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PubMed2003

Blood schizontocidal activity of WR 238605 (Tafenoquine) against Plasmodium cynomolgi and Plasmodium fragile infections in rhesus monkeys.

A new 8-aminoquinoline antimalarial WR 238605 (Tafenoquine), developed initially as a primaquine alternative for prevention of Plasmodium vivax relapses was evaluated for blood schizontocidal activity against two simian malaria infections namely Plasmodium cynomolgi B and Plasmodium fragile in rhesus monkeys. Treatment with WR 238605 at a dose of 3.16 mg(base)/kg/day x 7 days cured established trophozoite induced infections in monkeys with both these parasites. The lower dose of 1.00 mg/kg/day cured 9 out of 12 monkeys infected with P. cynomolgi B and 10 out of 11 monkeys infected with P. fragile. Primaquine was only partially curative at 10.0 mg(base)/kg/day x 7 dose regimen against both these infections. The potent blood schizontocidal activity of tafenoquine adds to the armoury of antimalarial drugs.

Aminoquinolines↗

PubMed1991

Primary structure of the merozoite surface antigen 1 of Plasmodium vivax reveals sequences conserved between different Plasmodium species.

Merozoite surface antigen 1 (MSA1) of several species of plasmodia has been shown to be a promising candidate for a vaccine directed against the asexual blood stages of malaria. We report the cloning and characterization of the MSA1 gene of the human malaria parasite Plasmodium vivax. This gene, which we call Pv200, encodes a polypeptide of 1726 amino acids and displays features described for MSA1 genes of other species, such as signal peptide and anchoring sequences, conserved cysteine residues, number of potential N-glycosylation sites, and repeats consisting here of 23 glutamine residues in a row. When the nucleotide and deduced amino acid sequences of the MSA1 of P. vivax are compared to those of another human malaria parasite, Plasmodium falciparum, and to those of the rodent parasite Plasmodium yoelii, 10 regions of high amino acid similarity are observed despite the very different dG + dC contents of the corresponding genes. All of the interspecies conserved regions reside within the conserved or semiconserved blocks delimited by the sequences of different alleles of the MSA1 gene of P. falciparum.

Amino Acid Sequence↗

PubMed2003

Rediscovery and redescription of Plasmodium pifanoi and description of two additional Plasmodium parasites of Venezuelan lizards.

Plasmodium pifanoi Scorza and Dagert B., known only from the type host, Ameiva ameiva, is redescribed from Kentropyx calcarata collected in Territorio Amazonas, Venezuela. Schizonts, 6.2 x 4.5 (4-8 x 3-6), produce on average 11.9 (7-16) merozoites. Gametocytes average 12.4 x 6.0 (8-16 x 4-10), with length x width (LW) 72.9 (52-112) and L/W 2.18 (1.1-3.3), and always contain 1-5 prominent vacuoles. Macrogametocytes in active infection are longer than microgametocytes, with greater LW, but gametocytes in chronic infection are not sexually dimorphic in dimension and are slightly smaller. Two additional malarial parasites are described from K. calcarata. Plasmodium lepidoptiformis has small schizonts, 4.6 x 3.2 (3-6 x 2.5-3), that produce 5.1 (4-8) merozoites and commonly resemble a butterfly in appearance. Gametocytes are elongate, 9.0 x 4.3 (7-10 x 3-6), with LW 38.3 (24-51) and L/W 2.2 (1.3-3.3), and sexually dimorphic, with macrogametocytes longer than microgametocytes, with greater LW. Plasmodium minasense calcaratae is characterized by very small, usually fan-shaped, schizonts. 3.4 x 2.6 (2.5-4.5 x 2.0-3.0), that produce 3.9 (3-4) merozoites. Gametocytes are spherical or ovoid, 6.7 x 5.0 (4.5-9.0 x 3.0-7.0), with LW 33.7 (15-54) and L/W 1.4 (1.0-2.3), with no sexual dimorphism in dimensions.

Animals↗

PubMed1994

In vitro cultivation of exoerythrocytic stages of the simian malaria parasites Plasmodium fieldi and Plasmodium simiovale in rhesus monkey hepatocytes.

Exoerythrocytic stage parasites of Plasmodium fieldi and Plasmodium simiovale, 2 simian malaria parasites related to the human malaria parasite Plasmodium ovale, were cultured in vitro by inoculating primary cultures of hepatocytes from rhesus monkeys (Macaca mulatta) with sporozoites. Less than 1% of sporozoites developed into schizonts for either species. Structure and size of the liver stages in both species were similar to previous in vivo descriptions, and the time required for in vitro maturation correlated well with the prepatent periods described for each species. Such monkey models could be very useful in conducting scientific investigations on the pre-erythrocytic stages of P. ovale-like malaria parasites.

