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PubMed2006

Advancements in transfection technologies for Plasmodium.

Malaria is a global problem that affects millions of people annually. A relatively poor understanding of the malaria parasite biology has hindered vaccine and drug development against this disease. Robust methods for genetic analyses in Plasmodium have been lacking due to the difficulties in its genetic manipulation. Introduction of transfection technologies laid the foundation for genetic dissection of Plasmodium and recent years have seen the development of novel tools for genetic manipulation that will help us delineate the intriguing biology of this parasite. This review focuses on such recent advances in transfection technologies for Plasmodium that have improved our ability to carry out more thorough genetic analyses of the biology of the malaria parasite.

Animals↗
PubMed2003

Validation of the hexose transporter of Plasmodium falciparum as a novel drug target.

Chemotherapy of malaria parasites is limited by established drug resistance and lack of novel targets. Intraerythrocytic stages of Plasmodium falciparum are wholly dependent on host glucose for energy. Glucose uptake is mediated by a parasite-encoded facilitative hexose transporter (PfHT). We report that O-3 hexose derivatives inhibit uptake of glucose and fructose by PfHT when expressed in Xenopus oocytes. Selectivity of these derivatives for PfHT is confirmed by lack of inhibition of hexose transport by the major mammalian glucose and fructose transporters (Gluts) 1 and 5. A long chain O-3 hexose derivative is the most effective inhibitor of PfHT and also kills P. falciparum when it is cultured in medium containing either glucose or fructose as a carbon source. To extend our observations to the second most important human malarial pathogen, we have cloned and expressed the Plasmodium vivax orthologue of PfHT, and demonstrate inhibition of glucose uptake by the long chain O-3 hexose derivative. Furthermore, multiplication of Plasmodium berghei in a mouse model is significantly reduced by the O-3 derivative. Our robust expression system conclusively validates PfHT as a novel drug target and is an important step in the development of novel antimalarials directed against membrane transport proteins.

Animals↗
PubMed2000

Frequent umbilical cord-blood and maternal-blood infections with Plasmodium falciparum, P. malariae, and P. ovale in Kenya.

The prevalence of malaria infection in 102 paired maternal-blood and umbilical cord-blood samples was assessed by microscopy and polymerase chain reaction (PCR) in a holoendemic area in Kenya. Plasmodium falciparum single-species infection was detected in maternal peripheral blood (3.4%), whereas microscopy indicated that no Plasmodium species were in cord blood. In contrast, maternal-blood samples showed a PCR prevalence of 48% for P. falciparum, 25% for P. malariae, and 24% for P. ovale, and cord-blood samples showed a PCR prevalence of 32%, 23%, and 21%, respectively. Although mothers with mixed-species infections were more likely to have offspring infected with mixed species, the specific malaria species were discordant in paired maternal- and cord-blood samples. Triple-species infections were observed in 11 cord- and maternal-blood samples at a 5.5-fold greater frequency than expected. These findings indicate that Plasmodium species infections in cord blood are common, occur at lower densities, and may be acquired before parturition.

Adolescent↗
PubMed1993

Evolutionary relatedness of some primate models of Plasmodium.

Primate--and, specifically, monkey--malaria infections are commonly used for understanding the pathology of and immune response to the human disease because they are thought to resemble most closely the host-parasite relationship found in humans. Plasmodium cynomolgi is used extensively as a model for the human parasite, P. vivax, and P. knowlesi is used primarily as a model for the development of erythrocytic-stage vaccines. Both of these simian parasites can naturally infect man, resulting in mildly symptomatic episodes of the disease. The phylogenetic relationship between these two simian parasites and previously characterized Plasmodium species, including P. vivax, was examined by comparison of the asexually expressed small-subunit ribosomal RNA genes. Our analysis confirmed that P. vivax is most closely related to P. cynomolgi and that it remains an appropriate model of the human pathogen. Furthermore, with P. knowlesi and P. fragile, these two species form a group of closely related species, distant from other Plasmodium species. What is considered to be the most ancient of the human malaria pathogens, P. malariae, was also included in the analysis and does not group at all with other simian or human parasites.

