parasites ◽

Gametocyte Carriage ◽

Control Programmes ◽

Development Pipeline ◽

Malaria Eradication ◽

Sexual Stages

SUMMARYDrugs that kill or inhibit the sexual stages ofPlasmodiumin order to prevent transmission are important components of malaria control programmes. Reducing gametocyte carriage is central to the control ofPlasmodium falciparumtransmission as infection can result in extended periods of gametocytaemia. Unfortunately the number of drugs with activity against gametocytes is limited. Primaquine is currently the only licensed drug with activity against the sexual stages of malaria parasites and its use is hampered by safety concerns. This shortcoming is likely the result of the technical challenges associated with gametocyte studies together with the focus of previous drug discovery campaigns on asexual parasite stages. However recent emphasis on malaria eradication has resulted in an upsurge of interest in identifying compounds with activity against gametocytes. This review examines the gametocytocidal properties of currently available drugs as well as those in the development pipeline and examines the prospects for discovery of new anti-gametocyte compounds.

Download Full-text

Small Variant STEVOR Antigen Is Uniquely Located within Maurer's Clefts in Plasmodium falciparum-Infected Red Blood Cells

Eukaryotic Cell ◽

10.1128/ec.1.6.926-935.2002 ◽

2002 ◽

Vol 1 (6) ◽

pp. 926-935 ◽

Cited By ~ 94

Author(s):

M. Kaviratne ◽

S. M. Khan ◽

W. Jarra ◽

P. R. Preiser

Keyword(s):

Plasmodium Falciparum ◽

Multigene Family ◽

Infected Erythrocyte ◽

Asexual Parasite ◽

Parasite Life Cycle ◽

Host Parasite Interactions ◽

Erythrocyte Surface ◽

Maurer's Clefts ◽

Host Parasite ◽

Parasite Populations

ABSTRACT Malaria parasite antigens encoded by multigene families are important factors in virulence and in disease pathology. In Plasmodium falciparum, the virulence factor PfEMP-1 is encoded by the var multigene family and is exposed at the infected erythrocyte surface. PfEMP-1 is clonally variant, allowing the parasite to evade host immunity. The recently identified P. falciparum stevor multigene family and its products also have the potential to be involved in similar important aspects of host-parasite interactions. Here, we show tightly regulated stage-specific transcription of stevor occurring over just a few hours of the asexual parasite life cycle. Only a subset of stevor genes are transcribed in parasite populations maintained in cultures and in single micromanipulated parasites. Antibodies against STEVOR recognize proteins of the expected size (∼37 kDa) and localize STEVOR in Maurer's clefts, unique membranous structures located in the cytoplasm of infected erythrocytes. The fact that the timing of stevor expression and the location of STEVOR are clearly distinct from those of other parasite variant antigens suggests that this gene family may have a novel role in P. falciparum biology.

Download Full-text

Faculty Opinions recommendation of Skeleton-binding protein 1 functions at the parasitophorous vacuole membrane to traffic PfEMP1 to the Plasmodium falciparum-infected erythrocyte surface.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1046728.496735 ◽

2006 ◽

Author(s):

Patrick Duffy

Keyword(s):

Plasmodium Falciparum ◽

Infected Erythrocyte ◽

Binding Protein ◽

Parasitophorous Vacuole ◽

Parasitophorous Vacuole Membrane ◽

Vacuole Membrane ◽

Erythrocyte Surface

Download Full-text

Combinatorial Metabolism in Plasmodium falciparum-Infected Erythrocyte and Interplay of Glycosylation & Phosphorylation

Current Organic Chemistry ◽

10.2174/1385272043485855 ◽

2004 ◽

Vol 8 (5) ◽

pp. 453-461 ◽

Cited By ~ 1

Author(s):

Bentham Science Publisher Nasir-ud-Din ◽

Ishtiaq Ahmad ◽

Asma Iqbal ◽

Daniel Hoessli

Keyword(s):

Plasmodium Falciparum ◽

Infected Erythrocyte

Download Full-text

Trafficking and Association of Plasmodium falciparum MC-2TM with the Maurer’s Clefts

Pathogens ◽

10.3390/pathogens10040431 ◽

2021 ◽

Vol 10 (4) ◽

pp. 431

Author(s):

Raghavendra Yadavalli ◽

John W. Peterson ◽

Judith A. Drazba ◽

Tobili Y. Sam-Yellowe

Keyword(s):

Plasmodium Falciparum ◽

Erythrocyte Membrane ◽

Sodium Carbonate ◽

Infected Erythrocyte ◽

Brefeldin A ◽

Specific Expression ◽

Lipid Interactions ◽

And Topology ◽

Streptolysin O ◽

Maurer's Clefts

In this study, we investigated stage specific expression, trafficking, solubility and topology of endogenous PfMC-2TM in P. falciparum (3D7) infected erythrocytes. Following Brefeldin A (BFA) treatment of parasites, PfMC-2TM traffic was evaluated using immunofluorescence with antibodies reactive with PfMC-2TM. PfMC-2TM is sensitive to BFA treatment and permeabilization of infected erythrocytes with streptolysin O (SLO) and saponin, showed that the N and C-termini of PfMC-2TM are exposed to the erythrocyte cytoplasm with the central portion of the protein protected in the MC membranes. PfMC-2TM was expressed as early as 4 h post invasion (hpi), was tightly colocalized with REX-1 and trafficked to the erythrocyte membrane without a change in solubility. PfMC-2TM associated with the MC and infected erythrocyte membrane and was resistant to extraction with alkaline sodium carbonate, suggestive of protein-lipid interactions with membranes of the MC and erythrocyte. PfMC-2TM is an additional marker of the nascent MCs.

Download Full-text