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1
Gruenberg, Maria, Natalie E. Hofmann, Elma Nate, Stephan Karl, Leanne J. Robinson, Kjerstin Lanke, Thomas A. Smith, Teun Bousema, and Ingrid Felger. "qRT-PCR versus IFA-based Quantification of Male and Female Gametocytes in Low-Density Plasmodium falciparum Infections and Their Relevance for Transmission." Journal of Infectious Diseases 221, no. 4 (August 22, 2019): 598–607. http://dx.doi.org/10.1093/infdis/jiz420.
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Abstract Background Accurate quantification of female and male gametocytes and sex ratios in asymptomatic low-density malaria infections are important for assessing their transmission potential. Gametocytes often escape detection even by molecular methods, therefore ultralow gametocyte densities were quantified in large blood volumes. Methods Female and male gametocytes were quantified in 161 PCR-positive Plasmodium falciparum infections from a cross-sectional survey in Papua New Guinea. Ten-fold concentrated RNA from 800 µL blood was analyzed using female-specific pfs25 and male-specific pfmget or mssp qRT-PCR. Gametocyte sex ratios from qRT-PCR were compared with those from immunofluorescence assays (IFA). Results Gametocytes were identified in 58% (93/161) P. falciparum-positive individuals. Mean gametocyte densities were frequently below 1 female and 1 male gametocyte/µL by qRT-PCR. The mean proportion of males was 0.39 (95% confidence interval, 0.33–0.44) by pfs25/pfmget qRT-PCR; this correlated well with IFA results (Pearsons r2 = 0.91; P < .001). A Poisson model fitted to our data predicted 16% P. falciparum-positive individuals that are likely to transmit, assuming at least 1 female and 1 male gametocyte per 2.5 µL mosquito bloodmeal. Conclusions Based on model estimates of female and male gametocytes per 2.5 µL blood, P. falciparum-positive individuals detected exclusively by ultrasensitive diagnostics are negligible for human-to-mosquito transmission. Estimating the transmission potential of ultralow-density malaria infections informs interventions. Almost all infections with ≥1 female and male gametocyte per 2.5 µL mosquito bloodmeal, and thus with highest likelihood of contributing to human-to-mosquito transmission, were detectable by standard molecular diagnostics.
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NEAL, A. T. "Male gametocyte fecundity and sex ratio of a malaria parasite, Plasmodium mexicanum." Parasitology 138, no. 10 (July 15, 2011): 1203–10. http://dx.doi.org/10.1017/s0031182011000941.
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SUMMARYEvolutionary theory predicts that the sex ratio of Plasmodium gametocytes will be determined by the number of gametes produced per male gametocyte (male fecundity), parasite clonal diversity and any factor that reduces male gametes' ability to find and combine with female gametes. Despite the importance of male gametocyte fecundity for sex ratio theory as applied to malaria parasites, few data are available on gamete production by male gametocytes. In this study, exflagellating gametes, a measure of male fecundity, were counted for 866 gametocytes from 26 natural infections of the lizard malaria parasite, Plasmodium mexicanum. The maximum male fecundity observed was 8, but most gametocytes produced 2–3 gametes, a value consistent with the typical sex ratio observed for P. mexicanum. Male gametocytes in infections with higher gametocytaemia had lower fecundity. Male fecundity was not correlated with gametocyte size, but differed among infections, suggesting genetic variation for fecundity. Fecundity and sex ratio were correlated (more female gametocytes with higher fecundity) as predicted by theory. Results agree with evolutionary theory, but also suggest a possible tradeoff between production time and fecundity, which could explain the low fecundity of this species, the variation among infections, and the correlation with gametocytaemia.
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Ferrer, Patricia, Joel Vega-Rodriguez, Abhai K. Tripathi, Marcelo Jacobs-Lorena, and David J. Sullivan. "Antimalarial Iron Chelator FBS0701 Blocks Transmission by Plasmodium falciparum Gametocyte Activation Inhibition." Antimicrobial Agents and Chemotherapy 59, no. 3 (December 15, 2014): 1418–26. http://dx.doi.org/10.1128/aac.04642-14.
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ABSTRACTReducing the transmission of the malarial parasite byAnophelesmosquitoes using drugs or vaccines remains a main focus in the efforts to control malaria. Iron chelators have been studied as potential antimalarial drugs due to their activities against different stages of the parasite. The iron chelator FBS0701 affects the development ofPlasmodium falciparumearly gametocytes and lowers blood-stage parasitemia. Here, we tested the effect of FBS0701 on stage V gametocyte infectivity for mosquitoes. The incubation of stage V gametocytes for up to 3 days with increasing concentrations of FBS0701 resulted in a significant dose-related reduction in mosquito infectivity, as measured by the numbers of oocysts per mosquito. The reduction in mosquito infectivity was due to the inhibition of male and female gametocyte activation. The preincubation of FBS0701 with ferric chloride restored gametocyte infectivity, showing that the inhibitory effect of FBS0701 was quenched by iron. Deferoxamine, another iron chelator, also reduced gametocyte infectivity but to a lesser extent. Finally, the simultaneous administration of drug and gametocytes to mosquitoes without previous incubation did not significantly reduce the numbers of oocysts. These results show the importance of gametocyte iron metabolism as a potential target for new transmission-blocking strategies.
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SILVESTRINI, F., P. ALANO, and J. L. WILLIAMS. "Commitment to the production of male and female gametocytes in the human malaria parasite Plasmodium falciparum." Parasitology 121, no. 5 (November 2000): 465–71. http://dx.doi.org/10.1017/s0031182099006691.
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Commitment to the production of female and male gametocytes was studied in the NF54 line of the human malaria parasite Plasmodium falciparum. The development of sibling parasites derived from individual schizonts was followed, and 2 antisera against the female gametocyte-specific protein Pfg377 and the male gametocyte-specific protein α-tubulin II were used to determine the sex of sibling gametocytes. The experiment showed that individual cohorts of sibling gametocytes were stained in a mutually exclusive fashion by only one or the other antiserum, indicating that individual schizonts committed to yield sexual parasite progeny produce gametocytes of the same sex. This work suggests that in P. falciparum commitment to sexual differentiation occurs prior to schizont maturation, at the same moment when the sex of the resulting gametocytes is determined.
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NEAL, A. T., and J. J. SCHALL. "Gametocyte sex ratio in single-clone infections of the malaria parasite Plasmodium mexicanum." Parasitology 137, no. 13 (July 12, 2010): 1851–59. http://dx.doi.org/10.1017/s0031182010000909.
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SUMMARYSex ratio theory predicts that malaria parasites should bias gametocyte production toward female cells in single-clone infections because they will experience complete inbreeding of parasite gametes within the vector. A higher proportion of male gametocytes is favoured under conditions that reduce success of male gametes at reaching females such as low gametocyte density or attack of the immune system later in the infection. Recent experimental studies reveal genetic variation for gametocyte sex ratio in single-clone infections. We examined these issues with a study of experimental single-clone infections for the lizard malaria parasite Plasmodium mexicanum in its natural host. Gametocyte sex ratios of replicate single-clone infections were determined over a period of 3–4 months. Sex ratios were generally female biased, but not as strongly as expected under simple sex ratio theory. Gametocyte density was not related to sex ratio, and male gametocytes did not become more common later in infections. The apparent surplus of male gametocytes could be explained if male fecundity is low in this parasite, or if rapid clotting of the lizard blood reduces male gamete mobility. There was also a significant clone effect on sex ratio, suggesting genetic variation for some life-history trait, possibly male fecundity.
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Duez, Julien, John P. Holleran, Papa Alioune Ndour, Sasdekumar Loganathan, Pascal Amireault, Olivier Français, Wassim El Nemer, et al. "Splenic Retention of Plasmodium falciparum Gametocytes To Block the Transmission of Malaria." Antimicrobial Agents and Chemotherapy 59, no. 7 (May 4, 2015): 4206–14. http://dx.doi.org/10.1128/aac.05030-14.
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ABSTRACTPlasmodium falciparumis transmitted from humans toAnophelesmosquito vectors via the sexual erythrocytic forms termed gametocytes. Erythrocyte filtration through microsphere layers (microsphiltration) had shown that circulating gametocytes are deformable. Compounds reducing gametocyte deformability would induce their splenic clearance, thus removing them from the blood circulation and blocking malaria transmission. The hand-made, single-sample prototype for microsphiltration was miniaturized to a 96-well microtiter plate format, and gametocyte retention in the microsphere filters was quantified by high-content imaging. The stiffening activity of 40 pharmacological compounds was assessed in microtiter plates, using a small molecule (calyculin) as a positive control. The stiffening activity of calyculin was assessed in spleen-mimetic microfluidic chips and in macrophage-depleted mice. Marked mechanical retention (80% to 90%) of mature gametocytes was obtained in microplates following exposure to calyculin at concentrations with no effect on parasite viability. Of the 40 compounds tested, including 20 antimalarials, only 5 endoperoxides significantly increased gametocyte retention (1.5- to 2.5-fold; 24 h of exposure at 1 μM). Mature gametocytes exposed to calyculin accumulated in microfluidic chips and were cleared from the circulation of macrophage-depleted mice as rapidly as heat-stiffened erythrocytes, thus confirming results obtained using the microsphiltration assay. An automated miniaturized approach to select compounds for their gametocyte-stiffening effect has been established. Stiffening induces gametocyte clearance bothin vitroandin vivo. Based on physiologically validated tools, this screening cascade can identify novel compounds and uncover new targets to block malaria transmission. Innovative applications in hematology are also envisioned.