Animals↗
PubMed2003

In vivo antimalarial activities of mono- and bis quaternary ammonium salts interfering with Plasmodium phospholipid metabolism.

We previously showed that quaternary ammonium salts have potent antimalarial activities against the blood stage of drug-resistant Plasmodium falciparum. In the present study, 13 compounds of this series were comparatively assessed in murine in vivo malarial models. Mice infected with Plasmodium berghei were successfully treated with 11 quaternary ammonium salts in a 4-day suppressive test with a once-daily intraperitoneal administration. The dose required to decrease parasitemia by 50% (ED(50)) ranged from 0.04 to 4.5 mg/kg of body weight. For six mono- and three bis-quaternary ammonium salts, the therapeutic indices (i.e., 50% lethal dose and ED(50)) were higher than 5, and at best, around 20 to 30 for five of them (E6, E8, F4, G5, and G25), which is comparable to that of chloroquine under the same conditions. Plasmodium chabaudi was significantly more susceptible to G5, G15, and G25 compounds than P. berghei. Similar therapeutic indices were obtained, regardless of the administration mode or initial parasitemia (up to 11.2%). Parasitemia clearance was complete without recrudescence. Subcutaneously administered radioactive compounds had a short elimination half-life in mice (3.5 h) with low bioavailability (17.3%), which was likely due to the permanent cationic charge of the molecule. The high in vivo therapeutic index in the P. chabaudi-infected mouse model and the absence of recrudescence highlight the enormous potential of these quaternary ammonium salts for clinical malarial treatment.

Animals↗
PubMed2003

In vitro activities of 25 quinolones and fluoroquinolones against liver and blood stage Plasmodium spp.

The in vitro activities of 25 quinolones and fluoroquinolones against erythrocytic stages of Plasmodium falciparum and against liver stages of Plasmodium yoelii yoelii and P. falciparum were studied. All compounds were inhibitory for chloroquine-sensitive and chloroquine-resistant P. falciparum grown in red blood cells. This inhibitory effect increased with prolonged incubation and according to the logarithm of the drug concentration. Grepafloxacin, trovafloxacin, and ciprofloxacin were the most effective drugs, with 50% inhibitory concentrations of <10 micro g/ml against both strains. Only grepafloxacin, piromidic acid, and trovafloxacin had an inhibitory effect against hepatic stages of P. falciparum and P. yoelii yoelii; this effect combined reductions of the numbers and the sizes of schizonts in treated cultures. Thus, quinolones have a potential for treatment or prevention of malaria through their unique antiparasitic effect against erythrocytic and hepatic stages of Plasmodium.

4-Quinolones↗
PubMed1991

Characteristics of multidrug resistance in Plasmodium and Leishmania: detection of P-glycoprotein-like components.

