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PubMed2003

The 3D7var5.2 (var COMMON) type var gene family is commonly expressed in non-placental Plasmodium falciparum malaria.

Relapse variants in chronic Plasmodium falciparum infections are antigenically distinct from the parental parasites. The variable antigen PfEMP1 expressed at the surface of the infected erythrocyte (IE) is encoded by the var gene family with approximately 60 copies per haploid genome. Placental isolates commonly express DBLgamma containing subtypes of var genes with homology to either 3D7var5.2 (var(COMMON)) or FCR3var(CSA). Here we report that var(COMMON) related genes are constitutively transcribed in approximately 60% of malaria infected children in Gabon. var(COMMON) is conserved in field isolates over at least 2.1kb. In 3D7 parasites var(COMMON) is present on chromosome 5 (var5.2) and constitutively transcribed in the opposite direction to most other var genes. It lacks a regulatory intron, an acidic terminal segment and ends in telomeric repeat sequences. var(COMMON) encodes a large, hypothetical PfEMP1 of a structure similar to previous placenta-binding PfEMP1s but it is not present at the IE-surface. IE of a 3D7 clone (3D7S8) transcribe var(COMMON) but express a PfEMP1 distinct from var(COMMON) at the surface and adhere to placental tissues through var(COMMON) independent novel mechanisms. Our report suggests that expression of var(COMMON) type genes is not restricted to placental malaria.

Amino Acid Sequence↗
PubMed2003

Induction of crossreactive antibodies against the Plasmodium falciparum variant protein.

The variant antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), present on the surface of P. falciparum-parasitized erythrocytes (PE), plays a central role in naturally acquired immunity, although antibodies to PfEMP1 are predominantly variant specific. To overcome this major limitation for vaccine development, we immunized mice with three cysteine-rich interdomain 1 (CIDR1) domains of PfEMP1 that have the critical function of binding the PE to CD36 on endothelium and thus preventing spleen-dependent killing of the parasite. The immunizations consisted of different combinations of three CIDR1 encoded by DNA followed by recombinant protein boost. Immunizations with a single variant in a prime-boost regimen induced no or low cross-reactivity toward heterologous CIDR1; however, a broad range of crossreactivity was detected in mice that were immunized with all three variants simultaneously. The induced crossreactivity suggests that an anti-PfEMP1 vaccine may be possible.

Animals↗
PubMed1991

Immunization of owl monkeys with a recombinant protein containing repeated epitopes of a Plasmodium falciparum glycophorin-binding protein.

A Plasmodium falciparum glycophorin binding protein (GBP-130) has been implicated in protective immunity to malaria. The gene for GBP-130 encodes a protein containing 11 tandemly repetitive 50 amino acid units. We report an immunization trial in Aotus monkeys using a recombinant DNA protein containing three of these 50 amino acid repeats. When administered with aluminum hydroxide, this antigen induced low levels of antibodies that reacted with the recombinant protein by ELISA and with parasite antigens in immunoblot and immunofluorescence assays, but not by immunoprecipitation. When administered with Freund's complete adjuvant, this antigen induced high levels of antibodies that reacted in ELISA, immunoblot, immunofluorescence, and immunoprecipitation assays. Serum from immunized monkeys did not inhibit parasite growth, and protection from intravenous challenge with P. falciparum-infected erythrocytes was not observed in any experimental group. These results suggest that the repetitive region of GBP-130 is not a useful vaccine candidate.

Amino Acid Sequence↗
PubMed2005

Multiple replication origins within the inverted repeat region of the Plasmodium falciparum apicoplast genome are differentially activated.

The 35 kb circular genome (plDNA) of the Plasmodium falciparum apicoplast replicates by the bidirectional ori/D-loop mechanism. PlDNA replication was previously shown to initiate within the inverted repeat (IR) region of the apicoplast genome [Williamson DH, Preiser PR, Moore PW, McCready S, Strath M, Wilson RJM (Iain). The plastid DNA of the malaria parasite Plasmodium falciparum is replicated by two mechanisms. Mol Microbiol 2002;45:533-42; Singh D, Chaubey S, Habib S. Replication of the Plasmodium falciparum apicoplast DNA initiates within the inverted repeat region. Mol Biochem Parasitol 2003;126:9-14.] and the presence of at least two ori within each segment of the IR was postulated. Using 5' end-labelled nascent DNA as probe, we now demonstrate the utilization of several putative ori located within the IR for plDNA replication. Quantitation of signals obtained for different segments of the IR as well as determination of the number of molecules emanating from two ori regions by competitive PCR analysis indicated differential strengths of ori during plDNA replication prior to schizogony.

