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Maslachah, Lilik, Yoes Prijatna Dachlan, Chairul A. Nidom, and Loeki Enggar Fitri. "Induction of Plasmodium falciparum strain 2300 dormant forms by artemisinin." Universa Medicina 34, no. 1 (February 26, 2016): 25. http://dx.doi.org/10.18051/univmed.2015.v34.25-34.
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BACKGROUND The presence of Plasmodium falciparum resistance and decreased efficacy of artemisinin and its derivatives has resulted in the issue of malaria becoming increasingly complex, because there have been no new drugs as artemisinin replacements. The aims of this research were to evaluate in vitro changes in ultrastructural morphology of P. falciparum 2300 strain after exposure to artemisinin. METHODS The research used an experimental design with post test only control group. Cultures of P. falciparum 2300 strain in one control and one mutant group were treated by exposure to artemisinin at IC50 10-7 M for 48 hours. Ultrastructural phenotypic examination of ring, trophozoite and schizont morphology and developmental stage in the control and mutant group were done at 0, 12, 24, 36, 48 hours by making thin blood smears stained with 20% Giemsa for 20 minutes and examined using a microscope light at 1000x magnification. RESULTS Dormant forms occurred after 48 hours of incubation with IC50 10-7 M artemisinin in the control group. In the mutant group, dormant forms, trophozoites with blue cytoplasm and normal schizont developmental stages were seen. Ultrastructural phenotypic morphology at 0, 12, 24, 36, 48 hours showed that in the control group dormant formation already occurred with exposure to IC50 10-7 M, while in the mutant group dormant formation occurred only with exposure to IC50 2.5x10-5 M. CONCLUSION Exposure to artemisinin antimalarials in vitro can cause phenotypic morphological changes of dormancy in P. falciparum Papua 2300 strain.
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Grobler, Lizette, Marina Chavchich, Richard K. Haynes, Michael D. Edstein, and Anne F. Grobler. "Assessment of the Induction of Dormant Ring Stages in Plasmodium falciparum Parasites by Artemisone and Artemisone Entrapped in Pheroid VesiclesIn Vitro." Antimicrobial Agents and Chemotherapy 58, no. 12 (October 6, 2014): 7579–82. http://dx.doi.org/10.1128/aac.02707-14.
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ABSTRACTThein vitroantimalarial activities of artemisone and artemisone entrapped in Pheroid vesicles were compared, as was their ability to induce dormancy inPlasmodium falciparum. There was no increase in the activity of artemisone entrapped in Pheroid vesicles against multidrug-resistantP. falciparumlines. Artemisone induced the formation of dormant ring stages similar to dihydroartemisinin. Thus, the Pheroid delivery system neither improved the activity of artemisone nor prevented the induction of dormant rings.
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Dembélé, Laurent, Jean-François Franetich, Valérie Soulard, Nadia Amanzougaghene, Shahin Tajeri, Teun Bousema, Geert-Jan van Gemert, et al. "Chloroquine Potentiates Primaquine Activity against Active and Latent Hepatic Plasmodia Ex Vivo: Potentials and Pitfalls." Antimicrobial Agents and Chemotherapy 65, no. 1 (October 19, 2020): e01416-20. http://dx.doi.org/10.1128/aac.01416-20.
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ABSTRACTFor a long while, 8-aminoquinoline compounds have been the only therapeutic agents against latent hepatic malaria parasites. These have poor activity against the blood-stage plasmodia causing acute malaria and must be used in conjunction with partner blood schizontocidal agents. We examined the impacts of one such agent, chloroquine, upon the activity of primaquine, an 8-aminoquinoline, against hepatic stages of Plasmodium cynomolgi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium falciparum within several ex vivo systems—primary hepatocytes of Macaca fascicularis, primary human hepatocytes, and stably transformed human hepatocarcinoma cell line HepG2. Primaquine exposures to formed hepatic schizonts and hypnozoites of P. cynomolgi in primary simian hepatocytes exhibited similar 50% inhibitory concentration (IC50) values near 0.4 μM, whereas chloroquine in the same system exhibited no inhibitory activities. Combining chloroquine and primaquine in this system decreased the observed primaquine IC50 for all parasite forms in a chloroquine dose-dependent manner by an average of 18-fold. Chloroquine also decreased the primaquine IC50 against hepatic P. falciparum in primary human hepatocytes, P. berghei in simian primary hepatocytes, and P. yoelii in primary human hepatocytes. Chloroquine had no impact on primaquine IC50 against P. yoelii in HepG2 cells and, likewise, had no impact on the IC50 of atovaquone (hepatic schizontocide) against P. falciparum in human hepatocytes. We describe important sources of variability in the potentiation of primaquine activity by chloroquine in these systems. Chloroquine potentiated primaquine activity against hepatic forms of several plasmodia. We conclude that chloroquine specifically potentiated 8-aminoquinoline activities against active and dormant hepatic-stage plasmodia in normal primary hepatocytes but not in a hepatocarcinoma cell line.
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Chen, Nanhua, Alexis N. LaCrue, Franka Teuscher, Norman C. Waters, Michelle L. Gatton, Dennis E. Kyle, and Qin Cheng. "Fatty Acid Synthesis and Pyruvate Metabolism Pathways Remain Active in Dihydroartemisinin-Induced Dormant Ring Stages of Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 58, no. 8 (June 9, 2014): 4773–81. http://dx.doi.org/10.1128/aac.02647-14.
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ABSTRACTArtemisinin (ART)-based combination therapy (ACT) is used as the first-line treatment of uncomplicated falciparum malaria worldwide. However, despite high potency and rapid action, there is a high rate of recrudescence associated with ART monotherapy or ACT long before the recent emergence of ART resistance. ART-induced ring-stage dormancy and recovery have been implicated as possible causes of recrudescence; however, little is known about the characteristics of dormant parasites, including whether dormant parasites are metabolically active. We investigated the transcription of 12 genes encoding key enzymes in various metabolic pathways inP. falciparumduring dihydroartemisinin (DHA)-induced dormancy and recovery. Transcription analysis showed an immediate downregulation for 10 genes following exposure to DHA but continued transcription of 2 genes encoding apicoplast and mitochondrial proteins. Transcription of several additional genes encoding apicoplast and mitochondrial proteins, particularly of genes encoding enzymes in pyruvate metabolism and fatty acid synthesis pathways, was also maintained. Additions of inhibitors for biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase of the fatty acid synthesis pathways delayed the recovery of dormant parasites by 6 and 4 days, respectively, following DHA treatment. Our results demonstrate that most metabolic pathways are downregulated in DHA-induced dormant parasites. In contrast, fatty acid and pyruvate metabolic pathways remain active. These findings highlight new targets to interrupt recovery of parasites from ART-induced dormancy and to reduce the rate of recrudescence following ART treatment.
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Chavchich, Marina, Karin Van Breda, Kerryn Rowcliffe, Thierry T. Diagana, and Michael D. Edstein. "The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites." Antimicrobial Agents and Chemotherapy 60, no. 9 (June 13, 2016): 5167–74. http://dx.doi.org/10.1128/aac.02838-15.
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ABSTRACTIn vitrodrug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage inPlasmodium falciparum. This response has been proposed to play a role in the recrudescence ofP. falciparuminfections following monotherapy with artesunate and may contribute to the development of artemisinin resistance inP. falciparummalaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest ofP. falciparumparasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage ofP. falciparumand prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistantP. falciparummalaria.
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Cheng, Qin, Dennis E. Kyle, and Michelle L. Gatton. "Artemisinin resistance in Plasmodium falciparum: A process linked to dormancy?" International Journal for Parasitology: Drugs and Drug Resistance 2 (December 2012): 249–55. http://dx.doi.org/10.1016/j.ijpddr.2012.01.001.
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Teuscher, Franka, Nanhua Chen, Dennis E. Kyle, Michelle L. Gatton, and Qin Cheng. "Phenotypic Changes in Artemisinin-Resistant Plasmodium falciparum LinesIn Vitro: Evidence for Decreased Sensitivity to Dormancy and Growth Inhibition." Antimicrobial Agents and Chemotherapy 56, no. 1 (October 10, 2011): 428–31. http://dx.doi.org/10.1128/aac.05456-11.
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ABSTRACTThe appearance ofPlasmodium falciparumparasites with decreasedin vivosensitivity but no measurablein vitroresistance to artemisinin has raised the urgent need to characterize the artemisinin resistance phenotype. Changes in the temporary growth arrest (dormancy) profile of parasites may be one aspect of this phenotype. In this study, we investigated the link between dormancy and resistance, using artelinic acid (AL)-resistant parasites. Our results demonstrate that the AL resistance phenotype has (i) decreased sensitivity of mature-stage parasites, (ii) decreased sensitivity of the ring stage to the induction of dormancy, and (iii) a faster recovery from dormancy.