Multidrug-resistance (MDR) in neoplastic cells is frequently characterized by the overexpression of P-glycoprotein (PGP), a 170 kDa transmembrane glycoprotein that binds multiple cytotoxic drugs as well as calcium channel antagonists. Chloroquine resistance in Plasmodium falciparum appears to be analogous to MDR in neoplastic cells, where the induction of resistance with one drug confers resistance to other structurally and functionally unrelated drugs. To test the hypothesis that chloroquine resistance in P. falciparum and antimony resistance in Leishmania is mediated by a similar mechanism of MDR in mammalian neoplastic cells, a PGP-specific monoclonal antibody (C219) was used to determine the presence of PGP genes in resistant and sensitive Plasmodium and Leishmania parasites by indirect immunofluorescence assays and Western blotting procedures. These PGP-like components were detected in both drug-sensitive and -resistant Plasmodium and Leishmania cells. A 40-42 kDa component was observed to be greater in a chloroquine-resistant P. berghei (C line) than in a chloroquine-susceptible P line. Differences observed between Pentostam-resistant and -sensitive Leishmania promastigote clones and isolates included the increased expression of 96-106 and 23-25 kDa peptides in drug-resistant L. enrietti, and increased amounts of two different peptides in two drug-resistant L. panamensis clones (i.e., 96-106 and 43-45 kDa in WR-746-CL4, and 53 and 23-25 kDa in kDa) in amastigotes as in MDR KB carcinoma cells (KB-V1). Comparative indirect immunofluorescent studies suggested that a correlation existed between the degree of antimony susceptibility and the concentration of the moiety recognized by C219 in two L. panamensis clones. Binding of the C219 monoclonal antibody to the PGP-like component of Leishmania was blocked by Pentostam, while the binding of C219 to multiple-drug resistant KB-V1 PGP was not inhibited by Pentostam, regardless of the PGP concentration. This suggests some degree of specificity in the binding of Pentostam to the Leishmania PGP-like components. In addition, these studies have demonstrated that drug-sensitive Leishmania accumulate two to five times more 125Sb-Pentostam than resistant clones.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Phase switching of oscillatory contraction in relation to the regulation of amoeboid behavior by the plasmodium of Physarum polycephalum.

The plasmodium of the true slime mould Physarum polycephalum is a large aggregate of protoplasm and behaves like an amoeboid cell, exhibiting rhythmic contraction everywhere within the organism. Phase dynamics of these oscillations were studied in relation to the global organization of amoeboid behavior, by analysing the thickness oscillation, isotonic tension and the motive force of the streaming. Usually the plasmodium showed synchrony, the phase of the oscillation being the same everywhere excepting the peripheral part. We found several situations where this in-phase relationship switched to anti-phase. This occurred either at the early stages of the plasmodial coalescence, or when a single plasmodium was nearly separated by partition, or when the streaming of the protoplasm was hindered by applying the hydrostatic pressure. Furthermore, the motive force of the protoplasmic streaming increased once the anti-phase relationship was established. In this way, the weak interactions among plasmodial parts induce the switching of phase relationship from in-phase to anti-phase, and this transition in turn acts to increase the interaction by promoting a rapid mixing of the protoplasm. This global feedback mechanism by phase switching should help maintain a large single plasmodium without separating into parts. The possible mechanism of phase switching is discussed in terms of coupled nonlinear oscillators.

Animals↗
PubMed1985

Activities of the tetrahydrofuran derivative, BA-41,799, against Plasmodium cynomolgi infections in rhesus monkeys.

BA-41,799, a tetrahydrofuran derivative that at one time attracted considerable interest as an antimalarial agent because of a combination of structural novelty with activities against infections with Plasmodium berghei and Plasmodium berghei yoelii in mice, has been evaluated for its capacities to effect prophylaxis and radical cure in rhesus monkeys challenged or already infected with sporozoites of the drug-susceptible Ro strain or the pyrimethamine-resistant Ro/PM strain of Plasmodium cynomolgi, and for its capacity to effect suppressive cure of infections with trophozoites of these strains. At doses up to the maximum tolerated, BA-41,799 had only marginal activity against infections with the Ro strain and none against the Ro/PM strain. On the basis of past experiences, the above results suggest that BA-41,799 would have little to offer for prophylaxis, radical cure, or suppression of human infections with Plasmodium vivax.

Animals↗
PubMed2000

Toxoplasma gondii homologue of plasmodium apical membrane antigen 1 is involved in invasion of host cells.