Animals↗

PubMed2003

Phylogenetic analysis of CSP and MSP-9 gene sequences demonstrates the close relationship of Plasmodium coatneyi to Plasmodium knowlesi.

Plasmodium coatneyi is a simian malaria parasite with various biological features similar to the human malaria P. falciparum and potential as a model for severe cases of malaria. We have characterized two single-copy genes from P. coatneyi, the circumsporozoite protein and merozoite surface protein-9 genes, and determined its phylogenetic relationship among Plasmodium species. This study demonstrates that while it has similarities to P. falciparum, P. coatneyi belongs to a distant clade including several simian malaria parasites and the human malaria P. vivax. P. coatneyi forms a monophyletic group with P. knowlesi, demonstrating their close relationship despite some very distinctive biological characteristics.

Amino Acid Sequence↗

PubMed2002

Comparative characterization of hexose transporters of Plasmodium knowlesi, Plasmodium yoelii and Toxoplasma gondii highlights functional differences within the apicomplexan family.

Chemotherapy of apicomplexan parasites is limited by emerging drug resistance or lack of novel targets. PfHT1, the Plasmodium falciparum hexose transporter 1, is a promising new drug target because asexual-stage malarial parasites depend wholly on glucose for energy. We have performed a comparative functional characterization of PfHT1 and hexose transporters of the simian malarial parasite P. knowlesi (PkHT1), the rodent parasite P. yoelii (PyHT1) and the human apicomplexan parasite Toxoplasma gondii ( T. gondii glucose transporter 1, TgGT1). PkHT1 and PyHT1 share >70% amino acid identity with PfHT1, while TgGT1 is more divergent (37.2% identity). All transporters mediate uptake of D-glucose and D-fructose. PyHT1 has an affinity for glucose ( K (m) approximately 0.12 mM) that is higher than that for PkHT1 ( K (m) approximately 0.67 mM) or PfHT1 ( K (m) approximately 1 mM). TgGT1 is highly temperature dependent (the Q (10) value, the fold change in activity for a 10 degrees C change in temperature, was >7) compared with Plasmodium transporters ( Q (10), 1.5-2.5), and overall has the highest affinity for glucose ( K (m) approximately 30 microM). Using active analogues in competition for glucose uptake, experiments show that hydroxyl groups at the C-3, C-4 and C-6 positions are important in interacting with PkHT1, PyHT1 and TgGT1. This study defines models useful to study the biology of apicomplexan hexose permeation pathways, as well as contributing to drug development.

Amino Acid Sequence↗

PubMed2004

Changing scenario of malaria in central India, the replacement of Plasmodium vivax by Plasmodium falciparum (1986-2000).

OBJECTIVES: Since 1986, we have been studying the changing epidemiology of malaria in a forest belt of Mandla, which has the highest number of malaria cases in central India (Madhya Pradesh) to define the epidemiological characteristics of the infection with each Plasmodium species in different seasons of the year. Our long-term objective was to determine the dynamics of Plasmodium vivax vs.P. falciparum infections. METHODS: Five villages underwent fortnightly surveillance of fever cases. Drugs were distributed within 24 h after results of blood smears became available as per Indian National Anti-Malaria Programme. Indoor resting mosquitoes were also collected fortnightly. RESULTS: The only two Plasmodium species encountered were P. vivax and P. falciparum in both children and adults. Relatively more malaria infections were recorded in children (< or =14 years) than adults (>14 years) (chi2=89.94, P<0.00001). However, there were significant falling trends in P. vivax from 1986 to 2000 in both age groups (< or =14 years from 63 to 13, P<0.0001 and >14 years from 84 to 7, P<0.0001). The indoor resting density of Anopheles culicifacies, an efficient vector resistant to both dichlorodiphenyltrichloroethane (DDT) (4%) and hexachlorocyclohexane (HCH) (0.4%), was very high throughout this period in all villages (52.35 +/- 31.8, range 5-200 per man hour). Anopheles fluviatilis was present in small numbers 0.78 +/- 1.24 (range 0-7 per man hour). CONCLUSION: Major contributors of the changing epidemiology of malaria in this area are changing drug sensitivity along with insecticide sensitivity.

Adolescent↗

PubMed1998

Evaluation of the OptiMAL test for rapid diagnosis of Plasmodium vivax and Plasmodium falciparum malaria.

