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Transactions of the Royal Society of... 1977Asexual erythrocytic parasites of Plasmodium falciparum are killed by chloroquine, whilst mature gametocytes are not. The gametocytes of P. falciparum take 10 days to...
Asexual erythrocytic parasites of Plasmodium falciparum are killed by chloroquine, whilst mature gametocytes are not. The gametocytes of P. falciparum take 10 days to develop to maturity and their sensitivity to chloroquine during this time was studied in vitro to investigate when the switch from susceptibility to insusceptibility occurred and to compare the responses of asexual and immature sexual parasites to the drug. 45 to 50% of asexual parasites and immature gametocytes less than one day old survived in 0.1n. mols of chloroquine per ml but 0.3n. mols of drug per ml was lethal to both. Chloroquine at 1.0n mols per ml was lethal to developing gametocytes during their first six days of growth probably due, at least in part, to the drug disorganizing the parasite's digestion of host erythrocyte haemoglobin. The drug clumped the pigment of developing gametocytes. Only immature gametocytes in the final stage of development (stage 4) survive in high chloroquine concentrations.
Topics: Animals; Chloroquine; Pigmentation; Plasmodium falciparum
PubMed: 343314
DOI: 10.1016/0035-9203(77)90149-3 -
Science (New York, N.Y.) Nov 1987Chloroquine-resistant Plasmodium falciparum accumulate significantly less chloroquine than susceptible parasites, and this is thought to be the basis of their...
Chloroquine-resistant Plasmodium falciparum accumulate significantly less chloroquine than susceptible parasites, and this is thought to be the basis of their resistance. However, the reason for the lower accumulation of chloroquine was unknown. The resistant parasite has now been found to release chloroquine 40 to 50 times more rapidly than the susceptible parasite, although their initial rates of chloroquine accumulation are the same. Verapamil and two other calcium channel blockers, as well as vinblastine and daunomycin, each slowed the release and increased the accumulation of chloroquine by resistant (but not susceptible) Plasmodium falciparum. These results suggest that a higher rate of chloroquine release explains the lower chloroquine accumulation, and thus the resistance observed in resistant Plasmodium falciparum.
Topics: Animals; Biological Transport; Calcium Channel Blockers; Chloroquine; Daunorubicin; Drug Resistance; Kinetics; Plasmodium falciparum; Vinblastine
PubMed: 3317830
DOI: 10.1126/science.3317830 -
Malaria Journal Jan 2013Considering the distinct biological characteristics of Plasmodium species is crucial for control and elimination efforts, in particular when facing the spread of drug...
BACKGROUND
Considering the distinct biological characteristics of Plasmodium species is crucial for control and elimination efforts, in particular when facing the spread of drug resistance. Whereas the evolutionary fitness of all malarial species could be approximated by the probability of being taken by a mosquito and then infecting a new host, the actual steps in the malaria life cycle leading to a successful transmission event show differences among Plasmodium species. These "steps" are called fitness components. Differences in terms of fitness components may affect how selection imposed by interventions, e.g. drug treatments, differentially acts on each Plasmodium species. Thus, a successful malaria control or elimination programme should understand how differences in fitness components among different malaria species could affect adaptive evolution (e.g. the emergence of drug resistance). In this investigation, the interactions between some fitness components and natural selection are explored.
METHODS
A population-genetic model is formulated that qualitatively explains how different fitness components (in particular gametocytogenesis and longevity of gametocytes) affect selection acting on merozoites during the erythrocytic cycle. By comparing Plasmodium falciparum and Plasmodium vivax, the interplay of parasitaemia and gametocytaemia dynamics in determining fitness is modelled under circumstances that allow contrasting solely the differences between these two parasites in terms of their fitness components.
RESULTS
By simulating fitness components, it is shown that selection acting on merozoites (e.g., on drug resistant mutations or malaria antigens) is more efficient in P. falciparum than in P. vivax. These results could explain, at least in part, why resistance against drugs, such as chloroquine (CQ) is highly prevalent in P. falciparum worldwide, while CQ is still a successful treatment for P. vivax despite its massive use. Furthermore, these analyses are used to explore the importance of understanding the dynamic of gametocytaemia to ascertain the spreading of drug resistance.
