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PubMed2000

Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro.

Gametocytocidal activities of pyronaridine and DNA topoisomerase II inhibitors against two isolates of multidrug-resistant Plasmodium falciparum, KT1 and KT3 were determined. After sorbitol treatment, pure gametocyte cultures of Plasmodium falciparum containing mostly young gametocytes (stage II and III) obtained on day 11 were exposed to the drugs for 48 h. The effect of the drugs on gametocyte development was assessed by counting gametocytes on day 15 of culture. Pyronaridine was the most effective gametocytocidal drug against P. falciparum isolates KT1 and KT3 with 50% inhibitory concentration of 6 and 20 nM, respectively. Moreover, the 50% inhibitory concentration of pyronaridine was lower than that of primaquine which is the only drug used to treat malaria patients harboring gametocytes. Prokaryotic (norfloxacin) and eukaryotic (amsacrine and etoposide) DNA topoisomerase II inhibitors were only effective against asexual but not sexual stages of the malaria parasites. Pyronaridine has both schizontocidal and gametocytocidal activities against the human malaria parasite, P. falciparum.

Amsacrine↗
PubMed2002

Do Plasmodium ookinetes invade a specific cell type in the mosquito midgut?

Recent debate in Plasmodium ookinete invasion has been centered on whether the parasite chooses a specific cell type to cross the midgut epithelium in the mosquito. A few publications have described the mosquito midgut being composed of complex surface-structures, histochemically and biochemically diverse cell types, and have proposed that Plasmodium gallinaceum ookinetes prefers a specific cell type (Ross cell) in Aedes aegypti for crossing the midgut epithelium. Two recent publications reported, however, that with differential interference contrast microscopy, all midgut epithelial cells in uninfected mosquitoes appear structurally similar and argued that ookinetes do not invade a specific cell type. These observations are discussed here in the context of the 'Ross cell' hypothesis.

Aedes↗
PubMed2003

Pre-erythrocytic antigens of Plasmodium falciparum: from rags to riches?

A growing number of Plasmodium genomes have joined the sequencing treadmill, and the genome of Plasmodium falciparum has recently been published. Most malaria vaccinologists will soon be confronted by a bewildering array of new potential antigens from the recently completed genome of this parasite. However, for those aiming to target the pre-erythrocytic stages of the hepatic parasite, the wait might be long. In the absence of readily available materials and specific reagents, the selection of pre-erythrocytic antigens from raw sequence data is likely to prove difficult. Here, current knowledge of pre-erythrocytic antigens is updated in the light of recent results, and the post-genomic prospects of completing the antigenic repertoire of these immunologically important and intriguing stages is discussed.

Animals↗
PubMed2003

The Plasmodium vivax genome sequencing project.

With the successful completion of the project to sequence the Plasmodium falciparum genome, researchers are now turning their attention to other malaria parasite species. Here, an update on the Plasmodium vivax genome sequencing project is presented, as part of the Trends in Parasitology series of reviews expanding on various aspects of P. vivax research.

Animals↗
PubMed2003

Expression and purification of Plasmodium falciparum MSP-1(42): A malaria vaccine candidate.

The C-terminal 42.10(3) Da portion of the merozoite surface protein (MSP-1) of the human malaria parasite Plasmodium falciparum is of interest, not only because it may constitute an essential part of a future anti-malaria vaccine, but also due to its role during the infection of erythrocytes by the parasite. We have cloned and expressed two synthetic DNA sequences encoding the two prototypic MSP-1(42) variants in E. coli. When over-produced, both proteins form insoluble aggregates which were isolated in high purity and yield. After solubilisation and refolding in vitro, both proteins were purified to homogeneity by a three-step procedure applying Ni-chelate, size exclusion and immuno-affinity chromatography. After purification, both proteins meet key criteria of preparations for clinical use. First, conformational studies suggest proper folding of the proteins, particularly in the region containing two EGF-like domains. Polyclonal serum raised against E. coli produced MSP-1(42) recognizes native MSP-1 in Plasmodium infected erythrocytes as shown by immunofluorescence.

Amino Acid Sequence↗
PubMed1986

The mechanism of pyrimethamine resistance in Plasmodium falciparum.

The uptake of radioactive pyrimethamine by a sensitive and a resistant strain of Plasmodium falciparum, the metabolic fate of pyrimethamine inside these parasites and the kinetic properties of dihydrofolate reductase (DHFR) from both strains have been studied. Uptake of the drug was identical in both strains and no metabolite of pyrimethamine was found in either strain. DHFR from the resistant strain was 300 times less sensitive to inhibition by pyrimethamine than the enzyme from the sensitive strain, while the Michaelis constant for dihydrofolate remained unchanged and inhibition was competitive in both cases. Altered properties of plasmodial DHFR are apparently the only mechanism responsible for pyrimethamine resistance in the strain of Plasmodium falciparum studied.