The development of rapid and specific diagnostic tests to identify individuals infected with malaria is of paramount importance in efforts to control the severe public health impact of this disease. This study evaluated the ability of a newly developed rapid malaria diagnostic test, OptiMAL (Flow Inc., Portland, Oreg.), to detect Plasmodium vivax and Plasmodium falciparum malaria during an outbreak in Honduras. OptiMAL is a rapid (10-min) malaria detection test which utilizes a dipstick coated with monoclonal antibodies against the intracellular metabolic enzyme parasite lactate dehydrogenase (pLDH). Differentiation of malaria parasites is based on antigenic differences between the pLDH isoforms. Since pLDH is produced only by live Plasmodium parasites, this test has the ability to differentiate live from dead organisms. Results from the OptiMAL test were compared to those obtained by reading 100 fields of traditional Giemsa-stained thick-smear blood films. Whole-blood samples were obtained from 202 patients suspected of having malaria. A total of 96 samples (48%) were positive by blood films, while 91 (45%) were positive by the OptiMAL test. The blood films indicated that 82% (79 of 96) of the patients were positive for P. vivax and 18% (17 of 96) were infected with P. falciparum. The OptiMAL test showed that 81% (74 of 91) were positive for P. vivax and 19% (17 of 91) were positive for P. falciparum. These results demonstrated that the OptiMAL test had sensitivities of 94 and 88% and specificities of 100 and 99%, respectively, when compared to traditional blood films for the detection of P. vivax and P. falciparum malaria. Blood samples not identified by OptiMAL as malaria positive normally contained parasites at concentrations of less than 100/microl of blood. Samples found to contain P. falciparum were further tested by two other commercially available rapid malaria diagnostic tests, ParaSight-F (Becton Dickinson, Cockeysville, Md.) and ICT Malaria P.f. (ICT Diagnostics, Sydney, Australia), both of which detect only P. falciparum. Only 11 of the 17 (65%) P. falciparum-positive blood samples were identified by the ICT and ParaSight-F tests. Thus, OptiMAL correctly identified P. falciparum malaria parasites in patient blood samples more often than did the other two commercially available diagnostic tests and showed an excellent correlation with traditional blood films in the identification of both P. vivax malaria and P. falciparum malaria. We conclude that the OptiMAL test is an effective tool for the rapid diagnosis of malaria.

Humans↗

PubMed2002

Performance of OptiMAL(R) in the diagnosis of Plasmodium vivax and Plasmodium falciparum infections in a malaria referral center in Colombia.

Alternative, non-microscopic methods for the diagnosis of malaria have recently become available. Among these, rapid dipstick methods stand out. One such test, OptiMAL(R), is based on the immunochromatographic detection of Plasmodium lactate dehydrogenase (pLDH) and has the capacity to detect and distinguish infections caused by P. falciparum and Plasmodium sp. This capacity is particularly important in countries where different species of Plasmodium co-exist. In this study we evaluated the performance of OptiMAL(R) in an urban referral center for malaria diagnosis. Two sets of patients were included: one (n = 112) having predetermined infections with P. falciparum or P. vivax and individuals with negative blood smears; and another consisting of all eligible consecutive patients (n = 80) consulting for diagnosis at the referral center during one month. The overall diagnostic efficiency of OptiMAL(R) for both sets of patients was 96.9%. Efficiency was higher for P. vivax (98.1%) than for P. falciparum (94.9%). These results corroborate the diagnostic utility of OptiMAL(R) in settings where P. vivax and P. falciparum co-exist and support its implementation where microscopic diagnosis is unavailable and in circumstances that exceed the capacity of the local microscopic diagnosis facility.

Animals↗

PubMed2001

Contemporaneous and successive mixed Plasmodium falciparum and Plasmodium vivax infections are associated with Ascaris lumbricoides: an immunomodulating effect?

Following an investigation suggesting a protective role for Ascaris against cerebral malaria, possibly through immunomodulation, we examined whether Ascaris had any impact on mixed Plasmodium falciparum and Plasmodium vivax infections. We studied a cross section of 928 patient files between 1991 and 1999. Forty patients had contemporaneous mixed infections and 40 patients had P. falciparum infections, followed by P. vivax infections. There was a significant association between Ascaris infection and risk of having both contemporaneous or successive mixed P. falciparum and P. vivax infections (adjusted odds ratios respectively 6 [2-18] P = 0.001 and 3.6 [1.2-11.1] P = 0.02). There was a positive linear trend between the burden of Ascaris and the risk of mixed infections P < 0.0001. These results suggested the possibility that pre-existing Ascaris infection may increase tolerance of the host to different Plasmodium spp., thus facilitating their coexistence.