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Bouyer, Guillaume, Anne Cueff, Stéphane Egée, Justyna Kmiecik, Yelena Maksimova, Edyta Glogowska, Patrick G. Gallagher, and Serge L. Y. Thomas. "Erythrocyte peripheral type benzodiazepine receptor/voltage-dependent anion channels are upregulated by Plasmodium falciparum." Blood 118, no. 8 (August 25, 2011): 2305–12. http://dx.doi.org/10.1182/blood-2011-01-329300.
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Abstract Plasmodium falciparum relies on anion channels activated in the erythrocyte membrane to ensure the transport of nutrients and waste products necessary for its replication and survival after invasion. The molecular identity of these anion channels, termed “new permeability pathways” is unknown, but their currents correspond to up-regulation of endogenous channels displaying complex gating and kinetics similar to those of ligand-gated channels. This report demonstrates that a peripheral-type benzodiazepine receptor, including the voltage dependent anion channel, is present in the human erythrocyte membrane. This receptor mediates the maxi-anion currents previously described in the erythrocyte membrane. Ligands that block this peripheral-type benzodiazepine receptor reduce membrane transport and conductance in P falciparum-infected erythrocytes. These ligands also inhibit in vitro intraerythrocytic growth of P falciparum. These data support the hypothesis that dormant peripheral-type benzodiazepine receptors become the “new permeability pathways” in infected erythrocytes after up-regulation by P falciparum. These channels are obvious targets for selective inhibition in anti-malarial therapies, as well as potential routes for drug delivery in pharmacologic applications.
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Polenzani, Ilaria, Lucrezia Lisco, Mariarosaria Cozzolino, Stefania Casolari, Stefania Valenti, Simone Fontijn, Andrea Uva, Andrea Uva, and Federico Marchetti. "Quando la malaria tarda a farsi riconoscere: un’infezione da Plasmodium ovale." Medico e Bambino 41, no. 6 (June 28, 2022): 381–85. http://dx.doi.org/10.53126/meb41381.
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Plasmodium ovale is a cause of non-falciparum malaria infection that is endemic in tropical Western Africa. The life cycle of Plasmodium ovale includes hypnozoites, which are dormant stages in the liver. These stages can be reactivated after weeks, months, or years from the initial infection, causing disease relapse. This paper reports the case of a female adolescent who presented with high fever and abdominal pain. The girl was referring to a single travel to Nigeria 4 years ago. On that occasion she showed short-term gastrointestinal symptoms, without fever. The blood test revealed thrombocytopenia (76,000/µl) and she was unexpectedly diagnosed with ma-laria through blood smear. Considering the geographical area of her previous travel, a parasitemia by Plasmodium ovale was suspected. The diagnosis was soon confirmed by the positivity of the PCR. The literature describes some cases of recrudescence of the infection from the first episode. The diagnosis of Plasmodium ovale malaria can be challenging because of its possible delayed presentation.
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Druilhe, Pierre, Philippe Brasseur, Catherine Blanc, and Michael Makler. "Improved Assessment of Plasmodium vivax Response to Antimalarial Drugs by a Colorimetric Double-Site Plasmodium Lactate Dehydrogenase Antigen Capture Enzyme-Linked Immunosorbent Assay." Antimicrobial Agents and Chemotherapy 51, no. 6 (March 26, 2007): 2112–16. http://dx.doi.org/10.1128/aac.01385-06.
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ABSTRACT The occurrence of Plasmodium vivax resistance to chloroquine has been reported in several countries of Asia and South America. However, the resistance of P. vivax is insufficiently documented for three reasons: it has received far less attention than P. falciparum; in vivo investigations are handicapped by the existence of hypnozoites, which make it difficult to distinguish between recrudescences due to drug failure and relapses due to dormant forms in the liver; and in vitro studies are greatly limited by the poor growth of P. vivax. We report on the adaptation to P. vivax of a colorimetric double-site Plasmodium lactate dehydrogenase antigen capture enzyme-linked immunosorbent assay previously developed for P. falciparum. The assay proved remarkably sensitive, as under optimal conditions it could detect P. vivax parasitemia levels as low as 10−8. The technique, which relies on the detection of protein synthesis by the parasite, yielded steep drug-response curves, leading to the precise determination of the 50% inhibitory concentrations for a high proportion of isolates. Chloroquine-resistant parasites were identified in an area where this phenomenon had been documented by in vivo methods. Thus, the results indicate that the in vitro susceptibility of P. vivax can now be monitored easily and efficiently. The data suggest that the threshold of resistance is similar to that of P. falciparum, i.e., in the range of 100 nM for chloroquine and 15 nM for pyronaridine. However, further studies are required to precisely define the cutoff for resistance and the sensitivity to each drug.
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Ursing, Johan, Rasmus Johns, Berit Aydin-Schmidt, Carla Calçada, Poul-Erik Kofoed, Najia Karim Ghanchi, Maria Isabel Veiga, and Lars Rombo. "Chloroquine-susceptible and -resistant Plasmodium falciparum strains survive high chloroquine concentrations by becoming dormant but are eliminated by prolonged exposure." Journal of Antimicrobial Chemotherapy 77, no. 4 (February 8, 2022): 1005–11. http://dx.doi.org/10.1093/jac/dkac008.
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Abstract Background Plasmodium falciparum strains that are resistant to standard-dose chloroquine can be treated by higher chloroquine concentrations maintained for a longer time in vivo. Objectives To determine the relative importance of chloroquine concentrations versus exposure time for elimination of chloroquine-susceptible and -resistant P. falciparum in vitro. Methods Chloroquine-susceptible (3D7) and -resistant (FCR3) strains were exposed in vitro to 1, 2, 4, 8, 16 or 32 times their respective 90% inhibitory chloroquine concentrations for 3, 5, 7 or 14 days and then followed until recrudescence, or not, by 42 days after the end of exposure. Results Exposure to chloroquine appeared to eliminate susceptible and resistant parasites, leaving small pyknotic apparently dead parasites. Chloroquine-susceptible and -resistant parasites recrudesced after 3 and 5 days of chloroquine exposure. Recrudescence occurred in one out of four 7 day exposure series but not after 14 days exposure. The median time to recrudescence was 13 to 28 days with a range of 8 to 41 days after the end of exposure. Time to recrudescence after the end of exposure increased with duration of exposure for susceptible and resistant strains (P < 0.001). Time to recrudescence did not correlate with concentrations greater than 1× IC90. Conclusions Chloroquine-susceptible and -resistant P. falciparum probably become dormant. Elimination of dormant parasites is primarily dependent upon the duration of chloroquine exposure. Exposure to effective drug concentrations for 7 days eliminates most parasites in vitro. The results support in vivo data indicating that elimination of chloroquine-resistant P. falciparum correlates with Day 7 chloroquine concentrations.
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Gray, Karen-Ann, Karryn J. Gresty, Nanhua Chen, Veronica Zhang, Clare E. Gutteridge, Christopher L. Peatey, Marina Chavchich, Norman C. Waters, and Qin Cheng. "Correlation between Cyclin Dependent Kinases and Artemisinin-Induced Dormancy in Plasmodium falciparum In Vitro." PLOS ONE 11, no. 6 (June 21, 2016): e0157906. http://dx.doi.org/10.1371/journal.pone.0157906.
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Ndegwa, Duncan N., Prasun Kundu, Jessica B. Hostetler, Alejandro Marin-Menendez, Theo Sanderson, Kioko Mwikali, Lisa H. Verzier, Rachael Coyle, Sophie Adjalley, and Julian C. Rayner. "Using Plasmodium knowlesi as a model for screening Plasmodium vivax blood-stage malaria vaccine targets reveals new candidates." PLOS Pathogens 17, no. 7 (July 1, 2021): e1008864. http://dx.doi.org/10.1371/journal.ppat.1008864.