Animals↗
PubMed2005

Identifying Plasmodium falciparum cytoadherence-linked asexual protein 3 (CLAG 3) sequences that specifically bind to C32 cells and erythrocytes.

Adhesion of mature asexual stage Plasmodium falciparum parasite-infected erythrocytes (iRBC) to the vascular endothelium is a critical event in the pathology of Plasmodium falciparum malaria. It has been suggested that the clag gene family is essential in cytoadherence to endothelial receptors. Primers used in PCR and RT-PCR assays allowed us to determine that the gene encoding CLAG 3 (GenBank accession no. NP_473155) is transcribed in the Plasmodium falciparum FCB2 strain. Western blot showed that antisera produced against polymerized synthetic peptides from this protein recognized a 142-kDa band in P. falciparum schizont lysate. Seventy-one 20-amino-acid-long nonoverlapping peptides, spanning the CLAG 3 (cytoadherence-linked asexual protein on chromosome 3) sequence were tested in C32 cell and erythrocyte binding assays. Twelve CLAG peptides specifically bound to C32 cells (which mainly express CD36) with high affinity, hereafter referred to as high-affinity binding peptides (HABPs). Five of them also bound to erythrocytes. HABP binding to C32 cells and erythrocytes was independent of peptide charge or peptide structure. Affinity constants were between 100 nM and 800 nM. Cross-linking and SDS-PAGE analysis allowed two erythrocyte binding proteins of around 26 kDa and 59 kDa to be identified, while proteins of around 53 kDa were identified as possible receptor sites for C-32 cells. The HABPs' role in Plasmodium falciparum invasion inhibition was determined. Such an approach analyzing various CLAG 3 regions may elucidate their functions and may help in the search for new antigens important for developing antimalarial vaccines.

Amino Acid Sequence↗
PubMed1992

Alpha-tubulin II is a male-specific protein in Plasmodium falciparum.

The tubulin gene family in Plasmodium falciparum consists of one beta-tubulin and two alpha-tubulin genes (alpha-tubulin I and II). We present here data indicating that alpha-tubulin II is expressed only in male sexual stage parasites. An IgM mAb, 5E7, specifically reacted with stage III (day 4-5) through mature (day 10-11) male gametocytes and with emerging, exflagellating, or freely moving male gametes. No reactivity was detected in female gametocytes, female gametes, sporozoites, or asexual parasites. mAb 5E7 also specifically recognized male gametes of the avian parasite, Plasmodium gallinaceum, and immunoblotted a 50 kDa protein in extracts of male gametes from both species. This 50 kDa antigen was localized by immunoelectron microscopy to axonemes of male gametes in a pattern similar to that obtained with anti-alpha- and anti-beta-tubulin antibodies. Furthermore, mAb 5E7 specifically reacted with recombinant alpha-tubulin II protein obtained using the PCR-amplified alpha-tubulin II gene from a gametocyte-specific cDNA library. The sex-specific expression of alpha-tubulin II and its localization to axoneme of the male parasite suggest a role for this molecule in the morphologic changes that occur during exflagellation and in the motility of the parasite. alpha-Tubulin II and mAb 5E7 may prove useful tools in studies of the biology of sexual stage differentiation and development in P. falciparum in addition to the general understanding of post-translational modifications of tubulin isoforms.

Animals↗
PubMedDate not supplied

[In vivo study of chloroquine resistance of Plasmodium falciparum malaria in Mayotte].