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Delves, Michael J., Andrea Ruecker, Ursula Straschil, Jöel Lelièvre, Sara Marques, María José López-Barragán, Esperanza Herreros, and Robert E. Sinden. "Male and Female Plasmodium falciparum Mature Gametocytes Show Different Responses to Antimalarial Drugs." Antimicrobial Agents and Chemotherapy 57, no. 7 (April 29, 2013): 3268–74. http://dx.doi.org/10.1128/aac.00325-13.
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ABSTRACTIt is the mature gametocytes ofPlasmodiumthat are solely responsible for parasite transmission from the mammalian host to the mosquito. They are therefore a logical target for transmission-blocking antimalarial interventions, which aim to break the cycle of reinfection and reduce the prevalence of malaria cases. Gametocytes, however, are not a homogeneous cell population. They are sexually dimorphic, and both males and females are required for parasite transmission. Using two bioassays, we explored the effects of 20 antimalarials on the functional viability of both male and female mature gametocytes ofPlasmodium falciparum. We show that mature male gametocytes (as reported by their ability to produce male gametes, i.e., to exflagellate) are sensitive to antifolates, some endoperoxides, methylene blue, and thiostrepton, with submicromolar 50% inhibitory concentrations (IC50s), whereas female gametocytes (as reported by their ability to activate and form gametes expressing the marker Pfs25) are much less sensitive to antimalarial intervention, with only methylene blue and thiostrepton showing any significant activity. These findings show firstly that the antimalarial responses of male and female gametocytes differ and secondly that the mature male gametocyte should be considered a more vulnerable target than the female gametocyte for transmission-blocking drugs. Given the female-biased sex ratio ofPlasmodium falciparum(∼3 to 5 females:1 male), current gametocyte assays without a sex-specific readout are unlikely to identify male-targeted compounds and prioritize them for further development. Both assays reported here are being scaled up to at least medium throughput and will permit identification of key transmission-blocking molecules that have been overlooked by other screening campaigns.
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Koepfli, Cristian, Wang Nguitragool, Anne Cristine Gomes de Almeida, Andrea Kuehn, Andreea Waltmann, Eline Kattenberg, Maria Ome-Kaius, et al. "Identification of the asymptomatic Plasmodium falciparum and Plasmodium vivax gametocyte reservoir under different transmission intensities." PLOS Neglected Tropical Diseases 15, no. 8 (August 27, 2021): e0009672. http://dx.doi.org/10.1371/journal.pntd.0009672.
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Background Understanding epidemiological variables affecting gametocyte carriage and density is essential to design interventions that most effectively reduce malaria human-to-mosquito transmission. Methodology/Principal findings Plasmodium falciparum and P. vivax parasites and gametocytes were quantified by qPCR and RT-qPCR assays using the same methodologies in 5 cross-sectional surveys involving 16,493 individuals in Brazil, Thailand, Papua New Guinea, and Solomon Islands. The proportion of infections with detectable gametocytes per survey ranged from 44–94% for P. falciparum and from 23–72% for P. vivax. Blood-stage parasite density was the most important predictor of the probability to detect gametocytes. In moderate transmission settings (prevalence by qPCR>5%), parasite density decreased with age and the majority of gametocyte carriers were children. In low transmission settings (prevalence<5%), >65% of gametocyte carriers were adults. Per survey, 37–100% of all individuals positive for gametocytes by RT-qPCR were positive by light microscopy for asexual stages or gametocytes (overall: P. falciparum 178/348, P. vivax 235/398). Conclusions/Significance Interventions to reduce human-to-mosquito malaria transmission in moderate-high endemicity settings will have the greatest impact when children are targeted. In contrast, all age groups need to be included in control activities in low endemicity settings to achieve elimination. Detection of infections by light microscopy is a valuable tool to identify asymptomatic blood stage infections that likely contribute most to ongoing transmission at the time of sampling.
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Guinet, F., J. A. Dvorak, H. Fujioka, D. B. Keister, O. Muratova, D. C. Kaslow, M. Aikawa, A. B. Vaidya, and T. E. Wellems. "A developmental defect in Plasmodium falciparum male gametogenesis." Journal of Cell Biology 135, no. 1 (October 1, 1996): 269–78. http://dx.doi.org/10.1083/jcb.135.1.269.
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Asexually replicating populations of Plasmodium parasites, including those from cloned lines, generate both male and female gametes to complete the malaria life cycle through the mosquito. The generation of these sexual forms begins with the induction of gametocytes from haploid asexual stage parasites in the blood of the vertebrate host. The molecular processes that govern the differentiation and development of the sexual forms are largely unknown. Here we describe a defect that affects the development of competent male gametocytes from a mutant clone of P. falciparum (Dd2). Comparison of the Dd2 clone to the predecessor clone from which it was derived (W2'82) shows that the defect is a mutation that arose during the long-term cultivation of asexual stages in vitro. Light and electron microscopic images, and indirect immunofluorescence assays with male-specific anti-alpha-tubulin II antibodies, indicate a global disruption of male development at the gametocyte level with at least a 70-90% reduction in the proportion of mature male gametocytes by the Dd2 clone relative to W2'82. A high prevalence of abnormal gametocyte forms, frequently containing multiple and unusually large vacuoles, is associated with the defect. The reduced production of mature male gametocytes may reflect a problem in processes that commit a gametocyte to male development or a progressive attrition of viable male gametocytes during maturation. The defect is genetically linked to an almost complete absence of male gamete production and of infectivity to mosquitoes. This is the first sex-specific developmental mutation identified and characterized in Plasmodium.
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BUTTERWORTH, ALICE S., TINA S. SKINNER-ADAMS, DON L. GARDINER, and KATHARINE R. TRENHOLME. "Plasmodium falciparumgametocytes: with a view to a kill." Parasitology 140, no. 14 (August 19, 2013): 1718–34. http://dx.doi.org/10.1017/s0031182013001236.
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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.
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GAILLARD, F. O., C. BOUDIN, N. P. CHAU, V. ROBERT, and G. PICHON. "Togetherness amongPlasmodium falciparumgametocytes: interpretation through simulation and consequences for malaria transmission." Parasitology 127, no. 5 (October 17, 2003): 427–35. http://dx.doi.org/10.1017/s0031182003004025.
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Previous experimental gametocyte infections ofAnopheles arabiensison 3 volunteers naturally infected withPlasmodium falciparumwere conducted in Senegal. They showed that gametocyte counts in the mosquitoes are, like macroparasite intakes, heterogeneous (overdispersed). They followed a negative binomial distribution, the overdispersion coefficient seeming constant (k=3·1). To try to explain this heterogeneity, we used an individual-based model (IBM), simulating the behaviour of gametocytes in the human blood circulation and their ingestion by mosquitoes. The hypothesis was that there exists a clustering of the gametocytes in the capillaries. From a series of simulations, in the case of clustering the following results were obtained: (i) the distribution of the gametocytes ingested by the mosquitoes followed a negative binomial, (ii) thekcoefficient significantly increased with the density of circulating gametocytes. To validate this model result, 2 more experiments were conducted in Cameroon. Pooled experiments showed a distinct density dependency of thek-values. The simulation results and the experimental results were thus in agreement and suggested that an aggregation process at the microscopic level might produce the density-dependent overdispersion at the macroscopic level. Simulations also suggested that the clustering of gametocytes might facilitate fertilization of gametes.
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Tibúrcio, Marta, Makhtar Niang, Guillaume Deplaine, Sylvie Perrot, Emmanuel Bischoff, Papa Alioune Ndour, Francesco Silvestrini, et al. "A switch in infected erythrocyte deformability at the maturation and blood circulation of Plasmodium falciparum transmission stages." Blood 119, no. 24 (June 14, 2012): e172-e180. http://dx.doi.org/10.1182/blood-2012-03-414557.
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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.
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Ngwa, Che Julius, Meike Jutta Kiesow, Lindsey Marie Orchard, Afia Farrukh, Manuel Llinás, and Gabriele Pradel. "The G9a Histone Methyltransferase Inhibitor BIX-01294 Modulates Gene Expression during Plasmodium falciparum Gametocyte Development and Transmission." International Journal of Molecular Sciences 20, no. 20 (October 14, 2019): 5087. http://dx.doi.org/10.3390/ijms20205087.