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Plasmodium vivax is responsible for the majority of malaria cases outside Africa. Unlike P. falciparum, the P. vivax life-cycle includes a dormant liver stage, the hypnozoite, which can cause infection in the absence of mosquito transmission. An effective vaccine against P. vivax blood stages would limit symptoms and pathology from such recurrent infections, and therefore could play a critical role in the control of this species. Vaccine development in P. vivax, however, lags considerably behind P. falciparum, which has many identified targets with several having transitioned to Phase II testing. By contrast only one P. vivax blood-stage vaccine candidate based on the Duffy Binding Protein (PvDBP), has reached Phase Ia, in large part because the lack of a continuous in vitro culture system for P. vivax limits systematic screening of new candidates. We used the close phylogenetic relationship between P. vivax and P. knowlesi, for which an in vitro culture system in human erythrocytes exists, to test the scalability of systematic reverse vaccinology to identify and prioritise P. vivax blood-stage targets. A panel of P. vivax proteins predicted to function in erythrocyte invasion were expressed as full-length recombinant ectodomains in a mammalian expression system. Eight of these antigens were used to generate polyclonal antibodies, which were screened for their ability to recognize orthologous proteins in P. knowlesi. These antibodies were then tested for inhibition of growth and invasion of both wild type P. knowlesi and chimeric P. knowlesi lines modified using CRISPR/Cas9 to exchange P. knowlesi genes with their P. vivax orthologues. Candidates that induced antibodies that inhibited invasion to a similar level as PvDBP were identified, confirming the utility of P. knowlesi as a model for P. vivax vaccine development and prioritizing antigens for further follow up.
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Tucker, Matthew S., Tina Mutka, Kansas Sparks, Janus Patel, and Dennis E. Kyle. "Phenotypic and Genotypic Analysis ofIn Vitro-Selected Artemisinin-Resistant Progeny of Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 56, no. 1 (November 14, 2011): 302–14. http://dx.doi.org/10.1128/aac.05540-11.
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ABSTRACTEmergence of artemisinin resistance in Cambodia highlights the importance of characterizing resistance to this class of drugs. Previously, intermediate levels of resistance inPlasmodium falciparumwere generatedin vitrofor artelinic acid (AL) and artemisinin (QHS). Here we expanded on earlier selection efforts to produce levels of clinically relevant concentrations, and the resulting lines were characterized genotypically and phenotypically. Recrudescence assays determined the ability of resistant and parent lines to recover following exposure to clinically relevant levels of drugs. Interestingly, the parent clone (D6) tolerated up to 1,500 ng/ml QHS, but the resistant parasite, D6.QHS340×3, recovered following exposure to 2,400 ng/ml QHS. Resistant D6, W2, and TM91c235 parasites all exhibited elevated 50% inhibitory concentrations (IC50s) to multiple artemisinin drugs, with >3-fold resistance to QHS and AL; however, the degree of resistance obtained with standard methods was remarkably less than expected for parasite lines that recovered from 2,400-ng/ml drug pressure. A novel assay format with radiolabeled hypoxanthine demonstrated a greater degree of resistancein vitrothan the standard SYBR green method. Analysis of merozoite number in resistant parasites found D6 and TM91c235 resistant progeny had significantly fewer merozoites than parent strains, whereas W2 resistant progeny had significantly more. Amplification ofpfmdr1increased proportionately to the increased drug levels tolerated by W2 and TM91c235, but not in resistant D6. In summary, we define the artemisinin resistance phenotype as a decrease in susceptibility to artemisinins along with the ability to recover from drug-induced dormancy following supraclinical concentrations of the drug.
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Anwar, Md Nurul, Lauren Smith, Angela Devine, Somya Mehra, Camelia R. Walker, Elizabeth Ivory, Eamon Conway, et al. "Mathematical models of Plasmodium vivax transmission: A scoping review." PLOS Computational Biology 20, no. 3 (March 14, 2024): e1011931. http://dx.doi.org/10.1371/journal.pcbi.1011931.
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Plasmodium vivax is one of the most geographically widespread malaria parasites in the world, primarily found across South-East Asia, Latin America, and parts of Africa. One of the significant characteristics of the P. vivax parasite is its ability to remain dormant in the human liver as hypnozoites and subsequently reactivate after the initial infection (i.e. relapse infections). Mathematical modelling approaches have been widely applied to understand P. vivax dynamics and predict the impact of intervention outcomes. Models that capture P. vivax dynamics differ from those that capture P. falciparum dynamics, as they must account for relapses caused by the activation of hypnozoites. In this article, we provide a scoping review of mathematical models that capture P. vivax transmission dynamics published between January 1988 and May 2023. The primary objective of this work is to provide a comprehensive summary of the mathematical models and techniques used to model P. vivax dynamics. In doing so, we aim to assist researchers working on mathematical epidemiology, disease transmission, and other aspects of P. vivax malaria by highlighting best practices in currently published models and highlighting where further model development is required. We categorise P. vivax models according to whether a deterministic or agent-based approach was used. We provide an overview of the different strategies used to incorporate the parasite’s biology, use of multiple scales (within-host and population-level), superinfection, immunity, and treatment interventions. In most of the published literature, the rationale for different modelling approaches was driven by the research question at hand. Some models focus on the parasites’ complicated biology, while others incorporate simplified assumptions to avoid model complexity. Overall, the existing literature on mathematical models for P. vivax encompasses various aspects of the parasite’s dynamics. We recommend that future research should focus on refining how key aspects of P. vivax dynamics are modelled, including spatial heterogeneity in exposure risk and heterogeneity in susceptibility to infection, the accumulation of hypnozoite variation, the interaction between P. falciparum and P. vivax, acquisition of immunity, and recovery under superinfection.
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PONGSUMPUN, PUNTANI, and I.-MING TANG. "IMPACT OF CROSS-BORDER MIGRATION ON DISEASE EPIDEMICS: CASE OF THE P. FALCIPARUM AND P. VIVAX MALARIA EPIDEMIC ALONG THE THAI-MYANMAR BORDER." Journal of Biological Systems 18, no. 01 (March 2010): 55–73. http://dx.doi.org/10.1142/s0218339010003147.
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The transmission of Plasmodium falciparum and Plasmodium vivax malaria in a mixed population of Thais and migrant Burmese living along the Thai-Myanmar border is studied through a mathematical model. The population is separated into two groups: Thai and Burmese. Each population in turn is divided into susceptible, infected, recovered and in case of vivax infection, a dormant subclass. The model is then modified to allow for some of the Burmese (given as a fraction P) to be infectious when they enter into Thailand. The behaviour of the modified model is obtained using a standard dynamical analysis. A new basic reproduction number is obtained. Numerical simulations of the modified model show that when P ≠ 0 and the same set of parameter values used in the initial model are used, the Thai population will be in the epidemic state. In other words, the repeated introduction of infectious Burmese (no matter how small of a number) will result in a malaria epidemic among the Thais irregardless of the public health practice undertaken by the Thai government. In the presence of the infected Burmese, the Thai government would have to increase the facilitites to treat the people who are infected by the malaria.
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HOSHEN, M. B., K. NA-BANGCHANG, W. D. STEIN, and H. GINSBURG. "Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of ‘dormancy’, a partial cytostatic effect of the drug, and its implication for treatment regimens." Parasitology 121, no. 3 (September 2000): 237–46. http://dx.doi.org/10.1017/s0031182099006332.
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Although artesunate, one of the potent derivatives of the qinghaosu family of drugs for treating falciparum malaria, is already in use in the field, its therapeutic protocol has only been developed empirically by hit-or-miss. A pharmacokinetic–pharmacodynamic (PK–PD) model, required for creating such a protocol, is not straightforward. Artesunate presents extremely fast pharmacokinetics. As a result the stage specificity of its action must be treated explicitly. Also, use of standard PK–PD modelling fails to explain the clinical results. Our PK–PD modelling of its activity leads us to the postulation of the existence of a novel effect: a small fraction of the parasites, as a result of chemotherapeutic pressure, become cytostatic, or ‘dormant’. At this stage, the parasite cycle is halted, making them unsusceptible to further dosing until wakening. This slows down the antimalarial activity of the drug, entailing either many frequent doses or an extended period of treatment and surveillance. Based on our modelling, we suggest a method for deciding on rational models of chemotherapy against falciparum malaria.
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Lefterova, Martina I., Indre Budvytiene, Johanna Sandlund, Anna Färnert, and Niaz Banaei. "Simple Real-Time PCR and Amplicon Sequencing Method for Identification of Plasmodium Species in Human Whole Blood." Journal of Clinical Microbiology 53, no. 7 (May 13, 2015): 2251–57. http://dx.doi.org/10.1128/jcm.00542-15.