According to the existence of Plasmodium falciparum chloroquine-resisting cases in Madagascar and, someone, in the Comoro Archipelago, a study using in vivo W.H.O. test was conducted in Mayotte Island. Between the end of 1985 and 1987, despite the great difficulties for ambulatory blood collection in a rural population, 24% of malaria cases had been followed up during 28 days, using a dose of 25 mg/Kg in 3 days. During 1986 and 1987, 5 cases showed positive serology of thin blood films. Either the possibility of reinfection cannot be excluded, these cases may be notified as R I and R II resistant type according to the W.H.O. standard test. In vitro W.H.O. test is necessary to confirm this fact but is not possible in local laboratory conditions. Thus, the surveillance of chemosensitivity of Plasmodium falciparum local strains is a priority. Nevertheless, chloroquine remains efficient for prophylactic (new travelers only) or curative purpose in the main cases.

Animals↗
PubMed1993

The gamma-tubulin gene of the malaria parasite Plasmodium falciparum.

By screening of cDNA and genomic libraries of Plasmodium falciparum with a DNA probe derived from the cognate beta-tubulin gene, gene Pf gamma tub has been identified that codes for gamma-tubulin, a newly discovered member of the tubulin superfamily that is indispensible for nuclear division and microtubule assembly [12]. Gene Pf gamma tub is not interrupted by introns and only present as a single-copy in the parasite genome. Its encoded amino acid sequence (452 amino acids; M(r) 50,560) has a 63% similarity to the gamma-tubulins encoded by Aspergillus nidulans, Schizosaccharomyces pombe, Drosophila melanogaster, Xenopus laevis and Homo sapiens. This figure is significantly (approx. 8%) lower than the average identity between the gamma-tubulins of the latter five species suggesting that during evolution the genes have been exposed to different selection pressures. The identity of gamma-tubulin to the Plasmodium falciparum encoded alpha- and beta-tubulins is 30 and 33%, respectively.

Amino Acid Sequence↗
PubMed1989

[Comparative efficacy of alternative treatments in Plasmodium falciparum infections in Zaire].

The in vivo sensitivity of Plasmodium falciparum for chloroquine, quinine and pyrimethamine-sulfadoxine has been evaluated in 3 of 14 sentinel antimalarial drugs sensitivity surveillance centres between October 1986 and July 1987. Children of less than five years old were treated with chloroquine at 25 mg/kg dose administered during 3 days, or with 140 mg/kg quinine base administered in a daily dose of 20 mg/kg during 7 consecutive days, or with one standard dose of 1/2 a pyrimethamine-sulfadoxine tablet for children between 3 and 48 months old and 1 tablet for children between 49 and 59 months old, or the combination of 60 mg/kg quinine base at 20 mg/kg single dose during 3 consecutive days with the association pyrimethamine-sulfadoxine in single dose at the first day of treatment. A modified standard 7 days in vivo test of the World Health Organization was used 2, 3 and 7 days after the start of treatment. In one location an additional observation was made on day 14. The results, compared by location and by drug regimen, show a varying but relatively important reduction of the activity of chloroquine on the parasitological level. Quinine in maximal but single dose also shows reduction in activity, especially on day 14 in the Tshela centre. The pyrimethamine-sulfadoxine association shows a better activity. On the clinical level, e.g. temperature remission after treatment, all antimalarials still maintain their activity. As a result, and in view of its persisting high clinical activity, chloroquine at 25 mg/kg dose remains the drug of first choice for the treatment of uncomplicated Plasmodium falciparum infections.

Animals↗
PubMed1996

[In vitro sensitivity of 85 Plasmodium falciparum isolates in the Fatick region, Senegal].

Increasing resistance of Plasmodium falciparum to chloroquine and other antimalarials has been reported in Africa. Only fragmentary data are available for Senegal. Although combined chloroquine-proguanil is soon scheduled for released on the market, few studies have been published concerning the susceptibility of isolates to either drug. The in vitro susceptibility of 85 Plasmodium falciparum isolates obtained between October 24 and December 2, 1995 from malaria-infected patients living in the Fatick Region of Senegal to five classical antimalarial drugs (chloroquine, cycloguanil, quinine, mefloquine, and halofantrine) was evaluated using an isotopic, semi-microtest. Twenty-nine percent of isolates were resistant to chloroquine (IC50 > 100 nM), 22% to cycloguanil (IC50 > 500 nM), 1% to quinine (IC50 > 500 nM), 22% to mefloquine (IC50 > 20 nM), and 8% to halofantrine (IC50 > 5 nM). Five percent of isolates were resistant to both chloroquine and cycloguanil. Positive correlation was observed between quinine and halofantrine activity and between mefloquine and halofantrine activity. These findings suggest cross resistance or reduced susceptibility between these antimalarial agents which all exhibit a methanolic function.

