scholarly journals Plasmodium falciparumgametocytes: with a view to a kill

Parasitology ◽  
2013 ◽  
Vol 140 (14) ◽  
pp. 1718-1734 ◽  
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.

scholarly journals Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability

2020 ◽  
Author(s):  
Guillaume Bouyer ◽  
Daniela Barbieri ◽  
Florian Dupuy ◽  
Anthony Marteau ◽  
Abdoulaye Sissoko ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Infected Erythrocyte ◽  
Drug Uptake ◽  
Camp Signaling ◽  
Asexual Parasite ◽  
Artemisinin Derivatives ◽  
Mature Gametocyte ◽  
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 (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.

scholarly journals Characterization of apicomplexan amino acid transporters (ApiATs) in the malaria parasite Plasmodium falciparum

2021 ◽  
Author(s):  
Jan Stephan Wichers ◽  
Carolina van Gelder ◽  
Gwendolin Fuchs ◽  
Julia Mareike Ruge ◽  
Emma Pietsch ◽  
...  
Keyword(s):  
Amino Acids ◽  
Plasmodium Falciparum ◽  
Plasma Membrane ◽  
Amino Acid ◽  
Host Cell ◽  
Amino Acid Transporters ◽  
Asexual Parasite ◽  
Malaria Parasites ◽  
Functional Inactivation ◽  
Uptake Of Nutrients

ABSTRACTDuring the symptomatic human blood phase, malaria parasites replicate within red blood cells. Parasite proliferation relies on the uptake of nutrients, such as amino acids, from the host cell and the blood plasma, requiring transport across multiple membranes. Amino acids are delivered to the parasite through the parasite surrounding vacuolar compartment by specialized nutrient-permeable channels of the erythrocyte membrane and the parasitophorous vacuole membrane (PVM). However, further transport of amino acid across the parasite plasma membrane (PPM) is currently not well characterized. In this study, we focused on a family of Apicomplexan amino acid transporters (ApiATs) that comprises five members in Plasmodium falciparum. First, we localized four of the PfApiATs at the PPM using endogenous GFP-tagging. Next, we applied reverse genetic approaches to probe into their essentiality during asexual replication and gametocytogenesis. Upon inducible knockdown and targeted gene disruption a reduced asexual parasite proliferation was detected for PfApiAT2 and PfApiAT4. Functional inactivation of individual PfApiATs targeted in this study had no effect on gametocyte development. Our data suggest that individual PfApiATs are partially redundant during asexual in vitro proliferation and fully redundant during gametocytogenesis of P. falciparum parasites.IMPORTANCEMalaria parasites live and multiply inside cells. To facilitate their extremely fast intracellular proliferation they hijack and transform their host cells. This also requires the active uptake of nutrients, such as amino acids, from the host cell and the surrounding environment through various membranes that are the consequence of the parasite’s intracellular lifestyle. In this manuscript we focus on a family of putative amino acid transporters termed ApiAT. We show expression and localization of four transporters in the parasite plasma membrane of Plasmodium falciparum-infected erythrocytes that represent one interface of the pathogen to its host cell. We probed into the impact of functional inactivation of individual transporters on parasite growth in asexual and sexual blood stages of P. falciparum and reveal that only two of them show a modest but significant reduction in parasite proliferation but no impact on gametocytogenesis pointing towards redundancy within this transporter family.

scholarly journals Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability

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.

scholarly journals Antibody Responses to Crude Gametocyte Extract Predict Plasmodium falciparum Gametocyte Carriage in Kenya

2021 ◽  
Vol 11 ◽  
Author(s):  
Brian R. Omondi ◽  
Michelle K. Muthui ◽  
William I. Muasya ◽  
Benedict Orindi ◽  
Ramadhan S. Mwakubambanya ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Logistic Regression ◽  
Malaria Transmission ◽  
Predictive Power ◽  
Antibody Responses ◽  
Asexual Parasite ◽  
Igg Antibody ◽  
Gametocyte Carriage ◽  
Multivariable Logistic Regression ◽  
Multivariable Models