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Malaria is the leading identifiable cause of fever in returning travelers. AccuratePlasmodiumspecies identification has therapy implications forP. vivaxandP. ovale, which have dormant liver stages requiring primaquine. Compared to microscopy, nucleic acid tests have improved specificity for species identification and higher sensitivity for mixed infections. Here, we describe a SYBR green-based real-time PCR assay forPlasmodiumspecies identification from whole blood, which uses a panel of reactions to detect species-specific non-18S rRNA gene targets. A pan-Plasmodium18S rRNA target is also amplified to allow species identification or confirmation by sequencing if necessary. An evaluation of assay accuracy, performed on 76 clinical samples (56 positives using thin smear microscopy as the reference method and 20 negatives), demonstrated clinical sensitivities of 95.2% forP. falciparum(20/21 positives detected) and 100% for thePlasmodiumgenus (52/52),P. vivax(20/20),P. ovale(9/9), andP. malariae(6/6). The sensitivity of theP. knowlesi-specific PCR was evaluated using spiked whole blood samples (100% [10/10 detected]). The specificities of the real-time PCR primers were 94.2% forP. vivax(49/52) and 100% forP. falciparum(51/51),P. ovale(62/62),P. malariae(69/69), andP. knowlesi(52/52). Thirty-three specimens were used to test species identification by sequencing the pan-Plasmodium18S rRNA PCR product, with correct identification in all cases. The real-time PCR assay also identified two samples with mixedP. falciparumandP. ovaleinfection, which was confirmed by sequencing. The assay described here can be integrated into a malaria testing algorithm in low-prevalence areas, allowing definitivePlasmodiumspecies identification shortly after malaria diagnosis by microscopy.
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Thapar, Mita M., Jose P. Gil, and Anders Björkman. "In vitro recrudescence of Plasmodium falciparum parasites suppressed to dormant state by atovaquone alone and in combination with proguanil." Transactions of the Royal Society of Tropical Medicine and Hygiene 99, no. 1 (January 2005): 62–70. http://dx.doi.org/10.1016/j.trstmh.2004.01.016.
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Duvalsaint, Marvin, and Dennis E. Kyle. "Phytohormones, Isoprenoids, and Role of the Apicoplast in Recovery from Dihydroartemisinin-Induced Dormancy of Plasmodium falciparum." Antimicrobial Agents and Chemotherapy 62, no. 3 (January 8, 2018). http://dx.doi.org/10.1128/aac.01771-17.
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ABSTRACT Many organisms undergo dormancy as a stress response to survive under unfavorable conditions that might impede development. This is observed in seeds and buds of plants and has been proposed as a mechanism of drug evasion and resistance formation in Plasmodium falciparum . We explored the effects of the phytohormones abscisic acid (ABA) and gibberellic acid (GA) on dihydroartemisinin (DHA)-induced dormant erythrocytic stages of P. falciparum parasites. Dormant ring stages exposed to ABA and GA recovered from dormancy up to 48 h earlier than parasites exposed to DHA alone. Conversely, fluridone, an herbicide inhibitor of ABA synthesis, blocked emergence from dormancy. Additionally, the role of the apicoplast was assessed in dormant parasite recovery. Apicoplast-deficient P. falciparum remained viable for up to 8 days without the organelle and recrudesced only when supplemented with isopentyl pyrophosphate (IPP). IPP was not required for survival in the dormant state. Fosmidomycin inhibition of isoprenoid biosynthesis did not prevent dormancy release from occurring in parasites with an intact apicoplast, but IPP or geranylgeranyl pyrophosphate was needed for complete recrudescence. In addition, the apicoplast and specifically the isoprenoids it produces are essential for recovery of dormant parasites. In summary, ABA and GA have significant effects on dormant parasites, and the phenotypes produced by these phytohormones and the herbicide fluridone also provide a means to explore the mechanism(s) underlying dormancy and the regulatory network that promotes cell cycle arrest in P. falciparum .
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Peatey, Christopher, Nanhua Chen, Karryn Gresty, Karen Anderson, Paul Pickering, Rebecca Watts, Michelle L. Gatton, James McCarthy, and Qin Cheng. "Dormant Plasmodium falciparum Parasites in Human Infections Following Artesunate Therapy." Journal of Infectious Diseases, September 9, 2020. http://dx.doi.org/10.1093/infdis/jiaa562.
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Abstract Background Artemisinin monotherapy of Plasmodium falciparum infection is frequently ineffective due to recrudescence. Artemisinin-induced dormancy, shown in vitro and in animal models, provides a plausible explanation. To date, direct evidence of artemisinin-induced dormancy in humans is lacking. Methods Blood samples were collected from Plasmodium falciparum 3D7- or K13-infected participants before and 48–72 hours after single-dose artesunate (AS) treatment. Parasite morphology, molecular signature of dormancy, capability and dynamics of seeding in vitro cultures, and genetic mutations in the K13 gene were investigated. Results Dormant parasites were observed in post-AS blood samples of 3D7- and K13-infected participants. The molecular signature of dormancy, an up-regulation of acetyl CoA carboxylase, was detected in 3D7 and K13 samples post-AS, but not in pre-AS samples. Posttreatment samples successfully seeded in vitro cultures, with a significant delay in time to reach 2% parasitemia compared to pretreatment samples. Conclusions This study provides strong evidence for the presence of artemisinin-induced dormant parasites in P. falciparum infections. These parasites are a likely reservoir for recrudescent infection following artemisinin monotherapy and artemisinin combination therapy (ACT). Combination regimens that target dormant parasites or remain at therapeutic levels for a sufficient time to kill recovering parasites will likely improve efficacy of ACTs.
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Breglio, Kimberly F., Rifat S. Rahman, Juliana M. SÃ, Amanda Hott, David J. Roberts, and Thomas E. Wellems. "Kelch Mutations in Plasmodium falciparum Protein K13 Do Not Modulate Dormancy after Artemisinin Exposure and Sorbitol Selection In Vitro." Antimicrobial Agents and Chemotherapy 62, no. 5 (February 20, 2018). http://dx.doi.org/10.1128/aac.02256-17.
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ABSTRACT Some Kelch mutations of the Plasmodium falciparum K13 protein confer increased survival to dihydroartemisinin (DHA)-treated ring-stage parasites. Here, we asked if K13 mutations affect a dormancy phenotype allowing parasites to survive DHA exposure and then sorbitol selection. Although recrudescence from dormancy differed between two distinct parasite lines, it was similar for isogenic lines carrying single-site substitutions in K13. Therefore, K13 mutations do not alter the DHA-sorbitol combined dormancy phenotype; rather, traits from other loci likely determine this phenotype.
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Dembele, Laurent, Devendra Kumar Gupta, Michelle Yi-Xiu Lim, Xiaoman Ang, Jeremy J. Selva, Kesinee Chotivanich, Chea Nguon, et al. "Imidazolopiperazines Kill both Rings and Dormant Rings in Wild-Type and K13 Artemisinin-Resistant Plasmodium falciparum In Vitro." Antimicrobial Agents and Chemotherapy 62, no. 5 (March 12, 2018). http://dx.doi.org/10.1128/aac.02235-17.
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ABSTRACT Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART resistance has been associated with mutations in the Plasmodium falciparum kelch-13 ( Pfk13 ) propeller domain. Phenotypically, ART resistance is defined as delayed parasite clearance in patients due to the reduced susceptibility of early ring-stage parasites to the active metabolite of ART dihydroartemisinin (DHA). Early rings can enter a state of quiescence upon DHA exposure and resume growth in its absence. These quiescent rings are referred to as dormant rings or DHA-pretreated rings (here called dormant rings). The imidazolopiperazines (IPZ) are a novel class of antimalarial drugs that have demonstrated efficacy in early clinical trials. Here, we characterized the stage of action of the IPZ GNF179 and evaluated its activity against rings and dormant rings in wild-type and ART-resistant parasites. Unlike DHA, GNF179 does not induce dormancy. We show that GNF179 is more rapidly cidal against schizonts than against ring and trophozoite stages. However, with 12 h of exposure, the compound effectively kills rings and dormant rings of both susceptible and ART-resistant parasites within 72 h. We further demonstrate that in combination with ART, GNF179 effectively prevents recrudescence of dormant rings, including those bearing pfk13 propeller mutations.
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Malvy, Denis, Marylin Torrentino-Madamet, Coralie L'Ollivier, Marie-Catherine Receveur, Fakhri Jeddi, Laurence Delhaes, Renaud Piarroux, Pascal Millet, and Bruno Pradines. "Plasmodium falciparum Recrudescence Two Years after Treatment of an Uncomplicated Infection without Return to an Area Where Malaria Is Endemic." Antimicrobial Agents and Chemotherapy 62, no. 2 (December 11, 2017). http://dx.doi.org/10.1128/aac.01892-17.
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ABSTRACT We report evidence, confirmed by the lack of travel activity outside of France and genetic diversity analysis using polymorphic microsatellite markers, that Plasmodium falciparum malaria infection effectively treated with an artemisinin-based combination can remain dormant and relapse during pregnancy at least 2 years after treatment.