Animals↗
PubMed1988

Evidence of increased chloroquine sensitivity in Thai isolates of Plasmodium falciparum.

Sensitivity of Thai isolates of Plasmodium falciparum to chloroquine collected over the years 1978-1986 was measured by two methods: (i) by growth of previously cultured isolates for 72 h in presence of drug, and (ii) by the WHO standard in vitro microtest. During this period there were signs of a gradual increase in drug sensitivity, coinciding with the withdrawal of chloroquine for treatment of falciparum malaria in Thailand.

Animals↗
PubMed2002

Plasmodium malariae infection boosts Plasmodium falciparum gametocyte production.

We analyzed records of malaria therapy patients sequentially or simultaneously inoculated with Plasmodium falciparum and Plasmodium malariae. Gametocyte production was enhanced in P. falciparum by prior or concurrent P. malariae infection but diminished or unaffected in P. malariae by P. falciparum. Conversely, asexual-form production was diminished in P. malariae but unaffected in P. falciparum.

Animals↗
PubMed2005

[Comparative analysis at the nucleotide level of the genes encoding the lactate dehydrogenase enzyme of Plasmodium vivax and Plasmodium falciparum.].

In this study, the nucleotide sequence of the enzyme lactate dehydrogenase from Plasmodium vivax has been compared to the same enzyme from another malaria parasite Plasmodium falciparum. It was found that the identity between two sequences was 74.8%. The percentage of the GC value was found to be higher in the Plasmodium vivax lactate dehydrogenase (46.6%) than in that of Plasmodium falciparum (33%). The nucleotide sequence that corresponds to the 5 amino acid insertion in Plasmodium lactate dehydrogenase is also present in Plasmodium vivax. This site will be targeted in the design of novel antimalarials for Plasmodium vivax as has been for Plasmodium falciparum.

English Abstract↗
PubMed2003

Switching rates of Plasmodium falciparum var genes: faster than we thought?

Plasmodium falciparum undergoes antigenic variation by switching the expressed erythrocyte membrane protein (PfEMP)1. This family of proteins plays an important role in the development of chronic, recrudescent P. falciparum malaria, acquired immunity and severe malaria. However, little is known about the switching mechanism or switching rates in the human host. Here, we estimate the switch rate of var genes, using recently published data describing the var gene transcripts detected in blood taken from human volunteers during acute P. falciparum infections and a mathematical model of the in-host dynamics. The overall switch rate of PfEMP1 predicted during the initial stage of infection ( approximately 18% switching parasites per generation) is much higher than previously reported. The implications of the predicted switching rates are discussed.

Animals↗
PubMed1999

Structural and antigenic properties of merozoite surface protein 4 of Plasmodium falciparum.

Merozoite surface protein 4 (MSP4) of Plasmodium falciparum is a glycosylphosphatidylinositol-anchored integral membrane protein of 272 residues that possesses a single epidermal growth factor (EGF)-like domain near the carboxyl terminus. We have expressed both full-length MSP4 and a number of fragments in Escherichia coli and have used these recombinant proteins to raise experimental antisera. All recombinant proteins elicited specific antibodies that reacted with parasite-derived MSP4 by immunoblotting. Antibody reactivity was highly dependent on the protein conformation. For example, reduction and alkylation of MSP4 almost completely abolished the reactivity of several antibody preparations, including specificities directed to regions of the protein that do not contain cysteine residues and are far removed from the cysteine-containing EGF-like domain. This indicated the presence of conformation-dependent epitopes in MSP4 and demonstrated that proper folding of the EGF-like domain influenced the antigenicity of the entire molecule. The recombinant proteins were used to map epitopes recognized by individuals living in areas where malaria is endemic, and at least four distinct regions are naturally antigenic during infection. Binding of human antibodies to the EGF-like domain was essentially abrogated after reduction of the recombinant protein, indicating the recognition of conformational epitopes by the human immune responses. This observation led us to examine the importance of conformation dependence in responses to other integral membrane proteins of asexual stages. We analyzed the natural immune responses to a subset of these antigens and demonstrated that there is diminished reactivity to several antigens after reduction. These studies demonstrate the importance of reduction-sensitive structures in the maintenance of the antigenicity of several asexual-stage antigens and in particular the importance of the EGF-like domain in the antigenicity of MSP4.