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Transmission of the malaria parasite Plasmodium falciparum from the human to the mosquito is initiated by specialized sexual cells, the gametocytes. In the human, gametocytes are formed in response to stress signals and following uptake by a blood-feeding Anopheles mosquito initiate sexual reproduction. Gametocytes need to fine-tune their gene expression in order to develop inside the mosquito to continue life-cycle progression. Previously, we showed that post-translational histone acetylation controls gene expression during gametocyte development and transmission. However, the role of histone methylation remains poorly understood. We here use the histone G9a methyltransferase inhibitor BIX-01294 to investigate the role of histone methylation in regulating gene expression in gametocytes. In vitro assays demonstrated that BIX-01294 inhibits intraerythrocytic replication with a half maximal inhibitory concentration (IC50) of 13.0 nM. Furthermore, BIX-01294 significantly impairs gametocyte maturation and reduces the formation of gametes and zygotes. Comparative transcriptomics between BIX-01294-treated and untreated immature, mature and activated gametocytes demonstrated greater than 1.5-fold deregulation of approximately 359 genes. The majority of these genes are transcriptionally downregulated in the activated gametocytes and could be assigned to transcription, translation, and signaling, indicating a contribution of histone methylations in mediating gametogenesis. Our combined data show that inhibitors of histone methylation may serve as a multi-stage antimalarial.
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Rogers, Nicola J., Belinda S. Hall, Jacktone Obiero, Geoffrey A. T. Targett, and Colin J. Sutherland. "A Model for Sequestration of the Transmission Stages of Plasmodium falciparum: Adhesion of Gametocyte-Infected Erythrocytes to Human Bone Marrow Cells." Infection and Immunity 68, no. 6 (June 1, 2000): 3455–62. http://dx.doi.org/10.1128/iai.68.6.3455-3462.2000.
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ABSTRACT With the aim of developing an appropriate in vitro model of the sequestration of developing Plasmodium falciparumsexual-stage parasites, we have investigated the cytoadherence of gametocytes to human bone marrow cells of stromal and endothelial origin. Developing stage III and IV gametocytes, but not mature stage V gametocytes, adhere to bone marrow cells in significantly higher densities than do asexual-stage parasites, although these adhesion densities are severalfold lower than those encountered in classical CD36-dependent assays of P. falciparum cytoadherence. This implies that developing gametocytes undergo a transition from high-avidity, CD36-mediated adhesion during stages I and II to a lower-avidity adhesion during stages III and IV. We show that this adhesion is CD36 independent, fixation sensitive, stimulated by tumor necrosis factor alpha, and dependent on divalent cations and serum components. These data suggest that gametocytes and asexual parasites utilize distinct sets of receptors for adhesion during development in their respective sequestered niches. To identify receptors for gametocyte-specific adhesion of infected erythrocytes to bone marrow cells, we tested a large panel of antibodies for the ability to inhibit cytoadherence. Our results implicate ICAM-1, CD49c, CD166, and CD164 as candidate bone marrow cell receptors for gametocyte adhesion.
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Kuehn, Andrea, and Gabriele Pradel. "The Coming-Out of Malaria Gametocytes." Journal of Biomedicine and Biotechnology 2010 (2010): 1–11. http://dx.doi.org/10.1155/2010/976827.
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The tropical disease malaria, which results in more than one million deaths annually, is caused by protozoan parasites of the genusPlasmodiumand transmitted by blood-feeding Anopheline mosquitoes. Parasite transition from the human host to the mosquito vector is mediated by gametocytes, sexual stages that are formed in human erythrocytes, which therefore play a crucial part in the spread of the tropical disease. The uptake by the blood-feeding mosquito triggers important molecular and cellular changes in the gametocytes, thus mediating the rapid adjustment of the parasite from the warm-blooded host to the insect host and subsequently initiating reproduction. The contact with midgut factors triggers gametocyte activation and results in their egress from the enveloping erythrocyte, which then leads to gamete formation and fertilization. This review summarizes recent findings on the role of gametocytes during transmission to the mosquito and particularly focuses on the molecular mechanisms underlying gametocyte activation and emergence from the host erythrocyte during gametogenesis.
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Dantzler, Kathleen W., Siyuan Ma, Priscilla Ngotho, Will J. R. Stone, Dingyin Tao, Sanna Rijpma, Mariana De Niz, et al. "Naturally acquired immunity against immature Plasmodium falciparum gametocytes." Science Translational Medicine 11, no. 495 (June 5, 2019): eaav3963. http://dx.doi.org/10.1126/scitranslmed.aav3963.
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The recent decline in global malaria burden has stimulated efforts toward Plasmodium falciparum elimination. Understanding the biology of malaria transmission stages may provide opportunities to reduce or prevent onward transmission to mosquitoes. Immature P. falciparum transmission stages, termed stages I to IV gametocytes, sequester in human bone marrow before release into the circulation as mature stage V gametocytes. This process likely involves interactions between host receptors and potentially immunogenic adhesins on the infected red blood cell (iRBC) surface. Here, we developed a flow cytometry assay to examine immune recognition of live gametocytes of different developmental stages by naturally exposed Malawians. We identified strong antibody recognition of the earliest immature gametocyte-iRBCs (giRBCs) but not mature stage V giRBCs. Candidate surface antigens (n = 30), most of them shared between asexual- and gametocyte-iRBCs, were identified by mass spectrometry and mouse immunizations, as well as correlations between responses by protein microarray and flow cytometry. Naturally acquired responses to a subset of candidate antigens were associated with reduced asexual and gametocyte density, and plasma samples from malaria-infected individuals were able to induce immune clearance of giRBCs in vitro. Infected RBC surface expression of select candidate antigens was validated using specific antibodies, and genetic analysis revealed a subset with minimal variation across strains. Our data demonstrate that humoral immune responses to immature giRBCs and shared iRBC antigens are naturally acquired after malaria exposure. These humoral immune responses may have consequences for malaria transmission potential by clearing developing gametocytes, which could be leveraged for malaria intervention.
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Miguel-Blanco, Celia, Joël Lelièvre, Michael J. Delves, Ana I. Bardera, Jesús L. Presa, María José López-Barragán, Andrea Ruecker, Sara Marques, Robert E. Sinden, and Esperanza Herreros. "Imaging-Based High-Throughput Screening Assay To Identify New Molecules with Transmission-Blocking Potential against Plasmodium falciparum Female Gamete Formation." Antimicrobial Agents and Chemotherapy 59, no. 6 (March 23, 2015): 3298–305. http://dx.doi.org/10.1128/aac.04684-14.
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ABSTRACTIn response to a call for the global eradication of malaria, drug discovery has recently been extended to identify compounds that prevent the onward transmission of the parasite, which is mediated byPlasmodium falciparumstage V gametocytes. Lately, metabolic activity has been usedin vitroas a surrogate for gametocyte viability; however, as gametocytes remain relatively quiescent at this stage, their ability to undergo onward development (gamete formation) may be a better measure of their functional viability. During gamete formation, female gametocytes undergo profound morphological changes and express translationally repressed mRNA. By assessing female gamete cell surface expression of one such repressed protein, Pfs25, as the readout for female gametocyte functional viability, we developed an imaging-based high-throughput screening (HTS) assay to identify transmission-blocking compounds. This assay, designated theP. falciparumfemale gametocyte activation assay (FGAA), was scaled up to a high-throughput format (Z′ factor, 0.7 ± 0.1) and subsequently validated using a selection of 50 known antimalarials from diverse chemical families. Only a few of these agents showed submicromolar 50% inhibitory concentrations in the assay: thiostrepton, methylene blue, and some endoperoxides. To determine the best conditions for HTS, a robustness test was performed with a selection of the GlaxoSmithKline Tres Cantos Antimalarial Set (TCAMS) and the final screening conditions for this library were determined to be a 2 μM concentration and 48 h of incubation with gametocytes. TheP. falciparumFGAA has been proven to be a robust HTS assay faithful toPlasmodiumtransmission-stage cell biology, and it is an innovative useful tool for antimalarial drug discovery which aims to identify new molecules with transmission-blocking potential.
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Piper, Karen P., Rhian E. Hayward, Martin J. Cox, and Karen P. Day. "Malaria Transmission and Naturally Acquired Immunity to PfEMP-1." Infection and Immunity 67, no. 12 (December 1, 1999): 6369–74. http://dx.doi.org/10.1128/iai.67.12.6369-6374.1999.
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ABSTRACT Why there are so few gametocytes (the transmission stage of malaria) in the blood of humans infected with Plasmodiumspp. is intriguing. This may be due either to reproductive restraint by the parasite or to unidentified gametocyte-specific immune-mediated clearance mechanisms. We propose another mechanism, a cross-stage immunity to Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1). This molecule is expressed on the surface of the erythrocyte infected with either trophozoite or early gametocyte parasites. Immunoglobulin G antibodies to PfEMP-1, expressed on both life cycle stages, were measured in residents from an area where malaria is endemic, Papua New Guinea. Anti-PfEMP-1 prevalence increased with age, mirroring the decline in both the prevalence and the density of asexual and transmission stages in erythrocytes. These data led us to propose that immunity to PfEMP-1 may influence malaria transmission by regulation of the production of gametocytes. This regulation may be achieved in two ways: (i) by controlling asexual proliferation and density and (ii) by affecting gametocyte maturation.
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Muthui, Michelle K., Polycarp Mogeni, Kennedy Mwai, Christopher Nyundo, Alex Macharia, Thomas N. Williams, George Nyangweso, et al. "Gametocyte carriage in an era of changing malaria epidemiology: A 19-year analysis of a malaria longitudinal cohort." Wellcome Open Research 4 (April 5, 2019): 66. http://dx.doi.org/10.12688/wellcomeopenres.15186.1.