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Connelly, Sean V., Javier Manzella-Lapeira, Zoë C. Levine, Joseph Brzostowski, Ludmila Krymskaya, Rifat S. Rahman, Angela C. Ellis, Shuchi N. Amin, Juliana M. Sá, and Thomas E. Wellems. "Restructured Mitochondrial-Nuclear Interaction in Plasmodium falciparum Dormancy and Persister Survival after Artemisinin Exposure." mBio, May 28, 2021. http://dx.doi.org/10.1128/mbio.00753-21.
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The major first-line treatment for malaria, especially the deadliest form caused by Plasmodium falciparum , is combination therapy with an artemisinin-based drug (ART) plus a partner drug to assure complete cure. Without an effective partner drug, ART administration alone can fail because of the ability of small populations of blood-stage malaria parasites to enter into a dormant state and survive repeated treatments for a week or more.
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Habtewold, Tibebu, Aayushi A. Sharma, Claudia A. S. Wyer, Ellen K. G. Masters, Nikolai Windbichler, and George K. Christophides. "Plasmodium oocysts respond with dormancy to crowding and nutritional stress." Scientific Reports 11, no. 1 (February 4, 2021). http://dx.doi.org/10.1038/s41598-021-81574-0.
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AbstractMalaria parasites develop as oocysts in the mosquito for several days before they are able to infect a human host. During this time, mosquitoes take bloodmeals to replenish their nutrient and energy reserves needed for flight and reproduction. We hypothesized that these bloodmeals are critical for oocyst growth and that experimental infection protocols, typically involving a single bloodmeal at the time of infection, cause nutritional stress to the developing oocysts. Therefore, enumerating oocysts disregarding their growth and differentiation state may lead to erroneous conclusions about the efficacy of transmission blocking interventions. Here, we examine this hypothesis in Anopheles coluzzii mosquitoes infected with the human and rodent parasites Plasmodium falciparum and Plasmodium berghei, respectively. We show that oocyst growth and maturation rates decrease at late developmental stages as infection intensities increase; an effect exacerbated at very high infection intensities but fully restored with post infection bloodmeals. High infection intensities and starvation conditions reduce RNA Polymerase III activity in oocysts unless supplemental bloodmeals are provided. Our results suggest that oocysts respond to crowding and nutritional stress with a dormancy-like strategy, which urges the development of alternative methods to assess the efficacy of transmission blocking interventions.
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NORTEY-MENSAH, RICHARD, MARIAN A. TEYE, and MICHAEL F. OFORI. "The carotenoid biosynthesis pathway in the asexual intraerythrocytic stages of Plasmodium falciparum." Asian Journal of Tropical Biotechnology 18, no. 1 (July 11, 2021). http://dx.doi.org/10.13057/biotek/c180102.
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Abstract. Nortey-Mensah R, Teye MA, Ofori MF. 2021. The carotenoid biosynthesis pathway in the asexual intraerythrocytic stages of Plasmodium falciparum. Asian J Trop Biotechnol 18: 13-27. Plasmodium falciparum, like other Apicomplexans, possesses a dormant plastid called the apicoplast. Because it houses metabolic pathways peculiar to the parasite, such as isoprenoid production, this organelle promises a new and promising target for the chemotherapeutic control of malaria. Although the phytoene synthase (PSY) gene has been shown to be critical for carotenogenesis, nothing is known about its evolutionary relationship with P. falciparum and other Apicomplexans. The goal of this work was to identify the evolutionary history and relatedness of the PSY gene in Apicomplexans and other animals, as well as to profile the carotenoids generated in the asexual intraerythrocytic stages of P. falciparum. Fluridone's IC50 and effect on parasite population were determined utilizing in vitro inhibition experiments on the asexual intraerythrocytic stages of P. falciparum. To examine the evolutionary history and relatedness of the PSY gene in Apicomplexans and other taxa, HPLC was used to profile carotenoids created at the asexual phases, and an unrooted phylogenetic tree was built using MEGA 6. Dose-dependent inhibition of parasite population was observed with fluridone treatment on all the asexual stages, with the ring stages being the most vulnerable. The carotenoid profiles revealed that carotenoids are generated cumulatively in P. falciparum throughout the asexual intraerythrocytic phases, with carotenoids such as lycopene, ?-, ?-carotene among those synthesized. The discovery of relatively high quantities of abscisic acid (ABA) in the schizont stages but not in the other stages was an interesting novel finding of this study. This is the first time ABA has been shown to be synthesized by P. falciparum, and additional research into the specific role of ABA in P. falciparum schizont phases would be groundbreaking. The phylogenetic study revealed that the P. falciparum PSY was most closely related to P. reichenowi, a chimpanzee strain of the malaria-causing parasites, supporting the hypothesis that malaria species in humans originated in chimps.
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McLean, Kyle Jarrod, and Marcelo Jacobs-Lorena. "Plasmodium falciparum Maf1 Confers Survival upon Amino Acid Starvation." mBio 8, no. 2 (March 28, 2017). http://dx.doi.org/10.1128/mbio.02317-16.
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ABSTRACT The target of rapamycin complex 1 (TORC1) pathway is a highly conserved signaling pathway across eukaryotes that integrates nutrient and stress signals to regulate the cellular growth rate and the transition into and maintenance of dormancy. The majority of the pathway’s components, including the central TOR kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. Plasmodium falciparum encodes a putative ortholog of the RNA polymerase (Pol) III repressor Maf1, which has been demonstrated to modulate Pol III transcription in a TOR-dependent manner in a number of organisms. Here, we investigate the role of P. falciparum Maf1 (PfMaf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered Maf1 expression profile, we demonstrated that proper Maf1 expression is necessary for survival of the dormancy-like state induced by prolonged amino acid starvation and is needed for full recovery from other stresses that slow or stall the parasite cell cycle. This Maf1 mutant is defective in the downregulation of pre-tRNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stress-responsive regulator of structural RNA transcription is conserved in P. falciparum. Recent work has demonstrated that parasites carrying artemisinin-resistant K13 alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pre-tRNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping, PfMaf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation. IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR pathway is a well-studied signaling pathway found throughout eukaryotes that is known to integrate a variety of signals to regulate organismal growth in response to starvation and other stresses. The human malaria parasite Plasmodium falciparum appears to have lost the TOR pathway over the course of evolution, and it is unclear how the parasite modulates its growth in response to starvation and drug treatment. Here, we show that Maf1, a protein regulated by TOR in other eukaryotes, plays an important role in maintaining the parasite’s viability in the face of starvation and other forms of stress. This suggests that PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway. IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR pathway is a well-studied signaling pathway found throughout eukaryotes that is known to integrate a variety of signals to regulate organismal growth in response to starvation and other stresses. The human malaria parasite Plasmodium falciparum appears to have lost the TOR pathway over the course of evolution, and it is unclear how the parasite modulates its growth in response to starvation and drug treatment. Here, we show that Maf1, a protein regulated by TOR in other eukaryotes, plays an important role in maintaining the parasite’s viability in the face of starvation and other forms of stress. This suggests that PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway.
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Sá, Juliana M., Sarah R. Kaslow, Roberto R. Moraes Barros, Nicholas F. Brazeau, Christian M. Parobek, Dingyin Tao, Rebecca E. Salzman, et al. "Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross." Nature Communications 10, no. 1 (September 20, 2019). http://dx.doi.org/10.1038/s41467-019-12256-9.
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Abstract Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control. Here we investigate the genetics of P. vivax CQR by a cross of parasites differing in drug response. Gametocytogenesis, mosquito infection, and progeny production are performed with mixed parasite populations in nonhuman primates, as methods for P. vivax cloning and in vitro cultivation remain unavailable. Linkage mapping of progeny surviving >15 mg/kg CQ identifies a 76 kb region in chromosome 1 including pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene. Transcriptional analysis supports upregulated pvcrt expression as a mechanism of CQR.
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Aniweh, Yaw, Alamissa Soulama, Jersley Chirawurah, Felix Ansah, Harry A. Danwonno, Fanta Sogore, Melanie Rouillier, et al. "Comparative Susceptibility of Plasmodium ovale and Plasmodium falciparum Field Isolates to Reference and Lead Candidate Antimalarial Drugs in Ghana." Microbiology Spectrum, April 24, 2023. http://dx.doi.org/10.1128/spectrum.04916-22.
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Current malaria control and elimination tools such as drug treatments are not specifically targeting P.ovale . P. ovale can form hypnozoite and cause relapsing malaria. P. ovale is the third most dominant species in Africa and requires radical cure treatment given that it can form liver dormant forms called hypnozoites that escape all safe treatments. The inappropriate treatment of P. ovale would sustain its transmission in Africa where the medical need is the greatest.
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Kumar, Ashwani, Puspendra Pal Singh, Suchi Tyagi, K. Hari Kishan Raju, Sudhanshu S. Sahu, and Manju Rahi. "Vivax malaria: a possible stumbling block for malaria elimination in India." Frontiers in Public Health 11 (January 8, 2024). http://dx.doi.org/10.3389/fpubh.2023.1228217.
