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Title

Studies on plasmepsins I and II from the malarial parasite Plasmodium falciparum and their exploitation as drug targets

Author(s)

Moon RP, Bur D, Loetscher H, D'Arcy A, Tyas L, Oefner C, Grueninger-Leitch F, Mona D, Rupp K, Dorn A, Matile H, Certa U, Berry C, Kay J, Ridley RG

Source

Adv.Exp.Med.Biol. 436 (1998)

Page(s)

397-406

Document

Article

Abstract

not available

Title

Plasmepsins I and II from the malarial parasite Plasmodium falciparum

Author(s)

Tyas L, Moon RP, Loetscher H, Dunn BM, Kay J, Ridley RG, Berry C

Source

Adv.Exp.Med.Biol. 436 (1998)

Page(s)

407-411

Document

Article

Abstract

not available

Title

Seasonal variation in agglutination of Plasmodium falciparum-infected erythrocytes

Author(s)

Giha HA, Theander TG, Staalso T, Roper C, Elhassan IM, Babiker H, Satti GMH, Arnot DE, Hviid L

Source

Am.J.Trop.Med.Hyg. 58 4 (1998 Apr)

Page(s)

399-405

Document

Article

Abstract

Agglutination and rosette formation are in vitro characteristics of Plasmodium falciparum-infected erythrocytes, which have been associated with host protective immune responses and also with parasite virulence. The present study was carried out in an area of seasonal and unstable malaria transmission in eastern Sudan. Plasma samples were obtained before, during, and after the transmission season from a volunteer cohort of 64 individuals seven years of age and older. These plasmas were assayed for their ability to agglutinate cultured parasitized erythrocytes originally obtained from acute malaria infection samples taken from five of the cohort members. Our data show that the capacity of donor plasma samples to agglutinate parasitized cells depended largely on the time of sampling relative to the transmission season, at least within this epidemiologic setting. Thus, although less than half of the pretransmission season samples could agglutinate any of the five lines of cultured parasites, all post-transmission season samples could agglutinate at least one of the parasite lines, with 74% agglutinating two or more lines. This increase in the agglutination capacity of individual plasma samples after the transmission season occurred essentially regardless of whether and individual had experienced a clinical malaria attack during the transmission season. The study thus confirms the acquisition of agglutinating antibodies following episodes of clinical malaria, but also demonstrates that such acquisition can take place in the absence of disease, presumably as a consequence of subclinical infection. This is the first demonstration of marked seasonal fluctuations in the capacity of individuals' sera to agglutinate parasitized red blood cells. Possible explanations for this effect include a decrease in the levels of agglutinating antibodies between seasons, or shifts in the antigens being recognized by such antibodies from one transmission season to the next. Finally, we showed the existence of marked seasonal fluctuation in the levels of agglutinating antibodies, either because levels of such antibodies are not sustained between seasons or because the antigens recognized change from one season to the next.

Title

IgG3 antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2): Increasing prevalence with age and association with clinical immunity to malaria

Author(s)

Taylor RR, Allen SJ, Greenwood BM, Riley EM

Source

Am.J.Trop.Med.Hyg. 58 4 (1998 Apr)

Page(s)

406-413

Document

Article

Abstract

In a cross-sectional survey carried out in west Africa (The Gambia), where Plasmodium falciparum malaria is endemic with seasonal transmission, 178 individuals 1-75 years of age were assessed for their antibody response to the malaria vaccine candidate, merozoite surface protein 2 (MSP2). Total IgG to recombinant antigens representing full-length, repetitive, and group-specific domains of both allelic families of MSP2 was determined by ELISA. The IgG-subclass profile of IgG-positive sera was assessed. Antibody prevalence was age-dependent, reaching a peak during adolescence. In MSP2-seropositive individuals, there was a predominance of cytophilic antibodies (IgG1 and IgG3); IgG1 antibodies were prevalent in children less than 10 years of age, whereas in adolescents and adults MSP2-specific antibodies were predominantly IgG3. In parallel, we conducted a longitudinal study of children (3-8 years of age) from the same community; sera collected before the malaria transmission season were tested for the presence of anti-MSP2 antibodies. The subsequent susceptibility of these children to clinical malaria was monitored and the association between anti-MSP2 antibodies of different IgG subclasses and resistance to clinical malaria was tested. The presence of IgG3 antibodies to MSP2 serogroup A was negatively associated with the risk of clinical malaria whereas IgG1 antibodies to MSP2 serogroup B were associated with an increased risk of clinical infection. Our data suggest that age/exposure-related acquisition of IgG3 antibodies to MSP2, may contribute to the development of clinically protective immunity to malaria.