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Background: Interventions to block malaria transmission from humans to mosquitoes are currently in development. To be successfully implemented, key populations need to be identified where the use of these transmission-blocking and/or reducing strategies will have greatest impact. Methods: We used data from a longitudinally monitored cohort of children from Kilifi county located along the Kenyan coast collected between 1998-2016 to describe the distribution and prevalence of gametocytaemia in relation to transmission intensity, time and age. Data from 2,223 children accounting for 9,134 person-years of follow-up assessed during cross-sectional surveys for asexual parasites and gametocytes were used in logistic regression models to identify factors predictive of gametocyte carriage in this cohort. Results: Our analysis showed that children 1-5 years of age were more likely to carry microscopically detectable gametocytes than their older counterparts. Carrying asexual parasites and recent episodes of clinical malaria were also strong predictors of gametocyte carriage. The prevalence of asexual parasites and of gametocyte carriage declined over time, and after 2006, when artemisinin combination therapy (ACT) was introduced, recent episodes of clinical malaria ceased to be a predictor of gametocyte carriage. Conclusions: Gametocyte carriage in children in Kilifi has fallen over time. Previous episodes of clinical malaria may contribute to the development of carriage, but this appears to be mitigated by the use of ACTs highlighting the impact that gametocidal antimalarials can have in reducing the overall prevalence of gametocytaemia when targeted on acute febrile illness.
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Shah, Naman K., Allan Schapira, Jonathan J. Juliano, Bina Srivastava, Pia D. M. MacDonald, Charles Poole, Anup Anvikar, Steven R. Meshnick, Neena Valecha, and Neelima Mishra. "Nonrandomized Controlled Trial of Artesunate plus Sulfadoxine-Pyrimethamine with or without Primaquine for Preventing Posttreatment Circulation of Plasmodium falciparum Gametocytes." Antimicrobial Agents and Chemotherapy 57, no. 7 (April 15, 2013): 2948–54. http://dx.doi.org/10.1128/aac.00139-13.
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ABSTRACTArtemisinin combination therapies eliminate immaturePlasmodium falciparumgametocytes but not mature gametocytes, which may persist for up to 1 month posttreatment. A single dose of primaquine, which is inexpensive and effective against mature gametocytes, could be added to further reduce the potential for posttreatment parasite transmission. Currently, we have few data regarding the effectiveness or safety of doing so. We collected data from 21 therapeutic efficacy trials of the National Antimalarial Drug Resistance Monitoring System of India conducted during 2009 to 2010, wherein 9 sites used single-dose primaquine (0.75 mg/kg of body weight) administered on day 2 along with artesunate plus sulfadoxine-pyrimethamine (AS+SP) while 12 did not. We estimated the effect of primaquine on posttreatment gametocyte clearance and the total number of gametocyte-weeks as determined by microscopy. We compared the median area under the curve for gametocyte density and reported adverse events. One thousand three hundred thirty-five patients completed the antimalarial drug treatment. Adjusting for region, primaquine increased the rate of gametocyte clearance (hazard ratio, 1.9; 95% confidence interval [CI], 1.1 to 3.3), prevented 45% (95% CI, 19 to 62) of posttreatment gametocyte-weeks, and decreased the area under the gametocyte density curve over the 28-day follow-up compared to AS+SP alone (Pvalue = 0.01). The results were robust to other adjustment sets, and the estimated effect of primaquine increased during sensitivity analysis on the measurement of exposure time. No serious adverse events were detected. In conclusion, the addition of primaquine to AS+SP was effective in reducing the posttreatment presence ofP. falciparumgametocytes. Primaquine was well tolerated and could be administered along with an artemisinin combination therapy as the first-line therapy.
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West, Rachel, and David J. Sullivan. "Lactic Acid Supplementation Increases Quantity and Quality of Gametocytes in Plasmodium falciparum Culture." Infection and Immunity 89, no. 1 (October 19, 2020): e00635-20. http://dx.doi.org/10.1128/iai.00635-20.
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ABSTRACTMalaria infection by Plasmodium falciparum continues to afflict millions of people worldwide, with transmission being dependent upon mosquito ingestion of the parasite gametocyte stage. These sexually committed stages develop from the asexual stages, yet the factors behind this transition are not completely understood. Here, we found that lactic acid increases gametocyte quantity and quality in P. falciparum culture. Low-passage-number NF54 parasites exposed to 8.2 mM lactic acid for various times were monitored using blood film gametocyte counts and RNA analysis throughout 2 weeks of gametocyte development in vitro for a total of 5 biological cohorts. We found that daily continuous medium exchange and 8.2 mM lactic acid supplementation increased gametocytemia approximately 2- to 6-fold relative to controls after 5 days. In membrane feeding mosquito infection experiments, we found that gametocytes continuously exposed to 8.2 mM lactic acid supplementations were more infectious to Anopheles stephensi mosquitoes, essentially doubling prevalence of infected midguts and oocyst density. Supplementation on days 9 to 16 did not increase the quantity of gametocytes but did increase quality, as measured by oocyst density, by 2.4-fold. Lactic acid did not impact asexual growth, as measured by blood film counts and luciferase quantification, as well as radioactive hypoxanthine incorporation assays. These data indicate a novel role for lactic acid in sexual development of the parasite.
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Aguilar, Ruth, Ariel Magallon-Tejada, Ariel H. Achtman, Cinta Moraleda, Regina Joice, Pau Cisteró, Connie S. N. Li Wai Suen, et al. "Molecular evidence for the localization of Plasmodium falciparum immature gametocytes in bone marrow." Blood 123, no. 7 (February 13, 2014): 959–66. http://dx.doi.org/10.1182/blood-2013-08-520767.
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Key Points In P falciparum–infected anemic children, immature gametocytes are more prevalent and abundant in bone marrow than in peripheral blood. P falciparum–infected anemic children are gametocyte carriers that can potentially contribute to malaria transmission.
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REECE, S. E., A. B. DUNCAN, S. A. WEST, and A. F. READ. "Sex ratios in the rodent malaria parasite, Plasmodium chabaudi." Parasitology 127, no. 5 (October 17, 2003): 419–25. http://dx.doi.org/10.1017/s0031182003004013.
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The sex ratios of malaria and related Apicomplexan parasites play a major role in transmission success. Here, we address 2 fundamental issues in the sex ratios of the rodent malaria parasite, Plasmodium chabaudi. First we test the accuracy of empirical methods for estimating sex ratios in malaria parasites, and show that sex ratios made with standard thin smears may overestimate the proportion of female gametocytes. Secondly, we test whether the mortality rate differs between male and female gametocytes, as assumed by sex ratio theory. Conventional application of sex ratio theory to malaria parasites assumes that the primary sex ratio can be accurately determined from mature gametocytes circulating in the peripheral circulation. We stopped gametocyte production with chloroquine in order to study a cohort of gametocytes in vitro. The mortality rate was significantly higher for female gametocytes, with an average half-life of 8 h for female gametocytes and 16 h for male gametocytes.
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Neveu, Gaëlle, Cyrielle Richard, Florian Dupuy, Prativa Behera, Fiona Volpe, Pradeep Annamalai Subramani, Benjamin Marcel-Zerrougui, et al. "Plasmodium falciparum sexual parasites develop in human erythroblasts and affect erythropoiesis." Blood 136, no. 12 (September 17, 2020): 1381–93. http://dx.doi.org/10.1182/blood.2019004746.
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Abstract Plasmodium falciparum gametocytes, the sexual stage responsible for malaria parasite transmission from humans to mosquitoes, are key targets for malaria elimination. Immature gametocytes develop in the human bone marrow parenchyma, where they accumulate around erythroblastic islands. Notably though, the interactions between gametocytes and this hematopoietic niche have not been investigated. Here, we identify late erythroblasts as a new host cell for P falciparum sexual stages and show that gametocytes can fully develop inside these nucleated cells in vitro and in vivo, leading to infectious mature gametocytes within reticulocytes. Strikingly, we found that infection of erythroblasts by gametocytes and parasite-derived extracellular vesicles delay erythroid differentiation, thereby allowing gametocyte maturation to coincide with the release of their host cell from the bone marrow. Taken together, our findings highlight new mechanisms that are pivotal for the maintenance of immature gametocytes in the bone marrow and provide further insights on how Plasmodium parasites interfere with erythropoiesis and contribute to anemia in malaria patients.
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Muthui, Michelle K., Polycarp Mogeni, Kennedy Mwai, Christopher Nyundo, Alex Macharia, Thomas N. Williams, George Nyangweso, et al. "Gametocyte carriage in an era of changing malaria epidemiology: A 19-year analysis of a malaria longitudinal cohort." Wellcome Open Research 4 (May 28, 2019): 66. http://dx.doi.org/10.12688/wellcomeopenres.15186.2.