Animals↗
PubMed1989

The sex ratio of Plasmodium gametocytes.

Sex ratio theory usually predicts an equilibrium sex ratio and equal proportions of males and females in a population, including the progenitors of the reproductive cells of protozoans. This proposal was tested with three species of malarial parasites of lizards, Plasmodium mexicanum of the western fence lizard, and P. agamae and P. giganteum of the African rainbow lizard, using single samples from naturally infected lizards, repeated samples from free-ranging lizards (P. mexicanum only), and repeated samples from laboratory maintained animals. Macrogametocytes were usually more abundant than microgametocytes, and were slightly larger, revealing a typically greater investment of resources by the progenitors of female reproductive cells. However, the proportion of microgametocytes varied among the three species and among infections within each species of Plasmodium. The sex ratio of gametocytes often remained constant within infections followed over time even if the absolute number of gametocytes was changing. However, the equilibrium sex ratio of gametocytes varied among those infections that had an unchanging microgametocyte proportion. Thus, although an equilibrium sex ratio apparently occurs for most infections, there appears to be no characteristic proportion of microgametocytes for any of the species. Potential explanations for this conflict with theory are presented.

Animals↗
PubMed1990

The effects of chloroquine on the infectivity of chloroquine-sensitive and -resistant populations of Plasmodium yoelii nigeriensis to mosquitoes.

Subtherapeutic doses of chloroquine have been reported to enhance infectivity of drug-resistant Plasmodium species to their vectors. In this investigation, Plasmodium yoelii nigeriensis N67 strain showed enhanced infectivity to mosquitoes when stimulated by chloroquine. Both sensitive and resistant clones were derived from the N67 strain by dilution, showing that this strain is polymorphic for the resistant trait. A resistant subline was derived by selection under drug pressure from a chloroquine-sensitive clone, but neither the sensitive nor the resistant clones or sublines showed enhancement of infectivity in the presence of chloroquine. This suggests that the enhancement of infectivity shown by the N67 strain is a response to chloroquine stimulation shown only by certain of the genotypes within it, and that this response to chloroquine is not a trait causally connected with the genes coding for chloroquine resistance.

Animals↗
PubMed2001

Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum.

A new method has been established to define the limits on a spontaneous mutation rate for a gene in Plasmodium falciparum. The method combines mathematical modelling and large-scale in vitro culturing and calculates the difference in mutant frequencies at 2 separate time-points. We measured the mutation rate at 2 positions in the dihydrofolate reductase (DHFR) gene of 3D7, a pyrimethamine-sensitive line of P. falciparum. This line was re-cloned and an effectively large population was treated with a selective pyrimethamine concentration of 40 nM. We detected point mutations at codon-46 (TTA to TCA) and codon-108 (AGC to AAC), resulting in serine replacing leucine and asparagine replacing serine respectively in the corresponding gene product. The substitutions caused a decrease in pyrimethamine sensitivity. By mathematical modelling we determined that the mutation rate at a given position in DHFR was low and occurred at less than 2.5 x 10(-9) mutations/DHFR gene/replication. This result has important implications for Plasmodium genetic diversity and antimalarial drug therapy by demonstrating that even with low mutation rates anti-malarial resistance will inevitably arise when mutant alleles are selected under drug pressure.

Amino Acid Substitution↗
PubMed2004

Plasmodium falciparum malaria disease manifestations in humans and transmission to Anopheles gambiae: a field study in Western Kenya.

Transmission of the malaria parasite Plasmodium is influenced by many different host, vector and parasite factors. Here we conducted a field study at Mbita, an area of endemic malaria in Western Kenya, to test whether parasite transmission to mosquitoes is influenced by the severity of malaria infection in its human host at the time when gametocytes, the transmission forms, are present in the peripheral blood. We examined the infectivity of 81 Plasmodium falciparum gametocyte carriers to mosquitoes. Of these, 21 were patients with fever and other malaria-related symptoms, and 60 were recruited among apparently healthy volunteers. Laboratory-reared Anopheles gambiae s.s. (local strain) were experimentally infected with blood from these gametocyte carriers by membrane-feeding. The severity of the clinical symptoms was greater in febrile patients. These symptomatic patients had higher asexual parasitaemia and lower gametocyte densities (P = 0.05) than healthy volunteers. Ookinete development occurred in only 6 out of the 21 symptomatic patients, of which only 33.3% successfully yielded oocysts. The oocyst prevalence was only 0.6% in the 546 mosquitoes that were fed on blood from this symptomatic group, with mean oocyst intensity of 0.2 (range 0-2) oocysts per mosquito. In contrast, a higher proportion (76.7%) of healthy gametocyte carriers yielded ookinetes, generating an oocyst rate of 12% in the 1332 mosquitoes that fed on them (mean intensity of 6.3, range: 1-105 oocysts per mosquito). Statistical analysis indicated that the increased infectivity of asymptomatic gametocyte carriers was not simply due to their greater gametocyte abundance, but also to the higher level of infectivity of their gametocytes, possibly due to lower parasite mortality within mosquitoes fed on blood from healthy hosts. These results suggest that blood factors and/or conditions correlated with illness reduce P. falciparum gametocyte infectivity.