CONCLUSIONS
The strength of natural selection on mutations that express their advantage at the merozoite stage is different in P. vivax and P. falciparum. Species-specific differences in gametocytogenesis and longevity of gametocytes need to be accounted for when designing effective malaria control and elimination programmes. There is a need for reliable data on gametocytogenesis from field studies.
Topics: Antimalarials; Drug Resistance; Genetics, Population; Models, Theoretical; Plasmodium falciparum; Plasmodium vivax; Selection, Genetic
PubMed: 23305428
DOI: 10.1186/1475-2875-12-15 -
Experimental Parasitology Apr 1986DL-alpha-Difluoromethylornithine, an inhibitor of polyamine biosynthesis, was tested for its ability to synchronize Plasmodium falciparum. Asynchronous cultures were...
DL-alpha-Difluoromethylornithine, an inhibitor of polyamine biosynthesis, was tested for its ability to synchronize Plasmodium falciparum. Asynchronous cultures were pretreated with sorbitol and incubated for 28-30 hr. Then, when cultures consisted of mainly schizont stage parasites, DL-alpha-difluoromethylornithine was added to the growth medium for another 38-47 hr of incubation. Putrescine was added to parasites arrested at the early trophozoite stage. This resulted in a synchronous resumption of growth. After 19 hr, 83% of parasites were at the schizont stage. After 30 hr, more than 98% of the parasites were in the ring form stage. Furthermore, the transformation of early trophozoites to schizonts occurred within 3 hr, with a slight reduction in parasitemia. Synchrony was maintained for 4-5 biological cycles as confirmed also by flow fluorimetry. It appears that this new approach to synchronize P. falciparum cultures is simple, reproducible, and effective.
Topics: Animals; Eflornithine; Flow Cytometry; Kinetics; Ornithine; Ornithine Decarboxylase Inhibitors; Plasmodium falciparum; Polyamines
PubMed: 3082665
DOI: 10.1016/0014-4894(86)90156-6 -
Current Opinion in Microbiology Aug 2015A renewed global commitment to malaria elimination lends urgency to understanding the biology of Plasmodium transmission stages. Recent progress toward uncovering the... (Review)
Review
A renewed global commitment to malaria elimination lends urgency to understanding the biology of Plasmodium transmission stages. Recent progress toward uncovering the mechanisms underlying Plasmodium falciparum sexual differentiation and maturation reveals potential targets for transmission-blocking drugs and vaccines. The identification of parasite factors that alter sexual differentiation, including extracellular vesicles and a master transcriptional regulator, suggest that parasites make epigenetically controlled developmental decisions based on environmental cues. New insights into sexual development, especially host cell remodeling and sequestration in the bone marrow, highlight open questions regarding parasite homing to the tissue, transmigration across the vascular endothelium, and maturation in the parenchyma. Novel molecular and translational tools will provide further opportunities to define host-parasite interactions and design effective transmission-blocking therapeutics.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation; Host-Pathogen Interactions; Humans; Plasmodium falciparum
PubMed: 25867628
DOI: 10.1016/j.mib.2015.03.005 -
Experimental Parasitology Jun 1988Natural isolates of Plasmodium falciparum represent a genetically heterogeneous population of parasites. To obtain stable strains of the parasites for long term...
Natural isolates of Plasmodium falciparum represent a genetically heterogeneous population of parasites. To obtain stable strains of the parasites for long term experiments, a rapid and definitive method of cloning was developed using micropipets and a micromanipulator. Homogeneous parasite clones prepared by this technique were characterized and compared with the parent isolates during 4 years of continuous culture. The process of phenotypic dominance and selection of drug resistance which occur in nature was also simulated in vitro by evaluating population dynamics of two cocultured isolates of P. falciparum.
Topics: Animals; Antimalarials; Cells, Cultured; Clone Cells; Culture Media; Drug Resistance; Erythrocytes; Humans; Micromanipulation; Phenotype; Plasmodium falciparum
PubMed: 3284758
DOI: 10.1016/0014-4894(88)90053-7 -
The American Journal of Tropical... Sep 1982Infectious agents must acquire iron from their host to survive, and iron deficiency has been reported to protect against malaria in humans. We have tested the the...