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Background:Interventions to block malaria transmission from humans to mosquitoes are currently in development. To be successfully implemented, key populations need to be identified where the use of these transmission-blocking and/or reducing strategies will have greatest impact.Methods:We used data from a longitudinally monitored cohort of children from Kilifi county located along the Kenyan coast collected between 1998-2016 to describe the distribution and prevalence of gametocytaemia in relation to transmission intensity, time and age. Data from 2,223 children accounting for 9,134 person-years of follow-up assessed during cross-sectional surveys for asexual parasites and gametocytes were used in logistic regression models to identify factors predictive of gametocyte carriage in this cohort.Results:Our analysis showed that children 1-5 years of age were more likely to carry microscopically detectable gametocytes than their older counterparts. Carrying asexual parasites and recent episodes of clinical malaria were also strong predictors of gametocyte carriage. The prevalence of asexual parasites and of gametocyte carriage declined over time, and after 2006, when artemisinin combination therapy (ACT) was introduced, recent episodes of clinical malaria ceased to be a predictor of gametocyte carriage. Conclusions:Gametocyte carriage in children in Kilifi has fallen over time. Previous episodes of clinical malaria may contribute to the development of carriage, but this appears to be mitigated by the use of ACTs highlighting the impact that gametocidal antimalarials can have in reducing the overall prevalence of gametocytaemia when targeted on acute febrile illness.
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Skinner, Jeff, Chiung-Yu Huang, Michael Waisberg, Philip L. Felgner, Ogobara K. Doumbo, Aissata Ongoiba, Kassoum Kayentao, Boubacar Traore, Peter D. Crompton, and Kim C. Williamson. "Plasmodium falciparum Gametocyte-Specific Antibody Profiling Reveals Boosting through Natural Infection and Identifies Potential Markers of Gametocyte Exposure." Infection and Immunity 83, no. 11 (August 17, 2015): 4229–36. http://dx.doi.org/10.1128/iai.00644-15.
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ABSTRACTMalaria elimination efforts would benefit from vaccines that block transmission ofPlasmodium falciparumgametocytes from humans to mosquitoes. A clear understanding of gametocyte-specific antibody responses in exposed populations could help determine whether transmission-blocking vaccines (TBV) would be boosted by natural gametocyte exposure, and also inform the development of serologic tools to monitor gametocyte exposure in populations targeted for malaria elimination. To this end, plasma was collected from Malian children and adults before and after the 6-month malaria season and probed against a microarray containing 1,204P. falciparumproteins. Using publicly available proteomic data, we classified 91 proteins as gametocyte specific and 69 as proteins not expressed by gametocytes. The overall breadth and magnitude of gametocyte-specific IgG responses increased during the malaria season, although they were consistently lower than IgG responses to nongametocyte antigens. Notably, IgG specific for the TBV candidates Pfs48/45 and Pfs230 increased during the malaria season. In addition, IgGs specific for the gametocyte proteins Pfmdv1, Pfs16, PF3D7_1346400, and PF3D7_1024800 were detected in nearly all subjects, suggesting that seroconversion to these proteins may be a sensitive indicator of gametocyte exposure, although further studies are needed to determine the specificity and kinetics of these potential serologic markers. These findings suggest that TBV-induced immunity would be boosted through natural gametocyte exposure, and that antibody responses to particular antigens may reliably indicate gametocyte exposure.
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Beri, Divya, Balu Balan, and Utpal Tatu. "Commit, hide and escape: the story ofPlasmodiumgametocytes." Parasitology 145, no. 13 (July 16, 2018): 1772–82. http://dx.doi.org/10.1017/s0031182018000926.
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AbstractMalaria is the major cause of mortality and morbidity in tropical countries. The causative agent,Plasmodiumsp., has a complex life cycle and is armed with various mechanisms which ensure its continuous transmission. Gametocytes represent the sexual stage of the parasite and are indispensable for the transmission of the parasite from the human host to the mosquito. Despite its vital role in the parasite's success, it is the least understood stage in the parasite's life cycle. The presence of gametocytes in asymptomatic populations and induction of gametocytogenesis by most antimalarial drugs warrants further investigation into its biology. With a renewed focus on malaria elimination and advent of modern technology available to biologists today, the field of gametocyte biology has developed swiftly, providing crucial insights into the molecular mechanisms driving sexual commitment. This review will summarise key current findings in the field of gametocyte biology and address the associated challenges faced in malaria detection, control and elimination.
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GOUAGNA, L. C., H. M. FERGUSON, B. A. OKECH, G. F. KILLEEN, E. W. KABIRU, J. C. BEIER, J. I. GITHURE, and G. YAN. "Plasmodium falciparummalaria disease manifestations in humans and transmission toAnopheles gambiae: a field study in Western Kenya." Parasitology 128, no. 3 (March 2004): 235–43. http://dx.doi.org/10.1017/s003118200300444x.
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Transmission of the malaria parasitePlasmodiumis influenced by many different host, vector and parasite factors. Here we conducted a field study at Mbita, an area of endemic malaria in Western Kenya, to test whether parasite transmission to mosquitoes is influenced by the severity of malaria infection in its human host at the time when gametocytes, the transmission forms, are present in the peripheral blood. We examined the infectivity of 81Plasmodium falciparumgametocyte carriers to mosquitoes. Of these, 21 were patients with fever and other malaria-related symptoms, and 60 were recruited among apparently healthy volunteers. Laboratory-rearedAnopheles gambiaes.s. (local strain) were experimentally infected with blood from these gametocyte carriers by membrane-feeding. The severity of the clinical symptoms was greater in febrile patients. These symptomatic patients had higher asexual parasitaemia and lower gametocyte densities (P=0·05) than healthy volunteers. Ookinete development occurred in only 6 out of the 21 symptomatic patients, of which only 33·3% successfully yielded oocysts. The oocyst prevalence was only 0·6% in the 546 mosquitoes that were fed on blood from this symptomatic group, with mean oocyst intensity of 0·2 (range 0–2) oocysts per mosquito. In contrast, a higher proportion (76·7%) of healthy gametocyte carriers yielded ookinetes, generating an oocyst rate of 12% in the 1332 mosquitoes that fed on them (mean intensity of 6·3, range: 1–105 oocysts per mosquito). Statistical analysis indicated that the increased infectivity of asymptomatic gametocyte carriers was not simply due to their greater gametocyte abundance, but also to the higher level of infectivity of their gametocytes, possibly due to lower parasite mortality within mosquitoes fed on blood from healthy hosts. These results suggest that blood factors and/or conditions correlated with illness reduceP. falciparumgametocyte infectivity.
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Tanaka, Takeshi Q., W. Armand Guiguemde, David S. Barnett, Maxim I. Maron, Jaeki Min, Michele C. Connelly, Praveen Kumar Suryadevara, R. Kiplin Guy, and Kim C. Williamson. "Potent Plasmodium falciparum Gametocytocidal Activity of Diaminonaphthoquinones, Lead Antimalarial Chemotypes Identified in an Antimalarial Compound Screen." Antimicrobial Agents and Chemotherapy 59, no. 3 (December 15, 2014): 1389–97. http://dx.doi.org/10.1128/aac.01930-13.
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ABSTRACTForty percent of the world's population is threatened by malaria, which is caused byPlasmodiumparasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. IfPlasmodium falciparumgametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria.
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Bradley, John, Harouna M. Soumaré, Almahamoudou Mahamar, Halimatou Diawara, Michelle Roh, Michael Delves, Chris Drakeley, et al. "Transmission-blocking Effects of Primaquine and Methylene Blue Suggest Plasmodium falciparum Gametocyte Sterilization Rather Than Effects on Sex Ratio." Clinical Infectious Diseases 69, no. 8 (February 12, 2019): 1436–39. http://dx.doi.org/10.1093/cid/ciz134.
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Abstract Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects.
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CROOKS, L. "Problems with continuous-time malaria models in describing gametocytogenesis." Parasitology 135, no. 8 (July 2008): 881–96. http://dx.doi.org/10.1017/s0031182008004502.
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SUMMARYMost mathematical models of malaria infection represent parasites as replicating continuously at a constant rate whereas in reality, malaria parasites replicate at a fixed age. The behaviour of continuous-time models when gametocytogenesis is included, in comparison to a more realistic discrete-time model that incorporates a fixed replication age was evaluated. Both the infection dynamics under gametocytogenesis and implications for predicting the amount parasites should invest into gametocytes (level of investment favoured by natural selection) are considered. It is shown that the many malaria models with constant replication rates can be represented by just 3 basic types. For these 3 types, it is then shown that under gametocytogenesis (i) in 2 cases, parasite multiplication and gametocyte production is mostly much too low, (ii) in the third, parasite multiplication and gametocyte production is mostly much too high, (iii) the effect of gametocyte investment on parasite multiplication is mostly too high, (iv) the effect of gametocyte investment on gametocyte production is nearly always too low and (v) with a simple approximation of fitness, the predicted level of gametocyte investment is mostly much too low. However, a continuous model with 48 age-compartments compares well to the discrete model. These findings are a further argument for modelling malaria infections in discrete time.
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OSGOOD, S. M., and J. J. SCHALL. "Gametocyte sex ratio of a malaria parasite: response to experimental manipulation of parasite clonal diversity." Parasitology 128, no. 1 (January 2004): 23–29. http://dx.doi.org/10.1017/s0031182003004207.