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Plasmodium vivax is geographically the most widely dispersed human malaria parasite species. It has shown resilience and a great deal of adaptability. Genomic studies suggest that P. vivax originated from Asia or Africa and moved to the rest of the world. Although P. vivax is evolutionarily an older species than Plasmodium falciparum, its biology, transmission, pathology, and control still require better elucidation. P. vivax poses problems for malaria elimination because of the ability of a single primary infection to produce multiple relapses over months and years. P. vivax malaria elimination program needs early diagnosis, and prompt and complete radical treatment, which is challenging, to simultaneously exterminate the circulating parasites and dormant hypnozoites lodged in the hepatocytes of the host liver. As prompt surveillance and effective treatments are rolled out, preventing primaquine toxicity in the patients having glucose-6-phosphate dehydrogenase (G6PD) deficiency should be a priority for the vivax elimination program. This review sheds light on the burden of P. vivax, changing epidemiological patterns, the hurdles in elimination efforts, and the essential tools needed not just in India but globally. These tools encompass innovative treatments for eliminating dormant parasites, coping with evolving drug resistance, and the development of potential vaccines against the parasite.
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Won, Jeong Yeon, Ernest Mazigo, Seok Ho Cha, and Jin-Hee Han. "Functional characterization of Plasmodium vivax hexose transporter 1." Frontiers in Cellular and Infection Microbiology 13 (January 12, 2024). http://dx.doi.org/10.3389/fcimb.2023.1321240.
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Plasmodium vivax is the most widely distributed human malaria parasite. The eradication of vivax malaria remains challenging due to transmission of drug-resistant parasite and dormant liver form. Consequently, anti-malarial drugs with novel mechanisms of action are urgently demanded. Glucose uptake blocking strategy is suggested as a novel mode of action that leads to selective starvation in various species of malaria parasites. The role of hexose transporter 1 in Plasmodium species is glucose uptake, and its blocking strategies proved to successfully induce selective starvation. However, there is limited information on the glucose uptake properties via P. vivax hexose transporter 1 (PvHT1). Thus, we focused on the PvHT1 to precisely identify its properties of glucose uptake. The PvHT1 North Korean strain (PvHT1NK) expressed Xenopus laevis oocytes mediating the transport of [3H] deoxy-D-glucose (ddGlu) in an expression and incubation time-dependent manner without sodium dependency. Moreover, the PvHT1NK showed no exchange mode of glucose in efflux experiments and concentration-dependent results showed saturable kinetics following the Michaelis-Menten equation. Non-linear regression analysis revealed a Km value of 294.1 μM and a Vmax value of 1,060 pmol/oocyte/hr, and inhibition experiments showed a strong inhibitory effect by glucose, mannose, and ddGlu. Additionally, weak inhibition was observed with fructose and galactose. Comparison of amino acid sequence and tertiary structure between P. falciparum and P. vivax HT1 revealed a completely conserved residue in glucose binding pocket. This result supported that the glucose uptake properties are similar to P. falciparum, and PfHT1 inhibitor (compound 3361) works in P. vivax. These findings provide properties of glucose uptake via PvHT1NK for carbohydrate metabolism and support the approaches to vivax malaria drug development strategy targeting the PvHT1 for starving of the parasite.
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Thriemer, Kamala, Tamiru Shibru Degaga, Michael Christian, Mohammad Shafiul Alam, Benedikt Ley, Mohammad Sharif Hossain, Mohammad Golam Kibria, et al. "Reducing the risk of Plasmodium vivax after falciparum infections in co-endemic areas—a randomized controlled trial (PRIMA)." Trials 23, no. 1 (May 18, 2022). http://dx.doi.org/10.1186/s13063-022-06364-z.
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Abstract Background Plasmodium vivax forms dormant liver stages that can reactivate weeks or months following an acute infection. Recurrent infections are often associated with a febrile illness and can cause a cumulative risk of severe anaemia, direct and indirect mortality, and onward transmission of the parasite. There is an increased risk of P. vivax parasitaemia following falciparum malaria suggesting a rationale for universal use of radically curative treatment in patients with P. falciparum malaria even in the absence of detectable P. vivax parasitaemia in areas that are co-endemic for both species. Methods This is a multicentre, health care facility-based, randomized, controlled, open-label trial in Bangladesh, Indonesia and Ethiopia. Patients with uncomplicated falciparum malaria, G6PD activity of ≥70% of the adjusted male median (AMM) and haemoglobin levels ≥8g/dl are recruited into the study and randomized to either receive standard schizonticidal treatment plus 7-day high dose primaquine (total dose 7mg/kg) or standard care in a 1:1 ratio. Patients are followed up weekly until day 63. The primary endpoint is the incidence risk of any P. vivax parasitemia on day 63. Secondary endpoints include incidence risk on day 63 of symptomatic P. vivax malaria and the risk of any P. falciparum parasitaemia. Secondary safety outcomes include the proportion of adverse events and serious adverse events, the incidence risk of severe anaemia (Hb<5g/dl and <7g/dl) and/or the risk for blood transfusion, the incidence risk of ≥ 25% fall in haemoglobin with and without haemoglobinuria, and the incidence risk of ≥ 25% fall in haemoglobin to under 7g/dl with and without haemoglobinuria. Discussion This study evaluates the potential benefit of a universal radical cure for both P. vivax and P. falciparum in different endemic locations. If found safe and effective universal radical cure could represent a cost-effective approach to clear otherwise unrecognised P. vivax infections and hence accelerate P. vivax elimination. Trial registration NCT03916003. Registered on 12 April 2019.
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Mahamar, Almahamoudou, Kjerstin Lanke, Wouter Graumans, Halimatou Diawara, Koualy Sanogo, Kalifa Diarra, Sidi Mohamed Niambele, et al. "Persistence of mRNA indicative of Plasmodium falciparum ring-stage parasites 42 days after artemisinin and non-artemisinin combination therapy in naturally infected Malians." Malaria Journal 20, no. 1 (January 9, 2021). http://dx.doi.org/10.1186/s12936-020-03576-z.
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Abstract Background Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasite mRNA, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), was previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, the persistence of ring-stage parasitaemia following ACT and non-ACT treatment was examined. Methods Samples were used from naturally infected Malian gametocyte carriers who received dihydroartemisinin–piperaquine (DP) or sulfadoxine–pyrimethamine (SP–AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. Results At baseline, 89% (64/73) of participants had measurable ring-stage parasite mRNA. Following treatment, the proportion of ring-stage parasite-positive individuals and estimated densities declined for all four treatment groups. Ring-stage parasite prevalence and density was generally lower in arms that received DP compared to SP–AQ. This finding was most apparent days 1, 2, and 42 of follow-up (p < 0.01). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite density estimates on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitaemia compared to those who remained free of parasites until day 42 after initiation of treatment (pday 14 = 0.011 and pday 28 = 0.068). No association of ring-stage persistence with gametocyte carriage was observed. Conclusions The current findings of lower ring-stage persistence after ACT without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker. Lower persistence of ring-stage mRNA after ACT treatment suggests the marker may not reflect dormant parasites whilst it was predictive of re-appearance of parasitaemia.
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Mahamar, Almahamoudou, Kjerstin Lanke, Wouter Graumans, Halimatou Diawara, Koualy Sanogo, Kalifa Diarra, Sidi Mohamed Niambele, et al. "Persistence of mRNA indicative of Plasmodium falciparum ring-stage parasites 42 days after artemisinin and non-artemisinin combination therapy in naturally infected Malians." Malaria Journal 20, no. 1 (January 9, 2021). http://dx.doi.org/10.1186/s12936-020-03576-z.