Proteins with constitutive or transient localization on the surface of Apicomplexa parasites are of particular interest for their potential role in the invasion of host cells. We describe the identification and characterization of TgAMA1, the Toxoplasma gondii homolog of the Plasmodium apical membrane antigen 1 (AMA1), which has been shown to elicit a protective immune response against merozoites dependent on the correct pairing of its numerous disulfide bonds. TgAMA1 shows between 19% (Plasmodium berghei) and 26% (Plasmodium yoelii) overall identity to the different Plasmodium AMA1 homologs and has a conserved arrangement of 16 cysteine residues and a putative transmembrane domain, indicating a similar architecture. The single-copy TgAMA1 gene is interrupted by seven introns and is transcribed into an mRNA of approximately 3.3 kb. The TgAMA1 protein is produced during intracellular tachyzoite replication and initially localizes to the micronemes, as determined by immunofluorescence assay and immunoelectron microscopy. Upon release of mature tachyzoites, TgAMA1 is found distributed predominantly on the apical end of the parasite surface. A approximately 54-kDa cleavage product of the large ectodomain is continuously released into the medium by extracellular parasites. Mouse antiserum against recombinant TgAMA1 blocked invasion of new host cells by approximately 40%. This and our inability to produce a viable TgAMA1 knock-out mutant indicate that this phylogenetically conserved protein fulfills a key function in the invasion of host cells by extracellular T. gondii tachyzoites.

Amino Acid Sequence↗
PubMed1998

Plasmodium coatneyi in the rhesus monkey (Macaca mulatta) as a model of malaria in pregnancy.

Pregnant women with Plasmodium falciparum infection are at increased risk for complications such as anemia and cerebral malaria. In addition, the infants of these women suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection, and high infant mortality. Although much has been learned from studies of malaria during human pregnancy, progress has been limited by the lack of a suitable animal model. Nonhuman primates are of particular interest because, other than the armadillo, they are the only animals with a discoidal, villous, hemochorial placenta like that of humans. We have established a model of malaria during human pregnancy by inoculating pregnant rhesus monkeys (Macaca mulatta) with Plasmodium coatneyi (a sequestering parasite) during the first trimester. In our initial experiment, four monkeys were inoculated with a fresh inoculum containing 10(8) viable parasites from an infected donor monkey. All four monkeys became parasitemic seven days postinoculation (PI) and three monkeys aborted 7-10 days PI coincident with high peak parasitemias (41,088-374,325 parasites/mm3). Although abortion is one of the outcomes observed in Plasmodium-infected women, the intent of this study was to examine the effects of Plasmodium infection throughout gestation. Since the rapid onset of high parasitemia may have been responsible for the abortions, a decision was made to reduce the size of the effective inoculum. Six additional pregnant monkeys were inoculated with a frozen isolate taken from the same donor containing 10(6) parasites. These six animals became parasitemic by 14 days PI and, along with monkey E412, carried their infants to term. These seven infants weighed significantly less at term than the infants of uninfected mothers (P = 0.0355). Symmetrical IUGR was detected by ultrasound in one fetus with an LBW of 334 g. Another LBW infant (300 g) had asymmetrical growth retardation, which has been associated with uteroplacental insufficiency and was consistent with the lower placental weights found in infected dams compared with controls (P = 0.0455). The infant with symmetric IUGR died at five days of age, while the other is alive but congenitally infected. The IUGR, LBW, congenital infection, postnatal infant mortality, and early abortions observed in these animals suggest that P. coatneyi in pregnant rhesus monkeys is a valid model of malaria in human pregnancy. This model should provide the opportunity to study questions about malaria in pregnancy that have been difficult to study in humans.

Abortion, Veterinary↗
PubMed1998

[Molecular cloning and sequencing of genes encoding MSP2 isolates strains from two of Plasmodium falciparum from Chinese patients with cerebral malaria].