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Sex ratio theory posits that the adaptive proportion of male to female gametocytes of a malaria parasite within the vertebrate host depends on the degree of inbreeding within the vector. Gametocyte sex ratio could be phenotypically flexible, being altered based on the infection's clonal diversity, and thus likely inbreeding. This idea was tested by manipulating the clonal diversity of infections of Plasmodium mexicanum in its lizard host, Sceloporus occidentalis. Naive lizards were inoculated with infected blood from a single donor or 3 pooled donors. Donors varied in their gametocyte sex ratios (17–46% male), and sex ratio theory allowed estimation of the clonal diversity within donor and recipient infections. Phenotypic plasticity would produce a correlation between donor and recipient infections for infections initiated from a single donor, and a less female-biased gametocyte sex ratio in recipients that received a mixed blood inoculum (with predicted higher clonal diversity) than recipients receiving blood from a single donor. Neither pattern was observed. Gametocyte sex ratio of most infections ranged from 35 to 42% male, expected if clonal diversity was high for all infections. Alternative explanations are suggested for the observed variation of gametocyte sex ratio among P. mexicanum infections.
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MAENO, Y., R. CULLETON, N. T. QUANG, S. KAWAI, R. P. MARCHAND, and S. NAKAZAWA. "Plasmodium knowlesi and human malaria parasites in Khan Phu, Vietnam: Gametocyte production in humans and frequent co-infection of mosquitoes." Parasitology 144, no. 4 (November 29, 2016): 527–35. http://dx.doi.org/10.1017/s0031182016002110.
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SUMMARYFour species of malaria parasite, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium knowlesi infect humans living in the Khanh Phu commune, Khanh Hoa Province, Vietnam. The latter species also infects wild macaque monkeys in this region. In order to understand the transmission dynamics of the three species, we attempted to detect gametocytes of the three species in the blood of infected individuals, and sporozoites in the salivary glands of mosquitoes from the same region. For the detection of gametocyte-specific mRNA, we targeted region 3 of pfg377, pvs25, pmg and pks25 as indicators of the presence of P. falciparum, P. vivax, P. malariae and P. knowlesi gametocytes, respectively. Gametocyte-specific mRNA was present in 37, 61, 0 and 47% of people infected with P. falciparum (n = 95), P. vivax (n = 69), P. malariae (n = 6) or P. knowlesi (n = 32), respectively. We found that 70% of mosquitoes that had P. knowlesi in their salivary glands also carried human malaria parasites, suggesting that mosquitoes are infected with P. knowlesi from human infections.
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Ranawaka, G. R. R., S. L. Fleck, A. R. Alejo Blanco, and R. E. Sinden. "Characterization of the modes of action of anti-Pbs21 malaria transmission-blocking immunity: ookinete to oocyst differentiationin vivo." Parasitology 109, no. 4 (November 1994): 403–11. http://dx.doi.org/10.1017/s0031182000080653.
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SUMMARYThe impact of immune sera, and peripheral blood cells (PBC) from mice immunized withPlasmodium bergheiookinetes; and of purified immunoglobulin or Fab fragments from anti-Pbs21 monoclonal antibody 13.1, upon establishment of oocyst infections in the mosquito was studied. Infections were initiated either from gametocyte-infected mice, or membrane feeders which contained either gametocytes or mature ookinetes. PBC from ookinete-immunized mice presented with non-immune serum failed to show any transmission-blocking activity. Anti-ookinete serum, intact anti-Pbs21 monoclonal antibody 13.1 or its Fab fragments, all inhibited oocyst formation significantly. When gametocyte-infected mice or gametocytes in membrane feeds were used, inhibition did not directly correlate with antibody concentration. In membrane feeders that contained ookinetes and antibody, concentration-dependent inhibition usually occurred. The efficacy of purified 13.1 IgG was dependent upon the ookinete concentration. The ookinete plasmalemma and cytoplasm were significantly disturbed after 12h in bloodmeals that contained antibody 13.1, but not in the isotype controls. These changes may have caused the observed failure of the ookinete to migrate as rapidly as the controls from the destructive environment of the bloodmeal.
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Obaldia, Nicanor, Elamaran Meibalan, Juliana M. Sa, Siyuan Ma, Martha A. Clark, Pedro Mejia, Roberto R. Moraes Barros, et al. "Bone Marrow Is a Major Parasite Reservoir inPlasmodium vivaxInfection." mBio 9, no. 3 (May 8, 2018): e00625-18. http://dx.doi.org/10.1128/mbio.00625-18.
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ABSTRACTPlasmodium vivaxcauses heavy burdens of disease across malarious regions worldwide. MatureP. vivaxasexual and transmissive gametocyte stages occur in the blood circulation, and it is often assumed that accumulation/sequestration in tissues is not an important phase in their development. Here, we present a systematic study ofP. vivaxstage distributions in infected tissues of nonhuman primate (NHP) malaria models as well as in blood from human infections. In a comparative analysis of the transcriptomes ofP. vivaxandPlasmodium falciparumblood-stage parasites, we found a conserved cascade of stage-specific gene expression despite the greatly different gametocyte maturity times of these two species. Using this knowledge, we validated a set of conserved asexual- and gametocyte-stage markers both by quantitative real-time PCR and by antibody assays of peripheral blood samples from infected patients and NHP (Aotussp.). Histological analyses ofP. vivaxparasites in organs of 13 infected NHP (AotusandSaimirispecies) demonstrated a major fraction of immature gametocytes in the parenchyma of the bone marrow, while asexual schizont forms were enriched to a somewhat lesser extent in this region of the bone marrow as well as in sinusoids of the liver. These findings suggest that the bone marrow is an important reservoir for gametocyte development and proliferation of malaria parasites.IMPORTANCEPlasmodium vivaxmalaria continues to cause major public health burdens worldwide. Yet, significant knowledge gaps in the basic biology and epidemiology ofP. vivaxmalaria remain, largely due to limited available tools for research and diagnostics. Here, we present a systematic examination of tissue sequestration duringP. vivaxinfection. Studies of nonhuman primates and malaria patients revealed enrichment of developing sexual stages (gametocytes) and mature replicative stages (schizonts) in the bone marrow and liver, relative to those present in peripheral blood. Identification of the bone marrow as a majorP. vivaxtissue reservoir has important implications for parasite diagnosis and treatment.
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STONE, WILL J. R., KATHLEEN W. DANTZLER, SANDRA K. NILSSON, CHRIS J. DRAKELEY, MATTHIAS MARTI, TEUN BOUSEMA, and SANNA R. RIJPMA. "Naturally acquired immunity to sexual stageP. falciparumparasites." Parasitology 143, no. 2 (January 8, 2016): 187–98. http://dx.doi.org/10.1017/s0031182015001341.
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SUMMARYGametocytes are the specialized form ofPlasmodiumparasites that are responsible for human-to-mosquito transmission of malaria. Transmission of gametocytes is highly effective, but represents a biomass bottleneck for the parasite that has stimulated interest in strategies targeting the transmission stages separately from those responsible for clinical disease. Studying targets of naturally acquired immunity against transmission-stage parasites may reveal opportunities for novel transmission reducing interventions, particularly the development of a transmission blocking vaccine (TBV). In this review, we summarize the current knowledge on immunity against the transmission stages ofPlasmodium. This includes immune responses against epitopes on the gametocyte-infected erythrocyte surface during gametocyte development, as well as epitopes present upon gametocyte activation in the mosquito midgut. We present an analysis of historical data on transmission reducing immunity (TRI), as analysed in mosquito feeding assays, and its correlation with natural recognition of sexual stage specific proteins Pfs48/45 and Pfs230. Although high antibody titres towards either one of these proteins is associated with TRI, the presence of additional, novel targets is anticipated. In conclusion, the identification of novel gametocyte-specific targets of naturally acquired immunity against different gametocyte stages could aid in the development of potential TBV targets and ultimately an effective transmission blocking approach.
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Baker, D. A., O. Daramola, M. V. McCrossan, J. Harmer, and G. A. T. Targett. "Subcellular localization of Pfs16, a Plasmodium falciparum gametocyte antigen." Parasitology 108, no. 2 (February 1994): 129–37. http://dx.doi.org/10.1017/s0031182000068219.
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SUMMARYWe have used immunoelectron microscopy to investigate the subcellular location of Pfs16 in Plasmodium falciparum. It was detected in the outer membrane region of gametocytes and more specifically on the parasitophorous vacuole membrane (pvm), since, during gametogenesis when the pvm disintegrates, the majority of the antigen was detected on the remains of this membrane in multilaminated whorls and not on the gamete plasma membrane. The antigen was also present on other gametocyte cellular structures, including those which we believe to be Garnham bodies, present in the host cell cytoplasm of some gametocytes. The antigen was present too on the membrane surrounding cytostomes and the resulting food vacuoles in the parasite cytoplasm.
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Good, Michael F., and Stephanie K. Yanow. "A whole parasite transmission-blocking vaccine for malaria: an ignored strategy." Emerging Topics in Life Sciences 1, no. 6 (December 22, 2017): 547–52. http://dx.doi.org/10.1042/etls20170117.