Adolescent↗
PubMed2005

Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors.

Dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Plasmodium falciparum, a validated target for antifolate antimalarials, is a dimeric enzyme with interdomain interactions significantly mediated by the junction region as well as the Plasmodium-specific additional sequences (inserts) in the DHFR domain. The X-ray structures of both the wild-type and mutant enzymes associated with drug resistance, in complex with either a drug which lost, or which still retains, effectiveness for the mutants, reveal features which explain the basis of drug resistance resulting from mutations around the active site. Binding of rigid inhibitors like pyrimethamine and cycloguanil to the enzyme active site is affected by steric conflict with the side-chains of mutated residues 108 and 16, as well as by changes in the main chain configuration. The role of important residues on binding of inhibitors and substrates was further elucidated by site-directed and random mutagenesis studies. Guided by the active site structure and modes of inhibitor binding, new inhibitors with high affinity against both wild-type and mutant enzymes have been designed and synthesized, some of which have very potent anti-malarial activities against drug-resistant P. falciparum bearing the mutant enzymes.

Animals↗
PubMed2006

Purification and characterization of a novel 3'-5' DNA helicase from Plasmodium falciparum and its sensitivity to anthracycline antibiotics.

Plasmodium falciparum has developed resistance to most anti-malarials; therefore, an investigation of potential targets should be performed. DNA helicases are enzymes that catalyse the unwinding of double-stranded DNA to provide single-stranded templates for DNA replication, repair and recombination. In this study, a DNA helicase (PfDH A) was purified from a crude extract of Plasmodium falciparum. DNA helicase activity was measured by assaying unwinding activity. The apparent molecular weight of PfDH A as determined by SDS-PAGE was 90 kDa. PfDH A moved unidirectionally in the 3' -to- 5' direction along the bound strand and preferred a fork-like substrate structure and could not unwind blunt-ended duplex DNA. Unwinding activity required Mg2+ and could be inhibited by 200 mM NaCl or KCl and was dependent on hydrolysis of ATP or dATP. Anthracyclines, including daunorubicin, nogalamycin, doxorubicin, and aclarubicin, inhibited PfDH A activity with IC50 values of 2, 5, 8 and 9 microM, respectively. Based on the results, PfDH A differs from all known human DNA helicases. However, its function and roles in parasite DNA replication need to be elucidated in the future.

Animals↗
PubMed2006

Intraerythrocytic Plasmodium falciparum utilize a broad range of serum-derived fatty acids with limited modification for their growth.

Plasmodium falciparum causes the most severe form of malaria. Utilization of fatty acids in serum is thought to be necessary for survival of this parasite in erythrocytes, and thus characterization of the parasite fatty acid metabolism is important in developing a new strategy for controlling malaria. Here, we examined which combinations of fatty acids present in human serum support the continuous culture of P. falciparum in serum-free medium. Metabolic labelling and gas chromatography analyses revealed that, despite the need for particular fatty acids for the growth of intraerythrocytic P. falciparum, it can metabolize a broad range of serum-derived fatty acids into the major lipid species of their membranes and lipid bodies. In addition, these analyses showed that the parasite's overall fatty acid composition reflects that of the medium, although the parasite has a limited capacity to desaturate and elongate serum-derived fatty acids. These results indicate that the Plasmodium parasite is distinct from most cells, which maintain their fatty acid composition by coordinating de novo biosynthesis, scavenging, and modification (desaturation and elongation).

Animals↗
PubMed2006

Studies on cell-cycle synchronization in the asexual erythrocytic stages of Plasmodium falciparum.

Multiplication of Plasmodium parasites within human erythrocytes is essential to malarial disease. The cell-division cycle of this organism, however, is still poorly understood. In other eukaryotes, various techniques for (apparent) cell-cycle synchronization have been used to shed light on the mechanisms involved in cell division and its control. Thus far there is no technique for cell-cycle synchronization (as opposed to selection of parasites of a limited age-range) in Plasmodium. We therefore investigated the possibility that inhibitors of DNA synthesis, the mitotic spindle, or cell-cycle control elements (such as cyclin-dependent kinases) could be used to synchronize P. falciparum cultures to a particular cell-cycle phase. Surprisingly, most of these compounds did not cause a block at a specific phase. Three compounds, Hoechst 33342, roscovitine and L-mimosine, did block development at the trophozoite-schizont transition (S or G2 phase). The block caused by the latter 2 inhibitors was reversible, suggesting that they might be used as synchronizing agents. However, a consideration of the perturbing effects of inhibitors and problems with 'batch' synchronization techniques in general lead us to believe that any results obtained using roscovitine- or L-mimosine-treated parasites may not be reflective of the normal cell cycle.