BackgroundMalaria caused by Plasmodium falciparum remains a serious global public health challenge especially in Africa. Interventions that aim to reduce malaria transmission by targeting the gametocyte reservoir are key to malaria elimination and/or eradication. However, factors that are associated with gametocyte carriage have not been fully explored. Consequently, identifying predictors of the infectious reservoir is fundamental in the elimination campaign.MethodsWe cultured P. falciparum NF54 gametocytes (to stage V) and prepared crude gametocyte extract. Samples from a total of 687 participants (aged 6 months to 67 years) representing two cross-sectional study cohorts in Kilifi, Kenya were used to assess IgG antibody responses by ELISA. We also analyzed IgG antibody responses to the blood-stage antigen AMA1 as a marker of asexual parasite exposure. Gametocytemia and asexual parasitemia data quantified by microscopy and molecular detection (QT-NASBA) were used to determine the relationship with antibody responses, season, age, and transmission setting. Multivariable logistic regression models were used to study the association between antibody responses and gametocyte carriage. The predictive power of the models was tested using the receiver operating characteristic (ROC) curve.ResultsMultivariable logistic regression analysis showed that IgG antibody response to crude gametocyte extract predicted both microscopic (OR=1.81 95% CI: 1.06–3.07, p=0.028) and molecular (OR=1.91, 95% CI: 1.11–3.29, p=0.019) P. falciparum gametocyte carriage. Antibody responses to AMA1 were also associated with both microscopic (OR=1.61 95% CI: 1.08–2.42, p=0.020) and molecular (OR=3.73 95% CI: 2.03–6.74, p<0.001) gametocytemia. ROC analysis showed that molecular (AUC=0.897, 95% CI: 0.868–0.926) and microscopic (AUC=0.812, 95% CI: 0.758–0.865) multivariable models adjusted for gametocyte extract showed very high predictive power. Molecular (AUC=0.917, 95% CI: 0.891–0.943) and microscopic (AUC=0.806, 95% CI: 0.755–0.858) multivariable models adjusted for AMA1 were equally highly predictive.ConclusionIn our study, it appears that IgG responses to crude gametocyte extract are not an independent predictor of gametocyte carriage after adjusting for AMA1 responses but may predict gametocyte carriage as a proxy marker of exposure to parasites. Serological responses to AMA1 or to gametocyte extract may facilitate identification of individuals within populations who contribute to malaria transmission and support implementation of transmission-blocking interventions.

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

2004 ◽  
Vol 72 (11) ◽  
pp. 6597-6602 ◽  
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.

scholarly journals Genetic diversity and genotype multiplicity of Plasmodium falciparum infection in patients with uncomplicated malaria in Chewaka district, Ethiopia

2020 ◽  
Author(s):  
Abdulhakim Abamecha ◽  
Hassan El-Abid ◽  
Daniel Yilma ◽  
Wondimagegn Addisu ◽  
Achim Ibenthal ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Plasmodium Falciparum ◽  
Malaria Control ◽  
Allelic Variation ◽  
Multiplicity Of Infection ◽  
Chain Reactions ◽  
Allelic Family ◽  
Polymerase Chain Reactions ◽  
Control Programmes ◽  
Study Participants

Abstract Background: Genetic diversity in Plasmodium falciparum poses a major threat to malaria control and elimination interventions. Characterization of the genetic diversity of Plasmodium falciparum strains can be used to assess intensity of parasite transmission and identify potential deficiencies in malaria control programmes, which provides vital information to evaluating malaria elimination efforts. In this study, we investigated the P. falciparum genetic diversity and genotype multiplicity of infection in parasite isolates from cases with uncomplicated P. falciparum malaria in Southwest Ethiopia.Methods: A total of 80 P. falciparum microscopy and qPCR positive blood samples were collected from study participants aged six months to sixty years, who visited the health facilities during study evaluating the efficacy of arthemeter-lumefantrine from September-December, 2017. Polymorphic regions of the msp-1 and msp-2 were genotyped by nested polymerase chain reactions (nPCR) followed by gel electrophoresis for fragment analysis.Results: Of 80 qPCR-positive samples analyzed for polymorphisms on msp-1 and msp-2 genes, the efficiency of msp-1 and msp-2 gene amplification reactions with family-specific primers were 95 % and 98.8%, respectively. Allelic variation of 90% (72/80) for msp-1 and 86.2% (69/80) for msp-2 were observed. K1 was the predominant msp-1 allelic family detected in 20.8% (15/72) of the samples followed by MAD20 and RO33. Within msp-2, allelic family FC27 showed a higher frequency (26.1%) compared to IC/3D7 (15.9%). Ten different alleles were observed in msp-1 with 6 alleles for K1, 3 alleles for MAD20 and 1 allele for RO33. In msp-2, 19 individual alleles were detected with 10 alleles for FC27 and 9 alleles for 3D7. Eighty percent (80%) of isolates had multiple genotypes and the overall mean multiplicity of infection was 3.2 (95% CI: 2.87- 3.46). The heterozygosity indices were 0.43 and 0.85 for msp-1 and msp-2, respectively. There was no significant association between multiplicity of infection and age or parasite density.Conclusions: The study revealed high levels of genetic diversity and mixed-strain infections of P. falciparum populations in Chewaka district, Ethiopia, suggesting that both, endemicity level and malaria transmission remain high and that strengthened control efforts are needed in Ethiopia.

scholarly journals Adaptation of the [3H]Hypoxanthine Uptake Assay forIn Vitro-Cultured Plasmodium knowlesi Malaria Parasites

2016 ◽  
Vol 60 (7) ◽  
pp. 4361-4363 ◽  
Author(s):  
Megan S. J. Arnold ◽  
Jessica A. Engel ◽  
Ming Jang Chua ◽  
Gillian M. Fisher ◽  
Tina S. Skinner-Adams ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Discovery ◽  
Malaria Parasite ◽  
Plasmodium Knowlesi ◽  
Malaria Parasites ◽  
Content Type ◽  
Zoonotic Malaria ◽  
Uptake Assay