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Malaria vaccine approaches can be divided into ‘subunit’ and ‘whole parasite’, and these can be directed at the sporozoite, liver stage, asexual or sexual stages. All combinations of approach and stage are under development with the exception of a whole parasite sexual stage (gametocyte) vaccine. A gametocyte vaccine would aim primarily to block transmission of malaria from the human host to the mosquito vector and as such is referred to as a ‘transmission-blocking vaccine’. An immunological feature of whole parasite vaccines for the sporozoite/liver stage and for the asexual blood stage is the reliance on cellular immunity involving T-cells to control parasite growth. T-cells can also respond vigorously to gametocytes and kill them in the vertebrate host and/or arrest their development. To date, cellular immunity has not been exploited in transmission-blocking vaccine development. Here, the data supporting a gametocyte whole parasite vaccine are reviewed and a strategy for vaccine development and testing is outlined.
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Lobo, Cheryl-Ann, N. H. Ruud, Konings, and Nirbhay Kumar. "Expression of early gametocyte-stage antigens Pfg27 and Pfs16 in synchronized gametocytes and non-gametocyte producing clones of Plasmodium falciparum." Molecular and Biochemical Parasitology 68, no. 1 (November 1994): 151–54. http://dx.doi.org/10.1016/0166-6851(94)00155-3.
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Margos, Gabriele, Melissa R. van Dijk, Jai Ramesar, Chris J. Janse, Andrew P. Waters, and Robert E. Sinden. "Transgenic Expression of a Mosquito-Stage Malarial Protein, Pbs21, in Blood Stages of Transformed Plasmodium bergheiand Induction of an Immune Response upon Infection." Infection and Immunity 66, no. 8 (August 1, 1998): 3884–91. http://dx.doi.org/10.1128/iai.66.8.3884-3891.1998.
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ABSTRACT Pbs21 is a surface protein of the ookinete of Plasmodium berghei, which can induce a potent transmission-blocking immune response. Pbs21 is normally expressed only by parasite stages in the mosquito, i.e., female gametes/zygotes, ookinetes, and oocysts. However, the Pbs21 gene is transcribed in female gametocytes which circulate in the bloodstream of the host, where translation of the resulting mRNA is totally repressed. Episomal transfection has been used to investigate whether expression of Pbs21 protein could be achieved in blood stages of the parasite. By using plasmid pMD221, the complete mRNA-encoding region of Pbs21, flanked only by 218 nucleotides (nt) of its promoter region and 438 nt of its 3′ region downstream from the polyadenylation site, was introduced into the blood stages of gametocyte-producing and non-gametocyte-producing clones of P. berghei. In both of these transformed parasite lines, Pbs21 protein was expressed in asexual trophozoites, schizonts, and, when present, in both male and female gametocytes. Hence, the flanking regions present are sufficient to allow transcription but lack the elements that exert natural control of sex- and stage-specific transcription. The mRNA and the protein expressed by transformed blood stages were indistinguishable from the wild-type forms by the criteria tested, and the protein was recognized by both conformation-dependent and conformation-independent monoclonal antibodies raised against native Pbs21. In mice infected with transformed non-gametocyte-producing parasites, a Pbs21-specific immune response was induced and characterized with respect to isotype (IgG2a/IgG2b) and quantity (11.5 ± 10 μg/ml) of antibody produced. However, as found in previous studies, these antibody levels were insufficient to inhibit development of the parasites in the mosquito. The ability to express mosquito midgut-stage antigens in blood-stage parasites will facilitate further investigations of molecular and immunological properties of these proteins.
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Ayaz, M. M., M. Akhtar, I. Hussain, F. Muhammad, and A. U. Haq. "Immunoglobulin producing cells in chickens immunized with Eimeria tenella gametocyte antigen vaccines." Veterinární Medicína 53, No. 4 (April 23, 2008): 207–13. http://dx.doi.org/10.17221/1918-vetmed.
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The present paper reports on the IgA, IgG and IgM antibodies secreting cells (ASC) in the spleen of chickens vaccinated with <I>E. tenella</I> (local isolates) gametocyte vaccine(s) by using Enzyme Linked Immunospot (ELISPOT) assay. Irrespective of the vaccine used, the number of IgG antibody secreting cells (ASC) in the spleen of orally vaccinated chickens was higher than the number of IgA and IgM ASC. Maximum numbers of IgG, IgA and IgM ASC were found in chickens vaccinated with sonicated gametocyte formalin inactivated vaccine (Group III) followed by formalin inactivated gametocytes (Group II) and gametocytes (Group I). The number of ASC (IgG, IgA and IgM) per 10<sup>4</sup> cells in spleen was significantly higher (<I>P</I> < 0.05) in Group III as compared to Group II and Group I. Results of the challenge experiments revealed maximum protection against mixed species of the genus <I>Eimeria</I> in Group III (77.8%) followed by Group II (55.6%) and Group I (52.0%). Lesion scoring was directly proportional to the per cent mortality and oocysts per gram of droppings but inversely proportional to the per cent protection. Based on the results, it was assumed that the spleen in chickens is one of the major sources of cells producing IgA, IgG and IgM antibodies.
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Tanaka, Takeshi Q., Edgar Deu, Alvaro Molina-Cruz, Michael J. Ashburne, Omar Ali, Amreena Suri, Sandhya Kortagere, Matthew Bogyo, and Kim C. Williamson. "Plasmodium Dipeptidyl Aminopeptidases as Malaria Transmission-Blocking Drug Targets." Antimicrobial Agents and Chemotherapy 57, no. 10 (July 8, 2013): 4645–52. http://dx.doi.org/10.1128/aac.02495-12.
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ABSTRACTThePlasmodium falciparumandP. bergheigenomes each contain three dipeptidyl aminopeptidase (dpap) homologs.dpap1and -3 are critical for asexual growth, but the role ofdpap2, the gametocyte-specific homolog, has not been tested. If DPAPs are essential for transmission as well as asexual growth, then a DPAP inhibitor could be used for treatment and to block transmission. To directly analyze the role of DPAP2, adpap2-minusP. berghei(Pbdpap2Δ) line was generated. ThePbdpap2Δ parasites grew normally, differentiated into gametocytes, and generated sporozoites that were infectious to mice when fed to a mosquito. However,Pbdpap1transcription was >2-fold upregulated in thePbdpap2Δ clonal lines, possibly compensating for the loss ofPbdpap2. The role of DPAP1 and -3 in thedpap2Δ parasites was then evaluated using a DPAP inhibitor, ML4118S. When ML4118S was added to thePbdpap2Δ parasites just before a mosquito membrane feed, mosquito infectivity was not affected. To assess longer exposures to ML4118S and further evaluate the role of DPAPs during gametocyte development in a parasite that causes human malaria, thedpap2deletion was repeated inP. falciparum. ViableP. falciparum dpap2(Pfdpap2)-minus parasites were obtained that produced morphologically normal gametocytes. Both wild-type andPfdpap2-negative parasites were sensitive to ML4118S, indicating that, unlike many antimalarials, ML4118S has activity against parasites at both the asexual and sexual stages and that DPAP1 and -3 may be targets for a dual-stage drug that can treat patients and block malaria transmission.
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Penna-Coutinho, Julia, Maria Jesús Almela, Celia Miguel-Blanco, Esperanza Herreros, Paula M. Sá, Núbia Boechat, and Antoniana Ursine Krettli. "Transmission-Blocking Potential of MEFAS, a Hybrid Compound Derived from Artesunate and Mefloquine." Antimicrobial Agents and Chemotherapy 60, no. 5 (February 22, 2016): 3145–47. http://dx.doi.org/10.1128/aac.02216-15.
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ABSTRACTMost antimalarial drugs target asexual parasites without reducing gametocyte formation or development. Drugs with dual roles, i.e., those that can target both asexual parasites and gametocytes, would improve the control of malaria. In the current study, MEFAS, a hybrid drug derived from mefloquine and artesunate that has been shown to be an active blood schizonticidal drug, was assessed to determine its ability to block the infectivity ofPlasmodium falciparumgametocytes. MEFAS was 280 and 15 times more effective than mefloquine alone and artesunate alone, respectively.
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Nacher, Mathieu, Udomsak Silachamroon, Pratap Singhasivanon, Polrat Wilairatana, Weerapong Phumratanaprapin, Arnaud Fontanet, and Sornchai Looareesuwan. "Comparison of Artesunate and Chloroquine Activities against Plasmodium vivax Gametocytes." Antimicrobial Agents and Chemotherapy 48, no. 7 (July 2004): 2751–52. http://dx.doi.org/10.1128/aac.48.7.2751-2752.2004.
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ABSTRACT The gametocidal activities of chloroquine and artesunate were compared. The relative risk (RR) of having detectable gametocytes appear after treatment initiation was lower in artesunate-treated patients (n = 792) than in chloroquine-treated patients (n = 695) (RR = 0.29; 95% CI = 0.2 to 0.40; P < 0.0001). The duration and magnitude of gametocyte carriage were also lower for artesunate than chloroquine. By reducing the transmission of Plasmodium vivax to the vector, artesunate could therefore reduce the incidence of P. vivax malaria.