Title

Allopurinol as an additive to quinine in the treatment of acute complicated falciparum malaria

Author(s)

Sarma PSA, Mandal AK, Khamis HJ

Source

Am.J.Trop.Med.Hyg. 58 4 (1998 Apr)

Page(s)

454-457

Document

Article

Abstract

The emergence of chloroquine resistance, and a world-wide scarcity of quinine, have resulted in a search for newer antimalarial drugs directed against falciparum malaria. Allopurinol causes virtually complete inhibition of purine biosynthesis of malaria parasites, which may prove lethal to the parasites. This study was designed to examine if allopurinol is additive to quinine in the treatment of acute falciparum malaria. Forty-seven Asian-Indian adults with acute complicated falciparum malaria were assigned to a treatment period of five days. They were randomly assigned to receive either oral allopurinol (12 mg/kg in three divided doses for five days) plus quinine (600 mg intravenously every 8 hr for two days, followed by 600 mg orally every 8 hr for three days) (n = 24), or quinine alone (600 mg intravenously every 8 hr for two days, followed by 600 mg orally every 8 hr for three days) (n 23). The responses were assessed by parasite clearance time, defervescence time, splenomegaly disappearance time, and cure rate. In the allopurinol-quinine (ALLQUIN)-treated group, all the durations were significantly shorter than those in the quinine alone (QUIN)-treated group. They were ALLQUIN versus QUIN (mean +/- SD = 65.33 +/- 11.47 hr versus 76.78 +/- 18.30 hr; P = 0.0214; 57.66 +/- 13.01 hr versus 82.52 +/- 23.55 hr, P = 0.0002; 10 +/- 1.64 days versus 14.65 +/- 2.4 days; P = 0.0002), respectively. The cure rate was higher in the ALLQUIN group (91.7%) than in the QUIN group (87%). However this difference was not statistically significant. Therefore, this study indicates that allopurinol can be an additive to quinine to bring about both faster eradication of Plasmodium falciparum and clinical remission than with quinine alone.

Title

Genetic control of blood infection levels in human malaria: Evidence for a complex genetic model

Author(s)

Garcia A, Cot M, Chippaux JP, Ranque S, Feingold J, Demenais F, Abel L

Source

Am.J.Trop.Med.Hyg. 58 4 (1998 Apr)

Page(s)

480-488

Document

Article

Abstract

There is now accumulating evidence for the involvement of genetic factors in the control of immune response against malaria. These arguments come from numerous animal models, from population studies showing associations of red blood cell genetic defects as well as HLA antigens with severe malaria, and from familial studies including a recent segregation analysis, which led to detection of a major gene effect predisposing to high infection levels. The heterogeneity and complexity of this genetic control is one of the main findings of these previous studies, and probably a major cause of the difficulty in developing an effective malaria vaccine. A segregation analysis of blood infection levels is performed here in 44 pedigrees living in the tropical rain forest of southern Cameroon and exposed to high vectorial transmission intensity. The results confirm the existence of complex genetic factors controlling blood infection levels in human malaria but are not consistent with the parent-offspring transmission of a single Mendelian gene. This study also shows the dramatic effect of age on infection levels and its interaction with a putative major gene suggesting that genetic related differences are much more important in children than in adults. Further genetic studies focused on children may help to identify the nature of the genetic factors involved in the expression of human malaria, by means of linkage analyses using both familial information and genetic markers.

Title

Characterization of Ca2+ transport activity associated with a non-mitochondrial calcium pool in the rodent malaria parasite P-chabaudi

Author(s)

Passos APD, Garcia CRS

Source

Biochem.Mol.Biol.Int. 42 5 (1997 Aug)

Page(s)

919-925

Document

Article

Abstract

Non-mitochondrial calcium deposits were investigated in the intraerythrocytic malaria parasite Plasmodium chabaudi at the trophozoite stage by means of arsenate III in the presence of ATP and the mitochondrial poisons, antimycin and oligomycin. Addition of vanadate and 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ), both known to interact with SERCA pump, induced calcium release by permeabilized parasites when the medium free calcium concentration was kept at 3.5 mu M. The tumor promoter thapsigargin also caused elevation of the free calcium concentration in permeabilized parasites. Our results support the view that P. chabaudi sequesters calcium in an exchangeable form and maintains its calcium homeostasis by way of an endoplasmic reticulum Ca2+ pump.