Infectious agents must acquire iron from their host to survive, and iron deficiency has been reported to protect against malaria in humans. We have tested the the susceptibility of Plasmodium falciparum to iron deprivation by studying the effect of desferrioxamine (DF), a specific iron chelating agent, on parasite growth in an in vitro culture system. We have found that DF inhibits the growth of P. falciparum at concentrations readily achievable in vivo, by a mechanism that may involve interference with the completion of schizogony.
Topics: Deferoxamine; Iron; Plasmodium falciparum
PubMed: 6751113
DOI: 10.4269/ajtmh.1982.31.919 -
Cell Host & Microbe Oct 2011Plasmodium falciparum and Toxoplasma gondii are obligate intracellular apicomplexan parasites that rapidly invade and extensively modify host cells. Protein...
Plasmodium falciparum and Toxoplasma gondii are obligate intracellular apicomplexan parasites that rapidly invade and extensively modify host cells. Protein phosphorylation is one mechanism by which these parasites can control such processes. Here we present a phosphoproteome analysis of peptides enriched from schizont stage P. falciparum and T. gondii tachyzoites that are either "intracellular" or purified away from host material. Using liquid chromatography-tandem mass spectrometry, we identified over 5,000 and 10,000 previously unknown phosphorylation sites in P. falciparum and T. gondii, respectively, revealing that protein phosphorylation is an extensively used regulation mechanism both within and beyond parasite boundaries. Unexpectedly, both parasites have phosphorylated tyrosines, and P. falciparum has unusual phosphorylation motifs that are apparently shaped by its A:T-rich genome. This data set provides important information on the role of phosphorylation in the host-pathogen interaction and clues to the evolutionary forces operating on protein phosphorylation motifs in both parasites.
Topics: Adaptation, Biological; Chromatography, Liquid; Gene Expression Regulation; Mass Spectrometry; Phosphoproteins; Phosphorylation; Plasmodium falciparum; Protein Processing, Post-Translational; Proteome; Signal Transduction; Toxoplasma
PubMed: 22018241
DOI: 10.1016/j.chom.2011.09.004 -
Experimental Parasitology Feb 1984The asexual development cycle of Plasmodium falciparum, a malarial parasite of humans, has been synchronized in culture by treating ring-stage parasites with...
The asexual development cycle of Plasmodium falciparum, a malarial parasite of humans, has been synchronized in culture by treating ring-stage parasites with aphidicolin, an inhibitor of DNA synthesis. Optimization of both the concentration of drug added to ring stage containing red blood cells and the duration of exposure of parasites to drug led to a reversible block of their maturation at the early trophozoite stage. Release of the aphidicolin block led to a synchronous development of parasites that was manifested by about 80% of the new ring stages being produced within a 2- to 3-hr interval.
Topics: Animals; Aphidicolin; DNA; Diterpenes; Dose-Response Relationship, Drug; Erythrocytes; Humans; Parasitology; Plasmodium falciparum
PubMed: 6420180
DOI: 10.1016/0014-4894(84)90061-4 -
Briefings in Functional Genomics Jul 2013Plasmodium falciparum is an obligate intracellular parasite and the leading cause of severe malaria responsible for tremendous morbidity and mortality particularly in...
Plasmodium falciparum is an obligate intracellular parasite and the leading cause of severe malaria responsible for tremendous morbidity and mortality particularly in sub-Saharan Africa. Successful completion of the P. falciparum genome sequencing project in 2002 provided a comprehensive foundation for functional genomic studies on this pathogen in the following decade. Over this period, a large spectrum of experimental approaches has been deployed to improve and expand the scope of functionally annotated genes. Meanwhile, rapidly evolving methods of systems biology have also begun to contribute to a more global understanding of various aspects of the biology and pathogenesis of malaria. Herein we provide an overview on metabolic modelling, which has the capability to integrate information from functional genomics studies in P. falciparum and guide future malaria research efforts towards the identification of novel candidate drug targets.
Topics: Computational Biology; Genomics; Plasmodium falciparum; Protozoan Proteins
PubMed: 23793264
DOI: 10.1093/bfgp/elt017