OBJECTIVE: To provide the scientific evidence for designing safe and effective vaccines of human cerebral malaria. METHODS: Genomic DNA samples of two isolated Plasmodium falciparum isolate strains prepared directly from 5 cases of cerebral malaria patients' blood in mengla County, Yunnan Province (CMH/YN) and in Yingjiang County, Yunnan Province (CYJ/YN) were used for polymerase chain reaction (PCR) amplification and the two pairs of oligonucleotides for the highly conserved genes encoding FC27 merozoite surface protein 2 (MSP2) of Papua New Guinea strain of Plasmodium falciparum were used as primers. The PCR products were digested with BamH1 and Hind III respectively, and the generated fragment MSP2 were cloned into M13mp18 and M13mp19 vectors and their DNA was analyzed as the templates for DNA sequencing by the dideoxy chain-termination method. RESULTS: Compared with the published findings, FC27, K1, IC1 and CAMP sequences, DNA sequences of MSP2 from two isolated CMH/YN and CYJ/YN of Plasmodium falciparum strains from Chinese patients with cerebral malaria contained identical genes composed of 800 bp, encoding 264 amino acid, which were highly homologous up to 98.8% with that of FC27, K1 strain other than the IC1, CAMP strain. CONCLUSION: It is the first record of DNA sequencing of MSP2 determined from two isolated CMH/YN and CYJ/YN of Plasmodium falciparum strains from Chinese patients with cerebral malaria, MSP2 mutation may be one factor leading to the localized cerebral damage which causes clinical coma of human cerebral malaria.

Amino Acid Sequence↗
PubMed2005

Fibrinolytic activity in children with Plasmodium falciparum malaria.

BACKGROUND: Malaria infection is still one of the major causes of morbidity and mortality among the under five year children in tropical Africa. Clinical and laboratory methods of assessing the risk factors for severity in order to adequately manage these children, therefore needs to be identified so that prompt and adequate treatment can be instituted early. Fibrinolytic activity has been postulated as one of the risk factors associated with severity of malaria infection. OBJECTIVE: To measure fibrinolytic activity euglobulin lysis time, (ELT) and fibrinogen levels in 50 Nigerian children with Plasmodium falciparum infection. DESIGN: A cross sectional study. SETTING: University of Benin Teaching Hospital, Benin City, Nigeria between January and December 2002. SUBJECTS: Fifty Nigerian children who were admitted with Plasmodium falciparum malaria infection in the paediatric wards of the hospital were recruited into the study. Thirty-four apparently healthy children who did not have malaria fever but who came for growth monitoring exercise and had some investigations done as part of this exercise were used as control for the study. The fibrinolytic activity in all the 84 children (both that had malaria infection and those who did not have malaria infection) were estimated by measuring the euglobulin lysis time (ELT). The fibrinogen levels in all the children were also estimated. The packed cell volume of the children was determined and some severely anaemic children had blood transfusions. RESULTS: Euglobin lysis time (ELT) was found to be higher in children with Plasmodium falciparum malaria infection (430 +/- 149) than in the controls (158 +/- 21.7, P< 0.01). Fibrinogen levels of 3.40 +/- 0.98 in children with malaria infection were high when compared to 2.21 +/- 0.81 in the controls. The children with malaria infection therefore had a decreased fibrinolytic activity and a proportionately high fibrinogen level. The average packed cell volume of the children with malaria infection was 29.64 +/- 2.13 while in the control it was 36.41 +/- 3.24. The study also showed that 50% of children with malaria had severe anaemia and subsequently had blood transfusions. Twenty percent of those who had transfusions died while being transfused. CONCLUSION: Children who have malaria infection have decreased fibrinolytic activity and proportionately high fibrinogen level which may contribute to the possible thromboembolic process in these children and hence higher risk of mortality from Plasmodium falciparum malaria infection.

Blood Coagulation Tests↗
PubMed2005

[Congenital malaria as a result of Plasmodium malariae in an infant born to a HIV-seropositive woman].

Congenital malaria is uncommon in France. The purpose of this report is to describe a case involving a six-week-old infant who was hospitalized with fever, hepatosplenomegaly, anemia and thrombopenia. Thick and thin blood smears were positive for Plasmodium malariae. The infant responded favorably to chloroquine. Based on this experience, we performed a search of the literature to find case reports on congenital malaria in France and compare clinical and epidemiologic data with series reported in the United States and from endemic areas. The placenta appears to provide an effective barrier against Plasmodium since infection is much more common than disease. The delay for onset of clinical symptoms is longer in temperate zones than in endemic areas. The type of parasite could account for this difference since African congenital malaria are due to Plasmodium falciparum while most cases described in the United States are due to Plasmodium vivax. We also discuss the possible implications of coinfection by HIV in the mother.

