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PubMed1992

Selection for high-level chloroquine resistance results in deamplification of the pfmdr1 gene and increased sensitivity to mefloquine in Plasmodium falciparum.

A chloroquine resistant cloned isolate of Plasmodium falciparum, FAC8, which carries an amplification in the pfmdr1 gene was selected for high-level chloroquine resistance, resulting in a cell line resistant to a 10-fold higher concentration of chloroquine. These cells were found to have lost the amplification in pfmdr1 and to no longer over-produce the protein product termed P-glycoprotein homologue 1 (Pgh1). The pfmdr1 gene from this highly resistant cell line was not found to encode any amino acid changes that would account for increased resistance. Verapamil, which reverses chloroquine resistance in FAC8, also reversed high-level chloroquine resistance. Furthermore, verapamil caused a biphasic reversal of chloroquine resistance as the high-level resistance was very sensitive to low amounts of verapamil. These data suggest that over-expression of the P-glycoprotein homologue is incompatible with high levels of chloroquine resistance. In order to show that these results were applicable to other chloroquine selected lines, two additional mutants were selected for resistance to high levels of chloroquine. In both cases they were found to deamplify pfmdr1. Interestingly, while the level of chloroquine resistance of these mutants increased, they became more sensitive to mefloquine. This suggests a linkage between the copy number of the pfmdr1 gene and the level of chloroquine and mefloquine resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Classification of adhesive domains in the Plasmodium falciparum erythrocyte membrane protein 1 family.

The Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family of cytoadherent proteins has a central role in disease from malaria infection. This highly diverse gene family is involved in binding interactions between infected erythrocytes and host cells and is expressed in a clonally variant pattern at the erythrocyte surface. We describe by sequence analysis the structure and domain organization of 20 PfEMP1 from the GenBank database. Four domains comprise the majority of PfEMP1 extracellular sequence: the N-terminal segment (NTS) located at the amino terminus of all PfEMP1, the C2, the Cysteine-rich Interdomain Region (CIDR) and the Duffy Binding-like (DBL) domains. Previous work has shown that CIDR and DBL domains can possess adhesive properties. CIDR domains grouped as three distinct sequence classes (alpha, beta, and gamma) and DBL domains as five sequence classes (alpha, beta, gamma, delta, and epsilon). Consensus motifs are described for the different DBL and CIDR types. Whereas the number of DBL and CIDR domains vary between PfEMP1, PfEMP1 domain architecture is not random in that certain tandem domain associations--such as DBLalphaCIDRalpha, DBLdeltaCIDRbeta, and DBLbetaC2--are preferentially observed. This conservation may have functional significance for PfEMP1 folding, transport, or binding activity. Parasite binding phenotype appears to be a determinant of infected erythrocyte tissue tropism that contributes to parasite survival, transmission, and disease outcome. The sequence classification of DBL and CIDR types may have predictive value for identifying PfEMP1 domains with a particular binding property. This information might be used to develop interventions targeting parasite binding variants that cause disease.

Amino Acid Motifs↗
PubMed2002

Recombinant PfEMP1 peptide inhibits and reverses cytoadherence of clinical Plasmodium falciparum isolates in vivo.

The parasite ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) and host endothelial receptors represent potential targets for antiadhesive therapy for cytoadherence. In the present study, the major host receptor CD36 was targeted in vitro and in vivo with a recombinant peptide, PpMC-179, corresponding to the minimal CD36-binding domain from the cysteine-rich interdomain region 1 (CIDR1) within the MCvar1 PfEMP1. The in vitro inhibitory effect of PpMC-179 on human dermal microvascular endothelial cells (HDMECs) expressing multiple relevant adhesion molecules was investigated using a parallel-plate flow chamber. Pretreatment of endothelial monolayers with PpMC-179 (2 microM) inhibited the adhesion of infected erythrocytes (IRBCs) from all clinical isolates tested by 84.4% on resting and 62.8% on tumor necrosis factor alpha (TNF-alpha)-stimulated monolayers. Adhesion to stimulated cells was further inhibited (90.4%) when PpMC-179 was administered with an inhibitory anti-intercellular adhesion molecule 1 (ICAM-1) monoclonal antibody 84H10 (5 microg/mL). To determine the in vivo effectiveness of PpMC-179, we used a human/severe combined immunodeficiency (SCID) mouse chimeric model that allowed direct visualization of cytoadherence on intact human microvasculature. In unstimulated skin grafts, PpMC-179 inhibited adhesion by 86.3% and by 84.6% in TNF-alpha-stimulated skin grafts. More importantly, PpMC-179 administration resulted in the detachment of already adherent IRBCs by 80.7% and 83.3% on resting and stimulated skin grafts, respectively. The antiadhesive effect of PpMC-179 was rapid and sustained in vivo for at least 30 minutes. Our data indicate that targeting cytoadhesion in vivo is feasible and may offer a rapid antimalarial therapy.