Animals↗
PubMed1994

In vivo sensitivity of Plasmodium falciparum to halofantrine hydrochloride in Burkina Faso.

Plasmodium falciparum susceptibility to halofantrine hydrochloride was investigated in a small village near Ouagadougou, Burkina Faso, where the parasite was known to be chloroquine resistant. An in vivo test was carried out in July 1992 at the beginning of the rainy season in children ranging in age from two to eight years with P. falciparum monospecific infections, asexual parasitemia greater than 800/microliters of blood, and a negative result on a Bergqvist urine test for 4-aminoquinolines. Among 206 children screened, 74 were selected for study. Blood samples were collected on days 0, 2, 4, 7 and 14, and 100 microscopic fields of thick and thin blood smears were examined for parasite density and species identification. Halofantrine hydrochloride was administered under supervision at the standard dose of 24 mg/kg as 8 mg/kg given three times at 6-hr intervals with an observation period of 1 hr after each 8-mg/kg dose. Parasitemias cleared in all 74 cases by day 7, but there was a recurrence of parasitemia in six subjects (8.1%) on day 14. A second course of therapy with halofantrine resulted in prompt clearance of parasitemias in all of these children. The drug was well-tolerated and the hematologic and biochemical indices were not adversely affected by treatment.

Alanine Transaminase↗
PubMed1995

In vitro drug sensitivity and clinical aspects of Plasmodium falciparum malaria in African children.

In vitro Plasmodium falciparum drug sensitivity was investigated in 115 brazzavillians children, between 1 year and 10 years of age. On the basis of clinical aspects, four groups were constituted: Group 1: 39 asymptomatic school children, Group 2: 16 children with uncomplicated malaria, Group 3: 40 with severe but not pernicious malaria and Group 4: 20 with pernicious malaria. The drugs tested were chloroquine (CQ), quinine (QN) and mefloquine (MQ). The sensitivity level was assessed by a 48-hour in vitro maturation test involving the uptake of tritiated hypoxanthine, the initial blood level of parasite being > or = 0.1% in all cases. For QN and MQ, the median IC50 values showed no significant difference related to clinical status, age or parasitaemia levels. For CQ, the proportion of resistant strains and the 50 inhibitory concentration (IC50) values were greater in the cases of children hospitalised for malaria but there were no differences related to clinical severity of these hospitalised children nor, within each group, to the age or parasitaemia levels. The percentage of subjects with an IC50 value greater than the 90 percentile of the IC50 of the asymptomatic group, which we propose as the severity index related to chemoresistance, was 15% for uncomplicated malaria, 38% for severe but non-pernicious forms and 35% for pernicious malaria. The IC50 for QN was significantly higher in CQ-resistant strains and there was a positive correlation for CQ vs QN and for QN vs MQ.

Animals↗
PubMed1985

Variations in the organization of repetitive DNA sequences in the genomes of Plasmodium falciparum clones.

Repetitive DNA in cultured Plasmodium falciparum was examined by restriction digestion and transfer hybridization, using cloned repetitive DNA probes. The arrangement of repetitive DNA was unstable: after 6 months culture of a cloned population, variations could be detected. Significant differences can be seen between clones derived from a single isolate, and are even more marked between isolates of diverse geographical origin. No cross-species conservation was seen for the sequences examined, and no relationship was observed between their representation in the P. falciparum genome and the potential for sexual differentiation.

Animals↗