Title

Mitochondrial ubiquinol-cytochrome C reductase and cytochrome C oxidase: Chemotherapeutic targets in malarial parasites

Author(s)

Krungkrai J, Krungkrai SR, Suraveratum N, Prapunwattana P

Source

Biochem.Mol.Biol.Int. 42 5 (1997 Aug)

Page(s)

1007-1014

Document

Article

Abstract

In order to demonstrate that the mitochondrial electron transport system may be a target for antimalarial drug design in the human malarial parasite Plasmodium falciparum, ubiquinol-cytochrome c reductase and cytochrome c oxidase were purified from mitochondria of the parasite cultivated in vitro. It was found that the catalytic efficiency of the two enzymes from the malarial parasite were markedly lower than those from mouse liver mitochondria. The classical inhibitors affecting different quinone binding sites of the mammalian reductase, antimycin and myxothiazole, which had little antimalarial activities on P. falciparum growth in vitro, were found to exhibit little inhibitory effect against the parasite reductase. The malarial parasite reductase was more sensitive to inhibition by the antimalarial drug, 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, than the mammalian enzyme, suggesting both the therapeutic potential of the target and the drug.

Title

A rapid immunochromatographic test (ICT) for diagnosis of Plasmodium falciparum

Author(s)

Valecha N, Sharma VP, Devi CU

Source

Diagn.Microbiol.Infect.Dis. 30 4 (1998 Apr)

Page(s)

257-260

Document

Article

Abstract

A field study was conducted to assess the sensitivity and specificity of vapid immunodiagnostic test based on detection of Plasmodium falciparum histidine-rich protein-2 (PfHRP-2) in peripheral blood for diagnosis of P. falciparum infection. Evaluation in 173 patients showed that the assay seas 98.59% sensitive and 97.1% specific. There was no cross-reactivity with P. vivax. The test teas positive in few patients who were found to be negative by microscopy showing the presence of antigen after curative chemotherapy. The test is a valuable diagnostic tool for falciparum malaria, especially in emergency field situations requiring rapid diagnosis. (C) 1998 Elsevier Science Inc.

Title

Heme-dependent radical generation from antimalarial fungal metabolites, radicicol and heptelidic acid

Author(s)

Tanaka Y, Fang F, Zhang CG, Zhang XW, Omura S

Source

J.Antibiot.(Tokyo) 51 4 (1998 Apr)

Page(s)

451-453

Document

Letter

Abstract

not available

Title

Rational drug design approach for overcoming drug resistance: Application to pyrimethamine resistance in malaria

Author(s)

McKie JH, Douglas KT, Chan C, Roser SA, Yates R, Read M, Hyde JE, Dascombe MJ, Yuthavong Y, Sirawaraporn W

Source

J.Med.Chem. 41 9 (1998 Apr 23)

Page(s)

1367-1370

Document

Article

Abstract

Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (K-i 1.5 nM) with purified recombinant DHFR from P. falciparum, the K-i value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the K-i values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nhl, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with K-i 0.30 nM) and the doubly mutant (C59R + S108N) purified enzyme (with K-i 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 mu M for the m-methoxy and 0.6 mu M for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 mu M for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

Title

Plasmodium inui is not closely related to other quartan Plasmodium species

Author(s)

Kissinger JC, Collins WE, Li J, McCutchan TF

Source

J.Parasitol. 84 2 (1998 Apr)

Page(s)

278-282

Document

Article

Abstract

Plasmodium inui (Halberstaedter and von Prowazek, 1907), a malarial parasite of Old world monkeys that occurs in isolated pockets throughout the Celebes, Indonesia, Malaysia, and the Philippines. has traditionally been considered to be related more closely to Plasmodium malariae of humans (and its primate counterpart Plasmodium brasiliantum), than to other primate Plasmodium species. This inference was made in part because of the similarities in the periodicities or duration of the asexual cycle in the blood, the extended sporogonic cycle, and the longer period of time for development of the pre-erythrocytic stages in the liver Both P. inui and P. malariae have quartan (72 hr) periodicities associated with their asexual cycle, whereas other primate malarias, such as Plasmodium fragile and Plasmodium cynomolgi, are associated with tertian periodicities (48 hr), and Plasmodium knowlesi, with a quotidian (24 hr) periodicity. Phylogenetic analyses of portions of orthologous small subunit ribosomal genes reveal that P. inui is actually mon closely related to the Plasmodium species of the "vivax-type" lineage than to P. malariae. Ribosomal sequence analysis of many different, geographically isolated, antigenically distinct P. inui isolates reveals that the isolates are nearly identical in sequence and thus members of the same species.