Adhesiveness↗
PubMed1993

Biogenesis of rhoptry organelles in Plasmodium falciparum.

Biogenesis of the rhoptry organelle of Plasmodium falciparum was studied by examining the synthesis and assembly of rhoptry proteins at different stages of intraerythrocytic development. Rhoptry proteins examined in this study were those of the high molecular weight complex of 140/130/110 kDa and referred to as Rhop-H1,2,3 and the low molecular weight complex of 80 and 42 kDa referred to as Rhop-L1,2. Co-ordinate, stage-specific expression of three proteins, Rhop-H3, Rhop-L1 and Rhop-L2, was observed; maximum levels of mRNA at the 8 nucleus stage correlated with the onset of protein synthesis. In contrast, mRNA levels for DNA polymerase-alpha, a marker for DNA replication during schizogony, was maximum just prior to the onset of the first nuclear division, indicating that rhoptry biogenesis is not co-ordinate with nuclear division. The assembly of newly synthesized rhoptry proteins was followed by subcellular fractionation of schizonts at different stages of development. At the four-nucleus stage a vesicle could be isolated by sucrose gradient fractionation which had a peak density of 1.12 g ml-1 and contained only Rhop-H2 and Rhop-H3 proteins. This vesicle could represent an intermediate or pre-rhoptry compartment. At the 8-nucleus stage, the Rhop-L1 protein was also detected in a vesicle of low density. At the 16-nucleus stage, the proteins were present in vesicles having a significantly greater density in sucrose, 1.16 g ml-1, similar to that of the mature organelle. The study suggested that the rhoptry proteins first accumulate in a low density vesicle and that assembly into this compartment is staggered. Immunoelectronmicroscopy studies indicated that the Rhop-H3 protein is first present in small granular compartments that becomes more electron dense and enlarges due to the stage-dependent incorporation of proteins.

Animals↗
PubMed1991

Synthetic low-toxicity muramyl dipeptide and monophosphoryl lipid A replace Freund complete adjuvant in inducing growth-inhibitory antibodies to the Plasmodium falciparum major merozoite surface protein, gp195.

The Plasmodium falciparum major merozoite surface protein (gp195) is a protective antigen against lethal malaria. However, increasing evidence indicates that the efficacy of a malaria vaccine will require a strong adjuvant that is safe for human use. We compared the efficacies of two low-toxicity synthetic immunomodulators, B30-MDP (a lipophilic muramyl dipeptide derivative) and LA-15-PH (a synthetic equivalent of monophosphoryl lipid A), with that of Freund complete adjuvant (FCA) in eliciting an antibody response to gp195. Rabbits were immunized with native gp195 and B30-MDP, LA-15-PH, or the two in combination, with liposomes as the vehicle. Aluminum hydroxide and FCA were used as reference adjuvants. Results showed that adjuvant formulations based on B30-MDP alone or in combination with LA-15-PH induced high antibody titers to gp195, as compared with FCA. LA-15-PH alone was less effective. Aluminum hydroxide induced significantly lower antibody titers. The functional activity of the rabbit anti-gp195 antibodies induced by different adjuvants was evaluated in an in vitro parasite growth inhibition assay previously shown to correlate with anti-gp195 immunity in the Aotus monkey model. All rabbits immunized with B30-MDP-LA-15-PH and two of three rabbits immunized with B30-MDP alone produced sera that strongly inhibited parasite growth. The degree of growth inhibition was similar to that with FCA. The antibody titers of the rabbits receiving B30-MDP-LA-15-PH strongly correlated with the degree of in vitro growth inhibition. Our findings provided strong evidence that adjuvant formulations based on synthetic B30-MDP and LA-15-PH can replace FCA as adjuvants in stimulating protective immunity specific for gp195.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1999

Effect of insecticide-treated bed nets on the dynamics of multiple Plasmodium falciparum infections.