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Abstract Background Malaria control in sub-Saharan Africa relies upon prompt case management with artemisinin-based combination therapy (ACT). Ring-stage parasite mRNA, measured by sbp1 quantitative reverse-transcriptase PCR (qRT-PCR), was previously reported to persist after ACT treatment and hypothesized to reflect temporary arrest of the growth of ring-stage parasites (dormancy) following exposure to artemisinins. Here, the persistence of ring-stage parasitaemia following ACT and non-ACT treatment was examined. Methods Samples were used from naturally infected Malian gametocyte carriers who received dihydroartemisinin–piperaquine (DP) or sulfadoxine–pyrimethamine (SP–AQ) with or without gametocytocidal drugs. Gametocytes and ring-stage parasites were quantified by qRT-PCR during 42 days of follow-up. Results At baseline, 89% (64/73) of participants had measurable ring-stage parasite mRNA. Following treatment, the proportion of ring-stage parasite-positive individuals and estimated densities declined for all four treatment groups. Ring-stage parasite prevalence and density was generally lower in arms that received DP compared to SP–AQ. This finding was most apparent days 1, 2, and 42 of follow-up (p < 0.01). Gametocytocidal drugs did not influence ring-stage parasite persistence. Ring-stage parasite density estimates on days 14 and 28 after initiation of treatment were higher among individuals who subsequently experienced recurrent parasitaemia compared to those who remained free of parasites until day 42 after initiation of treatment (pday 14 = 0.011 and pday 28 = 0.068). No association of ring-stage persistence with gametocyte carriage was observed. Conclusions The current findings of lower ring-stage persistence after ACT without an effect of gametocytocidal partner drugs affirms the use of sbp1 as ring-stage marker. Lower persistence of ring-stage mRNA after ACT treatment suggests the marker may not reflect dormant parasites whilst it was predictive of re-appearance of parasitaemia.
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Auparakkitanon, Saranya, and Prapon Wilairat. "Ring stage dormancy of Plasmodium falciparum tolerant to artemisinin and its analogues – A genetically regulated “Sleeping Beauty”." International Journal for Parasitology: Drugs and Drug Resistance, January 2023. http://dx.doi.org/10.1016/j.ijpddr.2023.01.002.
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Rodríguez-Hernández, Diego, Kamalakannan Vijayan, Rachael Zigweid, Michael K. Fenwick, Banumathi Sankaran, Wanlapa Roobsoong, Jetsumon Sattabongkot, et al. "Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts." Nature Communications 14, no. 1 (September 5, 2023). http://dx.doi.org/10.1038/s41467-023-41119-7.
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AbstractDrugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs. Herein, we apply a structure-guided hybridization approach combining chemical moieties of previously reported NMT inhibitors to develop the next generation of PvNMT inhibitors. A high-resolution crystal structure of PvNMT bound to a representative selective hybrid compound reveals a unique binding site architecture that includes a selective conformation of a key tyrosine residue. The hybridized compounds significantly decrease P. falciparum blood-stage parasite load and consistently exhibit dose-dependent inhibition of P. vivax liver stage schizonts and hypnozoites. Our data demonstrate that hybridized NMT inhibitors can be multistage antimalarials, targeting dormant and developing forms of liver and blood stage.
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Manjurano, Alphaxard, Eric Lyimo, Coleman Kishamawe, Justin Omolo, Jacklin Mosha, Miyaye Donald, Paul Kazyoba, Saidi Kapiga, and John Changalucha. "Prevalence of G6PD deficiency and submicroscopic malaria parasites carriage in malaria hotspot area in Northwest, Tanzania." Malaria Journal 22, no. 1 (December 7, 2023). http://dx.doi.org/10.1186/s12936-023-04801-1.
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Abstract Background The use of primaquine for mass drug administration (MDA) is being considered as a key strategy for malaria elimination. In addition to being the only drug active against the dormant and relapsing forms of Plasmodium vivax, primaquine is the sole potent drug against mature/infectious Plasmodium falciparum gametocytes. It may prevent onward transmission and help contain the spread of artemisinin resistance. However, higher dose of primaquine is associated with the risk of acute haemolytic anaemia in individuals with a deficiency in glucose-6-phosphate dehydrogenase. In many P. falciparum endemic areas there is paucity of information about the distribution of individuals at risk of primaquine-induced haemolysis at higher dose 45 mg of primaquine. Methods A retrospective cross-sectional study was carried out using archived samples to establish the prevalence of G6PD deficiency in a malaria hotspot area in Misungwi district, located in Mwanza region, Tanzania. Blood samples collected from individuals recruited between August and November 2010 were genotyped for G6PD deficiency and submicroscopic parasites carriage using polymerase chain reaction. Results A total of 263 individuals aged between 0 and 87 were recruited. The overall prevalence of the X-linked G6PD A− mutation was 83.7% (220/263) wild type, 8% (21/263) heterozygous and 8.4% (22/263) homozygous or hemizygous. Although, assessment of the enzymatic activity to assign the phenotypes according to severity and clinical manifestation as per WHO was not carried out, the overall genotype and allele frequency for the G6PD deficiency was 16.4% and 13. 2%, respectively. There was no statistically significant difference in among the different G6PD genotypes (p > 0.05). Out of 248 samples analysed for submicroscopic parasites carriage, 58.1% (144/248) were P. falciparum positive by PCR. G6PD heterozygous deficiency were associated with carriage of submicroscopic P. falciparum (p = 0.029). Conclusions This study showed that 16.4% of the population in this part of North-western Tanzania carry the G6PD A− mutation, within the range of 15–32% seen in other parts of Africa. G6PD gene mutation is widespread and heterogeneous across the study area where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of higher dose of primaquine being associated with the risk of acute haemolytic anaemia (AHA) in individuals with a deficiency in glucose-6-phosphate dehydrogenase and call further research on mapping of G6PD deficiency in Tanzania. Therefore, screening and education programmes for G6PD deficiency is warranted in a programme of malaria elimination using a higher primaquine dose.
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Salazar, Yanka Evellyn Alves Rodrigues, Jaime Louzada, Maria Carolina Silva de Barros Puça, Luiz Felipe Ferreira Guimarães, José Luiz Fernandes Vieira, André Machado de Siqueira, José Pedro Gil, Cristiana Ferreira Alves de Brito, and Tais Nobrega de Sousa. "Delayed gametocyte clearance in Plasmodium vivax malaria is associated with polymorphisms in the cytochrome P450 reductase (CPR)." Antimicrobial Agents and Chemotherapy, February 27, 2024. http://dx.doi.org/10.1128/aac.01204-23.
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ABSTRACT Primaquine (PQ) is the main drug used to eliminate dormant liver stages and prevent relapses in Plasmodium vivax malaria. It also has an effect on the gametocytes of Plasmodium falciparum ; however, it is unclear to what extent PQ affects P. vivax gametocytes. PQ metabolism involves multiple enzymes, including the highly polymorphic CYP2D6 and the cytochrome P450 reductase (CPR). Since genetic variability can impact drug metabolism, we conducted an evaluation of the effect of CYP2D6 and CPR variants on PQ gametocytocidal activity in 100 subjects with P. vivax malaria. To determine gametocyte density, we measured the levels of pvs25 transcripts in samples taken before treatment (D0) and 72 hours after treatment (D3). Generalized estimating equations (GEEs) were used to examine the effects of enzyme variants on gametocyte densities, adjusting for potential confounding factors. Linear regression models were adjusted to explore the predictors of PQ blood levels measured on D3. Individuals with the CPR mutation showed a smaller decrease in gametocyte transcript levels on D3 compared to those without the mutation ( P = 0.02, by GEE). Consistent with this, higher PQ blood levels on D3 were associated with a lower reduction in pvs25 transcripts. Based on our findings, the CPR variant plays a role in the persistence of gametocyte density in P. vivax malaria. Conceptually, our work points to pharmacogenetics as a non-negligible factor to define potential host reservoirs with the propensity to contribute to transmission in the first days of CQ–PQ treatment, particularly in settings and seasons of high Anopheles human-biting rates.
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Lek, Dysoley, Yu-Cheng Tsai, Jillian Hirano, Siv Sovannaroth, Voeurng Bunreth, Prak Vonn, Or Vannthen, et al. "Radical cure for Plasmodium vivax malaria after G6PD qualitative testing in four provinces in Cambodia, results from Phase I implementation." Malaria Journal 23, no. 1 (February 23, 2024). http://dx.doi.org/10.1186/s12936-024-04884-4.