Animals↗

PubMed1998

Malaria diagnosis by dipstick assay in a Honduran population with coendemic Plasmodium falciparum and Plasmodium vivax.

A Plasmodium lactate dehydrogenase dipstick designed to separately detect P. falciparum and P. vivax malaria was evaluated in two Honduran populations where both species are endemic. The dipstick was compared to thick film microscopy; the polymerase chain reaction (PCR) was used to analyze discordant results. The dipstick had a sensitivity of 100% and a specificity of 95% compared with microscopy in the diagnosis of Plasmodium infections in a hospital population; the mean parasite density was approximately 590/mm3. In a field sample of mostly asymptomatic volunteers, the sensitivity of the dipstick for Plasmodium infection varied with parasite density. Additionally, the sensitivity and specificity of the dipstick was similar to thick film microscopy in the diagnosis of vivax malaria compared with the PCR. The dipstick was unable to detect P. vivax in the presence of P. falciparum because of cross-reactivity in the pan-specific band. Accurate species identification in mixed infections remains a problem in malaria diagnosis.

Clinical Enzyme Tests↗

PubMed1995

Plasmodium falciparum and Plasmodium vivax: lactate dehydrogenase activity and its application for in vitro drug susceptibility assay.

Lactate dehydrogenase, the terminal enzyme of anerobic Embden-Meyerhoff glycolysis, plays an important role in the carbohydrate metabolism of human malaria parasites. Based on the ability of malarial lactate dehydrogenase to use 3-acetylpyridine NAD as a coenzyme in a reaction leading to the formation of pyruvate from L-lactate, the enzymatic activity of fresh clinical isolates of Plasmodium falciparum and Plasmodium vivax was determined in relation to incubation time, asexual stages, and parasitemia and applied to a drug susceptibility assay. Lactate dehydrogenase activity was detectable at a parasitemia > 0.4%, at a hematocrit of 1.5%, and increased with parasitemia. Maximal lactate dehydrogenase activity was generally observed between 36 and 48 hr, when the trophozoites and schizonts predominated. The results of the in vitro drug susceptibility assays based on the inhibition of lactate dehydrogenase activity and on the incorporation of tritium-labeled hypoxanthine were correlated. For an optimal performance against fresh clinical malaria isolates, however, the enzymatic assay requires an initial parasitemia between 1 and 2% at a hematocrit of 1.5%.

Animals↗

PubMed2002

Mitochondrial NADH dehydrogenase from Plasmodium falciparum and Plasmodium berghei.

The mitochondrial electron transport system is necessary for growth and survival of malarial parasites in mammalian host cells. NADH dehydrogenase of respiratory complex I was demonstrated in isolated mitochondrial organelles of the human parasite Plasmodium falciparum and the mouse parasite Plasmodium berghei by using the specific inhibitor rotenone on oxygen consumption and enzyme activity. It was partially purified by two sequential steps of fast protein liquid chromatographic techniques from n-octyl glucoside solubilization of the isolated mitochondria of both parasites. In addition, physical and kinetic properties of the malarial enzymes were compared to the host mouse liver mitochondrial respiratory complex I either as intact or as partially purified forms. The malarial enzyme required both NADH and ubiquinone for maximal catalysis. Furthermore, rotenone and plumbagin (ubiquinone analog) showed strong inhibitory effect against the purified malarial enzymes and had antimalarial activity against in vitro growth of P. falciparum. Some unique properties suggest that the enzyme could be exploited as chemotherapeutic target for drug development, and it may have physiological significance in the mitochondrial metabolism of the parasite.

Animals↗

PubMed1999

The blood-stage dynamics of mixed Plasmodium malariae-Plasmodium falciparum infections.

We present the first mathematical model of the within-host dynamics of a mixed-species malaria infection in a human: the blood-stage population dynamics of a dual infection with Plasmodium malariae and Plasmodium falciparum. Our results reproduce several important features of such infections in nature, including the asymmetry of species asexual-form densities, inter-specific suppression through interactions with the human immune system, and seasonal alternations in species prevalence. Most importantly, our results suggest that an existing P. malariae infection can reduce the peak parasitemia of a subsequent P. falciparum superinfection by as much as 50%. This result integrates numerous empirical observations and supports the hypothesis that clinical outcomes of P. falciparum infections may be influenced by the presence of a congener.

Animals↗

PubMed2004

Genetic distance in housekeeping genes between Plasmodium falciparum and Plasmodium reichenowi and within P. falciparum.