Animals↗
PubMed2006

Characterization and application of multiple genetic markers for Plasmodium malariae.

Plasmodium malariae, a protozoan parasite that causes malaria in humans, has a global distribution in tropical and subtropical regions and is commonly found in sympatry with other Plasmodium species of humans. Little is known about the genetics or population structure of P. malariae. In the present study, we describe polymorphic genetic markers for P. malariae and present the first molecular epidemiological data for this parasite. Six microsatellite or minisatellite markers were validated using 76 P. malariae samples from a diverse geographical range. The repeat unit length varied from 2 to 17 bp, and up to 10 different alleles per locus were detected. Multiple genotypes of P. malariae were detected in 33 of 70 samples from humans with naturally acquired infection. Heterozygosity was calculated to be between 0.236 and 0.811. Allelic diversity was reduced for samples from South America and, at some loci, in samples from Thailand compared with those from Malawi. The number of unique multilocus genotypes defined using the 6 markers was significantly greater in Malawi than in Thailand, even when data from single genotype infections were used. There was a significant reduction in the multiplicity of infection in symptomatic infections compared with asymptomatic ones, suggesting that clinical episodes are usually caused by the expansion of a single genotype.

Alleles↗
PubMed1997

Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease.

The role of T-cells in development of experimental cerebral malaria was analysed in C57B1/6J and C57B1/10 mice infected with Plasmodium berghei K173 or Plasmodium berghei ANKA by treatment with anti-CD4 or anti-CD8 mAbs. Mice were protected against cerebral malaria (CM) when anti-CD4 or anti-CD8 mAbs were injected before or during infection. Even in mice in end-stage disease, i.e. with a body temperature below 35.5 degrees C, treatment with anti-CD4 or anti-CD8 antibodies or the combination protected against CM, whereas chloroquine treatment was completely ineffective in inhibiting further development of the cerebral syndrome.

Animals↗
PubMed1999

Interaction of Plasmodium gallinaceum ookinetes and oocysts with extracellular matrix proteins.

Plasmodium ookinetes are elongate, motile and invasive while inside the mosquito gut but promptly metamorphose into spherical immobile oocysts upon coming in contact with the basement membrane surrounding the midgut. There they begin a prolonged growth period characterized by massive DNA synthesis for the production of sporozoites. Living Plasmodium gallinaceum ookinetes attached avidly to the murine extracellular matrix proteins, laminin and collagen type IV. In ELISA-type assays, the main ookinete surface protein, Pgs28 was implicated as a mediator of parasite attachment to these basement membrane constituents. Laminin and collagen IV adhered to ookinete and oocyst lysates spotted onto nitrocellulose membranes. Receptor-ligand blot assays demonstrated that Pgs28 and an oocyst-specific antigen recognized by the mAb 10D6 interact with murine collagen IV and laminin. 10D6 antigen was also recognized by monospecific antiserum against the human epidermal growth factor receptor. Mosquito-derived laminin was incorporated into oocyst capsules of P. gallinaceum growing in Aedes aegypti. We hypothesize that contact with the mosquito basement membrane triggers the transformation of ookinetes into oocysts. Coalescence of basement membrane proteins onto the capsules masks developing oocysts from the mosquito's immune system and facilitates their prolonged extracellular development in the mosquito body cavity.

Aedes↗
PubMed2000

Plasmodium falciparum sporozoites increase feeding-associated mortality of their mosquito hosts Anopheles gambiae s.l.

There is some evidence that pathology induced by heavy malaria infections (many oocysts) increases mortality of infected mosquitoes. However, there is little or no published evidence that documented changes in feeding behaviour associated with malaria infection also contribute to higher mortality of infected mosquitoes relative to uninfected individuals. We show here for the first time that, in a natural situation, infection by the sporozoites of the malaria parasite Plasmodium falciparum significantly reduced survival of blood-feeding Anopheles gambiae, the major vector of malaria in sub-Saharan Africa. To estimate feeding-associated mortality of infected mosquitoes, we compared the percentage of sporozoite infection in host-seeking mosquitoes caught before and after feeding. The infection rate was 12% for mosquitoes caught during the night as they were entering a tent to feed; however, only 7.5% of the surviving members of the same cohort caught after they had had the opportunity to feed were infected. Thus, Plasmodium falciparum sporozoites increased the probability of dying during the night-time feeding period by 37.5%. The increase in mortality was probably due to decreased efficiency in obtaining blood and by increased feeding activity of the sporozoite-infected mosquitoes that elicited a greater degree of defensive behaviour of hosts under attack.

Animals↗