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Abstract Background Cambodia aims to eliminate all forms of malaria by 2025. In 2020, 90% of all malaria cases were Plasmodium vivax. Thus, preventing P. vivax and relapse malaria is a top priority for elimination. 14-day primaquine, a World Health Organization-recommended radical cure treatment regimen, specifically targets dormant hypnozoites in the liver to prevent relapse. Cambodia introduced P. vivax radical cure with primaquine after glucose-6-phosphate dehydrogenase (G6PD) qualitative testing in 2019. This paper presents Cambodia’s radical cure Phase I implementation results and assesses the safety, effectiveness, and feasibility of the programme prior to nationwide scale up. Methods Phase I implementation was carried out in 88 select health facilities (HFs) across four provinces. Males over 20kgs with confirmed P. vivax or mixed (P. vivax and Plasmodium falciparum) infections were enrolled. A descriptive analysis evaluated the following: successful referral to health facilities, G6PD testing results, and self-reported 14-day treatment adherence. P. vivax incidence was compared before and after radical cure rollout and a controlled interrupted time series analysis compared the estimated relapse rate between implementation and non-implementation provinces before and after radical cure. Results In the 4 provinces from November 2019 to December 2020, 3,239 P. vivax/mixed infections were reported, 1,282 patients underwent G6PD deficiency testing, and 959 patients received radical cure, achieving 29.6% radical cure coverage among all P. vivax/mixed cases and 98.8% coverage among G6PD normal patients. Among those who initiated radical cure, 747 patients (78%) completed treatment. Six patients reported side effects. In implementation provinces, an average 31.8 relapse cases per month were estimated signaling a 90% (286 cases) reduction in relapse compared to what would be expected if radical cure was not implemented. Conclusions Plasmodium vivax radical cure is a crucial tool for malaria elimination in Cambodia. The high coverage of radical cure initiation and adherence among G6PD normal patients demonstrated the high feasibility of providing radical cure at point of care in Cambodia. Incomplete referral from community to HFs and limited capacity of HF staff to conduct G6PD testing in high burden areas led to lower coverage of G6PD testing. Phase I implementation informed approaches to improve referral completion and patient adherence during the nationwide expansion of radical cure in 2021.
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Breglio, Kimberly F., Rifat S. Rahman, Juliana M. Sá, Amanda Hott, David J. Roberts, and Thomas E. Wellems. "Correction for Breglio et al., “Kelch Mutations in Plasmodium falciparum Protein K13 Do Not Modulate Dormancy after Artemisinin Exposure and Sorbitol Selection In Vitro”." Antimicrobial Agents and Chemotherapy 62, no. 11 (October 24, 2018). http://dx.doi.org/10.1128/aac.02070-18.
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Schneider, Kristan Alexander, and Carola Janette Salas. "Evolutionary genetics of malaria." Frontiers in Genetics 13 (November 3, 2022). http://dx.doi.org/10.3389/fgene.2022.1030463.
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Many standard-textbook population-genetic results apply to a wide range of species. Sometimes, however, population-genetic models and principles need to be tailored to a particular species. This is particularly true for malaria, which next to tuberculosis and HIV/AIDS ranks among the economically most relevant infectious diseases. Importantly, malaria is not one disease—five human-pathogenic species of Plasmodium exist. P. falciparum is not only the most severe form of human malaria, but it also causes the majority of infections. The second most relevant species, P. vivax, is already considered a neglected disease in several endemic areas. All human-pathogenic species have distinct characteristics that are not only crucial for control and eradication efforts, but also for the population-genetics of the disease. This is particularly true in the context of selection. Namely, fitness is determined by so-called fitness components, which are determined by the parasites live-history, which differs between malaria species. The presence of hypnozoites, i.e., dormant liver-stage parasites, which can cause disease relapses, is a distinct feature of P. vivax and P. ovale sp. In P. malariae inactivated blood-stage parasites can cause a recrudescence years after the infection was clinically cured. To properly describe population-genetic processes, such as the spread of anti-malarial drug resistance, these features must be accounted for appropriately. Here, we introduce and extend a population-genetic framework for the evolutionary dynamics of malaria, which applies to all human-pathogenic malaria species. The model focuses on, but is not limited to, the spread of drug resistance. The framework elucidates how the presence of dormant liver stage or inactivated blood stage parasites that act like seed banks delay evolutionary processes. It is shown that, contrary to standard population-genetic theory, the process of selection and recombination cannot be decoupled in malaria. Furthermore, we discuss the connection between haplotype frequencies, haplotype prevalence, transmission dynamics, and relapses or recrudescence in malaria.
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Rahmalia, Annisa, Jeanne Rini Poespoprodjo, Chandra U. R. Landuwulang, Maya Ronse, Enny Kenangalem, Faustina H. Burdam, Kamala Thriemer, et al. "Adherence to 14-day radical cure for Plasmodium vivax malaria in Papua, Indonesia: a mixed-methods study." Malaria Journal 22, no. 1 (May 20, 2023). http://dx.doi.org/10.1186/s12936-023-04578-3.
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Abstract Background Reducing the risk of recurrent Plasmodium vivax malaria is critical for malaria control and elimination. Primaquine (PQ) is the only widely available drug against P. vivax dormant liver stages, but is recommended as a 14-day regimen, which can undermine adherence to a complete course of treatment. Methods This is a mixed-methods study to assess socio-cultural factors influencing adherence to a 14-day PQ regimen in a 3-arm, treatment effectiveness trial in Papua, Indonesia. The qualitative strand, consisting of interviews and participant observation was triangulated with a quantitative strand in which trial participants were surveyed using a questionnaire. Results Trial participants differentiated between two types of malaria: tersiana and tropika, equivalent to P. vivax and Plasmodium falciparum infection, respectively. The perceived severity of both types was similar with 44.0% (267/607) perceiving tersiana vs. 45.1% (274/607) perceiving tropika as more severe. There was no perceived differentiation whether malaria episodes were due to a new infection or relapse; and 71.3% (433/607) acknowledged the possibility of recurrence. Participants were familiar with malaria symptoms and delaying health facility visit by 1–2 days was perceived to increase the likelihood of a positive test. Prior to health facility visits, symptoms were treated with leftover drugs kept at home (40.4%; 245/607) or bought over the counter (17.0%; 103/607). Malaria was considered to be cured with ‘blue drugs’ (referring to dihydroartemisinin-piperaquine). Conversely, ‘brown drugs,’ referring to PQ, were not considered malaria medication and instead were perceived as supplements. Adherence to malaria treatment was 71.2% (131/184), in the supervised arm, 56.9% (91/160) in the unsupervised arm and 62.4% (164/263) in the control arm; p = 0.019. Adherence was 47.5% (47/99) among highland Papuans, 51.7% (76/147) among lowland Papuans, and 72.9% (263/361) among non-Papuans; p < 0.001. Conclusion Adherence to malaria treatment was a socio-culturally embedded process during which patients (re-)evaluated the characteristics of the medicines in relation to the course of the illness, their past experiences with illness, and the perceived benefits of the treatment. Structural barriers that hinder the process of patient adherence are crucial to consider in the development and rollout of effective malaria treatment policies.
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Khan, Washim, Yan-Hong Wang, Narayan D. Chaurasiya, N. P. Dhammika Nanayakkara, H. M. Bandara Herath, Kerri A. Harrison, Gray Dale, et al. "Comparative metabolism and tolerability of racemic primaquine and its enantiomers in human volunteers during 7-day administration." Frontiers in Pharmacology 13 (January 16, 2023). http://dx.doi.org/10.3389/fphar.2022.1104735.
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Primaquine (PQ) is an 8-aminoquinoline antimalarial, active against dormant Plasmodium vivax hypnozoites and P. falciparum mature gametocytes. PQ is currently used for P. vivax radical cure and prevention of malaria transmission. PQ is a racemic drug and since the metabolism and pharmacology of PQ’s enantiomers have been shown to be divergent, the objectives of this study were to evaluate the comparative tolerability and metabolism of PQ with respect to its two enantiomers in human volunteers in a 7 days’ treatment schedule. Fifteen subjects with normal glucose-6-phosphate dehydrogenase (G6PDn) completed four arms, receiving each of the treatments, once daily for 7 days, in a crossover fashion, with a 7–14 days washout period in between: R-(−) enantiomer (RPQ) 22.5 mg; S-(+) enantiomer (SPQ) 22.5 mg; racemic PQ (RSPQ) 45 mg, and placebo. Volunteers were monitored for any adverse events (AEs) during the study period. PQ and metabolites were quantified in plasma and red blood cells (RBCs) by UHPLC-UV-MS/MS. Plasma PQ was significantly higher in SPQ treatment group than for RPQ. Carboxy-primaquine, a major plasma metabolite, was much higher in the RPQ treated group than SPQ; primaquine carbamoyl glucuronide, another major plasma metabolite, was derived only from SPQ. The ortho-quinone metabolites were also detected and showed differences for the two enantiomers in a similar pattern to the parent drugs. Both enantiomers and racemic PQ were well tolerated in G6PDn subjects with the 7 days regimen; three subjects showed mild AEs which did not require any intervention or discontinuation of the drug. The most consistent changes in G6PDn subjects were a gradual increase in methemoglobin and bilirubin, but these were not clinically important. However, the bilirubin increase suggests mild progressive damage to a small fraction of red cells. PQ enantiomers were also individually administered to two G6PD deficient (G6PDd) subjects, one heterozygous female and one hemizygous male. These G6PDd subjects showed similar results with the two enantiomers, but the responses in the hemizygous male were more pronounced. These studies suggest that although the metabolism profiles of individual PQ enantiomers are markedly different, they did not show significant differences in the safety and tolerability in G6PDn subjects.