The time to the most recent common ancestor of the extant populations of Plasmodium falciparum is controversial. The controversy primarily stems from the limited availability of sequences from Plasmodium reichenowi, a chimpanzee malaria parasite closely related to P. falciparum. Since the rate of nucleotide substitution differs in different loci and DNA regions, the estimation of genetic distance between P. falciparum and P. reichenowi should be performed using orthologous sequences that are evolving neutrally. Here, we obtained full-length sequences of two housekeeping genes, sarcoplasmic and endoplasmic reticulum Ca2+ -ATPase (serca) and lactate dehydrogenase (ldh), from 11 isolates of P. falciparum and 1 isolate of P. reichenowi and estimate the interspecific genetic distance (divergence) between the two species and intraspecific genetic distance (polymorphism) within P. falciparum. Interspecific distance and intraspecific distance at synonymous sites of interspecies-conserved regions of serca and ldh were 0.0672 +/- 0.0088 and 0.0011 +/- 0.0007, respectively, using the Nei and Gojobori method. Based on the ratio of interspecific distance to intraspecific distance, the time to the most recent common ancestor of P. falciparum was estimated to be (8.30 +/- 5.40) x 10(4) and (11.62 +/- 7.56) x 10(4) years ago, assuming the divergence time of the two parasite species to be 5 and 7 million years ago, respectively.

Amino Acid Sequence↗

PubMed1992

Inhibition of the growth of Plasmodium falciparum and Plasmodium berghei in vitro by an extract of Cochlospermum angolense (Welw.).

An extract of Cochlospermum angolense (Welw.) is used in the traditional medicine of Angola for the therapy of icterus and for the prophylaxis of malaria. From the roots of this plant red crystalline substances have been isolated and tested for their effect on Plasmodium falciparum in vitro and on the DNA and protein synthesis of Plasmodium berghei. The multiplication of P. falciparum was decreased to 50% of the control in the presence of 10 micrograms/ml extracted material and there was a total inhibition at a concentration of 50 micrograms/ml. If mice erythrocytes infected by P. berghei were incubated for 6 h with 25 micrograms/ml of the extract DNA synthesis was depressed to nearly background level. And, even more important, this effect could be demonstrated immediately. On the contrary, protein synthesis continued for at least 90 min at a reduced rate and stopped then. The results obtained show the direct antiparasitic effect of the substances extracted from C. angolense. The activity seems to be directed against DNA synthesis.

Animals↗

PubMed1992

Plasmodium falciparum and Plasmodium chabaudi: characterization of glycosylphosphatidylinositol-degrading activities.

Merozoites of malaria parasites have a membrane-bound serine protease whose solubilization and subsequent activity depend on a parasite-derived glycosylphosphatidylinositol-phospholipase C (GPI-PLC). The GPI-degrading activities from both Plasmodium falciparum and Plasmodium chabaudi have been characterized and partially purified by phenylboronate chromatography. They are membrane-bound, developmentally regulated, calcium-independent enzymes and as such they resemble GPI-PLC of Trypanosoma brucei. Furthermore, a T. brucei GPI-PLC-specific monoclonal antibody (mAT3) immunoprecipitates the plasmodial GPI-degrading activity. Thin-layer chromatography is suggestive of two activities: a GPI-PLC and a phospholipase A.

Animals↗

PubMed1995

Cutaneous delayed-type hypersensitivity responsiveness in patients during and after Plasmodium falciparum and Plasmodium vivax infections.

To assess cellular immune function in malaria, 61 patients admitted to the Bangkok Hospital for Tropical Diseases with Plasmodium falciparum (PF) or Plasmodium vivax malaria were examined with the MULTITEST CMI system (Merieux Institute, Florida) to evaluate delayed-type hypersensitivity (DTH) during and after acute disease over 4 weeks. All patients demonstrated significantly decreased responsiveness to seven commonly encountered recall antigens. This deficit was most severe immediately upon admission (prior to therapy). Uncomplicated Pf cases demonstrated significant hyporesponsiveness only during Week 1. Responses in moderate/severe falciparum and all vivax patients gradually increased in Weeks 2 and 3 but remained significantly below control values. This study confirms functional cell-mediated immune deficits in falciparum malaria and, for the first time, shows hyporesponsiveness in vivax malaria. We conclude that malaria causes a pronounced CMI deficit that is still detectable in some individuals for 3-4 weeks after treatment of acute infection. These changes in DTH should be a consideration in future vaccine development and in evaluation of immune status in endemic areas.

Acute Disease↗