Title

Identification of electrophoretically separated proteases from midgut and hemolymph of adult Anopheles stephensi mosquitoes

Author(s)

Rosenfeld A, Vanderberg JP

Source

J.Parasitol. 84 2 (1998 Apr)

Page(s)

361-365

Document

Article

Abstract

Digestion of blood within the mosquito midgut is mediated primarily by a series of proteases, and several previous studies have described protease activity within homogenates of the midgut of the malaria vector Anopheles stephensi. We have expanded on these previous data by resolving protease isoforms from the midgut as well as the hemolymph of adult An. stephensi mosquitoes via gel electrophoresis and zymography. Using this procedure, we have been able to identify multiple isozymes of trypsin, chymotrypsin, and aminopeptidase. We were able to detect an increase in the intensity of some of these protease bands plus the appearance of new bands 24 hr after mosquitoes had taken a blood meal. Furthermore, we detected 2 endogenous trypsin isozymes within the hemolymph. There was no upregulation of these hemolymph isozymes after a blood meal, thus suggesting that they may not be involved in digestion of the blood meal by the mosquito.

Title

Modulation of host cell receptors: a mechanism for the survival of malaria parasites

Author(s)

Hommel M

Source

Parasitology 115 (1997)

Page(s)

S45-S54

Document

Article

Abstract

Intra-erythrocytic stages of malaria parasites can alter the surface of their host cells and release toxins which induce the production of cytokines, which in turn can up-or down-regulate the expression of adhesion receptors on the surface of microvascular endothelial cells. New adhesion receptors on endothelial cells provide the parasite with increased chances of survival despite an increasing level of host immunity. In order to take advantage of these new opportunities for survival, the parasite itself needs to make best use of its considerable ability to vary its surface antigens and adherent molecules. The paper describes the various players in this survival game and articulates a working hypothesis to explain how it may all fit together.

Title

Immune evasion in malaria: altered peptide ligands of the circumsporozoite protein

Author(s)

Plebanski M, Lee EAM, Hill AVS

Source

Parasitology 115 (1997)

Page(s)

S55-S66

Document

Review

Abstract

T cells are central to immunity in malaria. CD4(+) helper T cells favour the generation of high-affinity antibodies that are effective against blood stages and they are necessary to establish immunological memory. The intrahepatic stage of infection can be eliminated by specific CD8(+) cytotoxic T cells (CTL). Cytokines secreted by CD4(+) T cells may also contribute to liver stage immunity. Evolution has selected varied mechanisms in pathogens to avoid recognition by T cells. T cells recognize foreign epitopes as complexes with host major histocompatibility (MHC) molecules. Thus, a simple form of evasion is to mutate amino acid residues which allow binding to an MHC allele. Recently, more sophisticated forms of polymorphic evasion have been described. In altered peptide ligand (APL) antagonism, the concurrent presentation of particular closely related epitope variants can prevent memory T cell effector functions such as cytotoxicity, lymphokine production and proliferation. In immune interference, the effect of the concurrent presentation of such related epitope variants can go a step further and prevent the induction of memory T cells from naive precursors. The analysis of immune responses to a protein of P. falciparum, the circumsporozoite protein (CSP), indicates that the malaria parasite may utilize these evasion strategies.

Title

Drug-resistant and mixed-species malaria infections in Mpumalanga, South Africa

Author(s)

Birkholtz L, Visser L, Brink A, Louw AI

Source

S.Afr.J.Sci. 94 1 (1998 Jan)

Page(s)

39-43

Document

Article

Abstract

Malaria infections in South Africa have surged to alarming levels over the last few years. This study was undertaken to establish the occurrence of antifolate-resistant parasites and of mixed-species malaria infections in the Mpumalanga province of South Africa. Blood samples from infected patients were subjected to molecular screening methods based on parasite nucleic acid properties. The assays consisted of restriction enzyme analyses specific for point mutations in the polymerase chain reaction (PCR) amplified gene of the antifolate target enzyme, dihydrofolate reductase (DHFR), which are known to confer drug resistance, Concurrently, the infective species were identified using PCR amplification of the small-subunit ribosomal RNA genes. Of the 56 samples analysed, sir (12%) showed mired-species infections, four being P. falciparum-P. ovale and two P. falciparum-P. vivax mixtures, Analyses of resistance to the antifolates revealed that out of 21 single P. falciparum-infected samples tested, 43% contained parasites resistant to pyrimethamine treatment. The mutations were located in codon 108 and all were substitutions of Ser to Asn. Despite the relatively small sample size, these results suggest that malaria resistance to antifolates in the Mpumalanga province, which includes the Kruger National Park, could significantly influence the chemotherapeutic regimens employed for the prophylaxis and treatment of the disease.

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