Antimalarials↗
PubMed1994

A change of Plasmodium species infecting children in Karachi over the last decade.

Febrile children of both sexes, aged between 0-15 years coming to the Civil Hospital over the last 12 years had their blood tested for malarial parasite. Five hundred and twenty-six slides positive for Plasmodium were analysed for species and stage identification. Of the total 59.3% children with malaria were between 5-15 years of age. Applying the test of proportion, Plasmodium vivax was the predominant species (P < 0.01) between 1981-1985 and plasmodium falciparum between 1986-1990. This trend persisted upto 1992. As malaria due to Plasmodium falciparum is more severe with multiple complications accurate and easier methods of its diagnosis are needed at primary health care level.

Adolescent↗
PubMed1996

[The halofantrine treatment of Plasmodium falciparum malaria. Clinical experience].

UNLABELLED: The objective of this study was to evaluate the efficacy of halofantrine in the treatment of malaria caused by Plasmodium falciparum since the resistance of these plasmodium to chloroquine is increasing in countries of Western Africa. MATERIAL AND METHOD: Between January 1991 and June 1994 we studied 50 children from Equatorial Guinea. All of them were black and between the ages of 8 months and 13 years. They were treated with 3 doses of halofantrine (8 mg/kg every 6 hours). The definitive diagnosis was made by the demonstration of the parasites on thick and thin blood smears, stained by standard methods, repeated every 24-72 yours after therapy. We considered the disappearance of fever and the clearance of plasmodium from the red blood cells as signs of response to the treatment. We also monitored the tolerance and the adverse side effects of the drug. RESULTS: All of the patients responded favorably with the disappearance of the fever after 24 hours and after 72 hours no parasites were seen in red blood cells. Only one patient had a recurrence, which occurred on the 10th day. All patient satisfactorily tolerated the drug and only 3 children showed an increase of aminotransferases that was spontaneously cured. CONCLUSIONS: We conclude that halofantrine is a safe and efficient drug for the treatment of children diagnosed with malaria caused by Plasmodium falciparum.

Adolescent↗
PubMed2005

Plasmodium (Haemamoeba) cathemerium gene sequences for phylogenetic analysis of malaria parasites.

The DNA sequence information on avian malaria parasites of the genus Plasmodium is quite limited. At present, sequences of only 6 out of 34 valid species are available. However, sequence data of avian malaria parasites are particularly important with regard to the resolution of the phylogenetic relationships of the most virulent human malaria agent, Plasmodium falciparum. The question as to whether P. falciparum originates from avian or from mammalian parasites would contribute to our understanding of its biology and would probably facilitate the interpretation of experimental results. To add to the body of molecular data, we sequenced three genes (cytochrome b, 18 SSU rRNA, caseinolytic protease C) of different organellar origin of one of the most widespread avian malaria parasites, Plasmodium (Haemamoeba) cathemerium, which once used to be an important laboratory in vivo model in human malaria research. The analysis of the new P. cathemerium sequences in direct comparison with the rodent parasite P. berghei and the four human malaria parasites by pairwise distance calculation do not suggest a closer relationship of P. cathemerium to P. falciparum than to the other species involved.

Animals↗
PubMed1988

Primary sequences of two small subunit ribosomal RNA genes from Plasmodium falciparum.

We have determined the complete sequence of two structurally distinct 18S ribosomal RNA genes from the malarial parasite Plasmodium falciparum. S1 nuclease analyses demonstrate that only one of the genes is represented in stable rRNA populations isolated from blood-stage parasites. Comparisons of homologous rRNA genes from Plasmodium berghei and P. falciparum reveal that they are identical at 86% of their positions. From comparisons of the Plasmodium genes to that of humans, it was possible to design genus-specific as well as species-specific oligonucleotide probes that can be used to distinguish the parasite 18S ribosomal RNA from that of its host. The utilization of these probes as diagnostic reagents is discussed.

Animals↗