ABSTRACTThe zoonotic malaria parasitePlasmodium knowlesihas recently been established in continuousin vitroculture. Here, thePlasmodium falciparum[3H]hypoxanthine uptake assay was adapted forP. knowlesiand used to determine the sensitivity of this parasite to chloroquine, cycloguanil, and clindamycin. The data demonstrate thatP. knowlesiis sensitive to all drugs, with 50% inhibitory concentrations (IC50s) consistent with those obtained withP. falciparum. This assay provides a platform to useP. knowlesi in vitrofor drug discovery.

scholarly journals KASP: a genotyping method to rapid identification of resistance in Plasmodium falciparum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ana Alvarez-Fernandez ◽  
María J. Bernal ◽  
Isabel Fradejas ◽  
Alexandra Martin Ramírez ◽  
Noor Azian Md Yusuf ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Control ◽  
Low Cost ◽  
Reference Method ◽  
Rapid Identification ◽  
Nucleotide Polymorphisms ◽  
Specific Pcr ◽  
Control Programmes ◽  
Allele Specific ◽  
Almost All

Abstract Background The emergence and spread of anti-malarial resistance continues to hinder malaria control. Plasmodium falciparum, the species that causes most human malaria cases and most deaths, has shown resistance to almost all known anti-malarials. This anti-malarial resistance arises from the development and subsequent expansion of Single Nucleotide Polymorphisms (SNPs) in specific parasite genes. A quick and cheap tool for the detection of drug resistance can be crucial and very useful for use in hospitals and in malaria control programmes. It has been demonstrated in different contexts that genotyping by Kompetitive Allele Specific PCR (KASP), is a simple, fast and economical method that allows a high-precision biallelic characterization of SNPs, hence its possible utility in the study of resistance in P. falciparum. Methods Three SNPs involved in most cases of resistance to the most widespread anti-malarial treatments have been analysed by PCR plus sequencing and by KASP (C580Y of the Kelch13 gene, Y86N of the Pfmdr1 gene and M133I of the Pfcytb gene). A total of 113 P. falciparum positive samples and 24 negative samples, previously analysed by PCR and sequencing, were selected for this assay. Likewise, the samples were genotyped for the MSP-1 and MSP-2 genes, and the Multiplicity of Infection (MOI) and parasitaemia were measured to observe their possible influence on the KASP method. Results The KASP results showed the same expected mutations and wild type genotypes as the reference method, with few exceptions that correlated with very low parasitaemia samples. In addition, two cases of heterozygotes that had not been detected by sequencing were found. No correlation was found between the MOI or parasitaemia and the KASP values of the sample. The reproducibility of the technique shows no oscillations between repetitions in any of the three SNPs analysed. Conclusions The KASP assays developed in this study were efficient and versatile for the determination of the Plasmodium genotypes related to resistance. The method is simple, fast, reproducible with low cost in personnel, material and equipment and scalable, being able to core KASP arrays, including numerous SNPs, to complete the main pattern of mutations associated to P. falciparum resistance.

scholarly journals Analysing malaria events from 1840 to 2020: the narrative told through postage stamps

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Bernard Brabin
Keyword(s):  
Malaria Control ◽  
World Health ◽  
Wide Audience ◽  
Postage Stamps ◽  
Control Programmes ◽  
History Of ◽  
Eradication Campaign ◽  
Malaria Eradication ◽  
Global Eradication ◽  
Health Organization

AbstractThe role played by postage stamps in the history of malaria control and eradication has largely gone unrecognized. Scientific investigators of malaria, especially Nobel laureates, were commemorated with special issues, but the work of the World Health Organization (WHO), which promoted an ambitious and global philatelic initiative in 1962 to support global eradication, is generally overlooked. This review examines the philatelic programme that helped to generate international commitment to the goal of malaria eradication in 1962 and established philatelic malaria icons that had worldwide recognition. Malaria-related postage stamps have continued to be issued since then, but the initial failure of malaria eradication and the changing goals of each new malaria programme, inevitably diluted their role. After the first Global Malaria Eradication Campaign was discontinued in 1969, few Nations released philatelic issues. Since the Spirit of Dakar Call for Action in 1996 a resurgence of postage stamp releases has occurred, largely tracking global malaria control initiatives introduced between 1996 and 2020. These releases were not co-ordinated by the WHO as before, were more commercialized and targeted stamp collectors, especially with attractive miniature sheets, often produced by photomontage. Having a different purpose, they demonstrated a much wider diversity in symbolism than the earlier stylized issues and at times, have been scientifically inaccurate. Nonetheless postage stamps greatly helped to communicate the importance of malaria control programmes to a wide audience and to some extent, have supported preventive health messages.

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