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Ngotho, Priscilla, Alexandra Blancke Soares, Franziska Hentzschel, Fiona Achcar, Lucia Bertuccini, and Matthias Marti. "Revisiting gametocyte biology in malaria parasites." FEMS Microbiology Reviews 43, no. 4 (April 9, 2019): 401–14. http://dx.doi.org/10.1093/femsre/fuz010.
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ABSTRACT Gametocytes are the only form of the malaria parasite that is transmissible to the mosquito vector. They are present at low levels in blood circulation and significant knowledge gaps exist in their biology. Recent reductions in the global malaria burden have brought the possibility of elimination and eradication, with renewed focus on malaria transmission biology as a basis for interventions. This review discusses recent insights into gametocyte biology in the major human malaria parasite, Plasmodium falciparum and related species.
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Ponnudurai, T., A. H. W. Lensen, J. F. G. M. Meis, and J. H. E. Th Meuwissen. "Synchronization of Plasmodium falciparum gametocytes using an automated suspension culture system." Parasitology 93, no. 2 (October 1986): 263–74. http://dx.doi.org/10.1017/s003118200005143x.
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SUMMARYAn automated suspension culture system for the cultivation of Plasmodium falciparum is described which retains a degree of flexibility which is absent in other automated culture apparatuses. Not only does this system of cultivation promote rapid multiplication of asexual parasites but also permits the development and maturation of gametocytes. Using a combination of gelatin flotation and N-acetyl glucosamine treatment synchronous development of gametocytes was achieved. The total time for gametocyte maturation in vitro under the conditions provided was 7 days. Stages II and V required 48 h for development whilst I, III and IV needed 24 h each. Mature microgametocytes were relatively long lived in comparison with macrogametocytes. Electron microscopic study of the synchronized stages confirmed the observations of Sinden (1982) but, in addition, we noted the presence of Garnham bodies, a cytostome in all stages and dense spherules in stages I–III similar to the fenestrated buttons in sporozoites and exoerythrocytic forms. The relationship between the number of osmiophilic bodies in the mature gametocytes and their ability to escape from the red cell is reaffirmed.
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Diarra, Amidou, Issiaka Soulama, Issa Nebie, Maurice Ouattara, Moise Kabore, Benjain Sombie, Alfred B. Tiono, Alphonse Ouedraogo, and Sodiomon B. Sirima. "PO 8492 REPEATED ARTEMISININ-BASED TREATMENT ON MALARIA SEXUAL PARASITE DISTRIBUTION IN POPULATION LIVING IN A MALARIA-ENDEMIC AREA OF BURKINA FASO." BMJ Global Health 4, Suppl 3 (April 2019): A45.2—A45. http://dx.doi.org/10.1136/bmjgh-2019-edc.119.
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BackgroundMalaria elimination and its ultimate eradication will require drugs targeting all stages of the parasite’s life cycle. Yet, very few drugs are known to be effective on the sexual stages (gametocytes) of Plasmodium falciparum. Artemisinin-based combination therapy (ACT) has been shown to have some early-stage gametocytocidal effects on in vitro and in feeding experiments. However, field studies showed that artesunate reduces but does not prevent post-treatment transmission of P. falciparum to mosquitos.Methods763 children and adult patients with acute uncomplicated Plasmodium sp. malaria were included in a phase IIIb/IV comparative, randomised, multi-centre, open label, parallel 3-arm clinical trial to assess safety and efficacy of repeated administration of pyronaridine-artesunate, dihydroartemisinin-piperaquine or artemether-lumefantrine or artesunate-amodiaquine over a two-year period. Drugs were given based on the body weight and volunteers were followed up for 42 days. Clinical signs and symptoms were recorded and filter paper and blood smears collected during each visit. Malaria parasites were assessed and parasite density development stages determined by light microscopy.ResultsP. falciparum gametocyte was 1.9%, during the two years of follow-up. From the three treatment arms, artesunate-amodiaquine was the arm bearing more P. falciparum gametocyte with 68.7%, dihydroartemisinin-piperaquine accounted for 6.3% and pyronaridine-artesunate for 25%. P. falciparum gametocyte was more pronounced in populations having parasite density ≤1 00 000 parasites/µl compared to above parasitaemia.ConclusionRepeated ACTs treatment didn’t clear P. falciparum gametocyte in a population infected with uncomplicated malaria.
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Sharp, Sarah, Thomas Lavstsen, Quinton L. Fivelman, Maha Saeed, Louisa McRobert, Thomas J. Templeton, Anja T. R. Jensen, David A. Baker, Thor G. Theander, and Colin J. Sutherland. "Programmed Transcription of the var Gene Family, but Not of stevor, in Plasmodium falciparum Gametocytes." Eukaryotic Cell 5, no. 8 (August 2006): 1206–14. http://dx.doi.org/10.1128/ec.00029-06.
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ABSTRACT The var genes encode Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins, a set of highly diverse surface-expressed proteins that mediate adhesion of erythrocytes infected with asexual blood-stage parasites to host endothelium. Switching among expressed PfEMP1 variants in the course of a blood-stage infection is a key component of antigenic variation, and thus immune evasion, by the parasite. The majority of var loci are found in the subtelomeric regions of P. falciparum chromosomes associated with members of other multigene families, including stevor. Both PfEMP1 and STEVOR are expressed in gametocytes, the transmissible parasite stage, but the role of these proteins in the biology of sexual-stage parasites remains unknown. PfEMP1 may continue to mediate antigenic variation in gametocytes, which need to persist in the host for many days before reaching maturity. Using quantitative reverse transcription-PCR and Northern hybridization, we demonstrate that transcription of a defined subset of type C var loci occurs during gametocyte development in vitro. This transcriptional program occurs in gametocytes regardless of the var expression phenotype of their asexual progenitors and therefore is subject to regulatory processes distinct from those that manage antigenic variation in the asexual parasite. In contrast, the same stevor variants are transcribed in both gametocytes and their asexual progenitors. We also provide evidence that for both asexual parasites and gametocytes, var and stevor transcription patterns are not linked to each other.
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Smith, Todd G., Lena Serghides, Samir N. Patel, Maria Febbraio, Roy L. Silverstein, and Kevin C. Kain. "CD36-Mediated Nonopsonic Phagocytosis of Erythrocytes Infected with Stage I and IIA Gametocytes of Plasmodium falciparum." Infection and Immunity 71, no. 1 (January 2003): 393–400. http://dx.doi.org/10.1128/iai.71.1.393-400.2003.
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ABSTRACT Gametocytes, the sexual stages of malaria parasites (Plasmodium spp.) that are transmissible to mosquitoes, have been the focus of much recent research as potential targets for novel drug and vaccine therapies. However, little is known about the host clearance of gametocyte-infected erythrocytes (GEs). Using a number of experimental strategies, we found that the scavenger receptor CD36 mediates the uptake of nonopsonized erythrocytes infected with stage I and IIA gametocytes of Plasmodium falciparum by monocytes and culture-derived macrophages (Mφs). Light microscopy and immunofluorescence assays revealed that stage I and IIA gametocytes were readily internalized by monocytes and Mφs. Pretreating monocytes and Mφs with a monoclonal antibody that blocked CD36 resulted in a significant reduction in phagocytosis, as did treating GEs with low concentrations of trypsin to remove P. falciparum erythrocyte membrane protein 1 (PfEMP-1), a parasite ligand for CD36. Pretreating monocytes and Mφs with peroxisome proliferator-activated receptor γ-retinoid X receptor agonists, which specifically upregulate CD36, resulted in a significant increase in the phagocytosis of GEs. Murine CD36 on mouse Mφs also mediated the phagocytosis of P. falciparum stage I and IIA gametocytes, as determined by receptor blockade with anti-murine CD36 monoclonal antibodies and the lack of uptake by CD36-null Mφs. These results indicate that phagocytosis of stage I and IIA gametocytes by monocytes and Mφs appears to be mediated to a large extent by the interaction of PfEMP-1 and CD36, suggesting that CD36 may play a role in innate clearance of these early sexual stages.
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Sinden, R. E. "Asexual blood stages of malaria modulate gametocyte infectivity to the mosquito vector – possible implications for control strategies." Parasitology 103, no. 2 (October 1991): 191–96. http://dx.doi.org/10.1017/s0031182000059473.
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In the rodent malarial parasitePlasmodium bergheisexual parasites are produced in a single major wave with maximal numbers between day 7 and day 16. Irrespective of their time of appearance during infection these sexual parasites are equally fertilein vitro. In contrast,in vivoinfectivity to the mosquito is maximal at day 3–5 when gametocyte numbers are only 9% of the peak levels seen between days 7 and 16. Up to 96% of natural potential infectivity of gametocytes for the mosquito is therefore suppressed. The suppression is humoral, reversible and correlates with the appearance of an effective host response to the initial rapid increase in asexual parasitaemia. These data are consistent with published evidence which indicates that a reduction in parasitaemia may cause an increase in infectivity of gametocytes to the mosquito vector. Therefore the impact of strategies aiming to control asexual parasites is re-examined. Inefficient strategies might be predicted to increase and not suppress malaria transmission.