The rates of acquisition and loss of individual genotypes belonging to the FC27 family of the Plasmodium falciparum merozoite surface protein 2 (msp2) gene were studied in 120 children aged 5 months to 2.5 years, in a randomized controlled trial of insecticide-treated bed nets (ITNs) in Kiberege village, Tanzania. Analysis of longitudinal changes in positivity for individual alleles in samples collected at intervals of one month indicated that the average duration of infections, allowing for undetected parasite genotypes, was 73 d in those aged < 18 months and 160 d in children aged > or = 18 months, consistent with a shift from acute to chronic infection with age. Overall, 51% of genotypes infecting the host were estimated to be detected by polymerase chain reaction-restriction fragment length polymorphism analysis in any one sample of 0.5 microL of packed peripheral blood cells. In children less than 18 months old this sensitivity was 61% (SE = 6%) compared with 41% (SE = 6%) in older children. Conversely, the rate of appearance of new parasite genotypes was higher in children < 18 months of age than in older children, but this partly reflected the difference in sensitivity. The overall incidence of new infections was estimated to be reduced by 17% in ITN users. There was no statistically significant difference between users and non-users in observed infection multiplicity, sensitivity, recovery rate, or estimated infection rates for individual alleles. This suggests that, in areas of high P. falciparum endemicity, ITNs have little effect on the establishment of chronic malaria infection.

Alleles↗
PubMed2002

The paradoxical population genetics of Plasmodium falciparum.

Among the leading causes of death in African children is cerebral malaria caused by the parasitic protozoan Plasmodium falciparum. Endemic forms of this disease are thought to have originated in central Africa 5000-10000 years ago, coincident with the innovation of slash-and-burn agriculture and the diversification of the Anopheles gambiae complex of mosquito vectors. Population genetic studies of P. falciparum have yielded conflicting results. Some evidence suggests that today's population includes multiple ancient lineages pre-dating human speciation. Other evidence suggests that today's population derives from only one, or a small number, of these ancient lineages. Resolution of this issue is important for the evaluation of the long-term efficacy of drug and immunological control strategies.

Animals↗
PubMed2002

Dynamics of gametocytes among Plasmodium falciparum clones in natural infections in an area of highly seasonal transmission.

The dynamics of gametocyte production in Plasmodium falciparum clones were studied in inhabitants of an area of highly seasonal malaria transmission in eastern Sudan. Reverse-transcriptase polymerase chain reaction was used to detect expression of 2 genes that encode gametocyte-specific proteins, pfs25 and pfg377, in parasites sampled from individuals throughout one year. Some patients who acquired infections during the wet season were found to harbor subpatent gametocytemia through the following dry season in the apparent absence of mosquito transmission. Genotyping of parasites in multiclonal infections showed considerable fluctuation of gametocyte production by individual clones. The gametocytes present at the end of the dry season provide the most probable source of the genetically complex cyclical malaria outbreaks following the rainy season in this region.

Animals↗
PubMed2003

PEST sequences in the malaria parasite Plasmodium falciparum: a genomic study.

BACKGROUND: Inhibitors of the protease calpain are known to have selectively toxic effects on Plasmodium falciparum. The enzyme has a natural inhibitor calpastatin and in eukaryotes is responsible for turnover of proteins containing short sequences enriched in certain amino acids (PEST sequences). The genome of P. falciparum was searched for this protease, its natural inhibitor and putative substrates. METHODS: The publicly available P. falciparum genome was found to have too many errors to permit reliable analysis. An earlier annotation of chromosome 2 was instead examined. PEST scores were determined for all annotated proteins. The published genome was searched for calpain and calpastatin homologs. RESULTS: Typical PEST sequences were found in 13% of the proteins on chromosome 2, including a surprising number of cell-surface proteins. The annotated calpain gene has a non-biological "intron" that appears to have been created to avoid an unrecognized frameshift. Only the catalytic domain has significant similarity with the vertebrate calpains. No calpastatin homologs were found in the published annotation. CONCLUSION: A calpain gene is present in the genome and many putative substrates of this enzyme have been found. Calpastatin homologs may be found once the re-annotation is completed. Given the selective toxicity of calpain inhibitors, this enzyme may be worth exploring further as a potential drug target.

Amino Acid Sequence↗
PubMedDate not supplied

In vivo and in vitro Plasmodium falciparum resistance to chloroquine, amodiaquine and quinine in the Brazilian Amazon.

In order to study the chemoresistance of Plasmodium falciparum to commonly used antimalarial drugs in Brazil the authors have studied ten patients with falciparum malaria, acquired in the Brazilian Amazon region. Patients were submitted to in vivo study of drug sensitivity, after chemotherapy with either 4-aminoquinolines (chloroquine or amodiaquine) or quinine. Adequate drug absorption was confirmed by standard urine excretion tests for antimalarials. Eight patients could be followed up to 28 days. Among these in vivo resistance (R I and R II responses) was seen in all patients who received 4-amino-quinolines. One patient treated with quinine exhibited a R III response. Peripheral blood samples of the same patients were submitted to in vitro microtests for sensitivity to antimalarials. Out of nine successful tests, resistance to chloroquine and amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates. Probit analysis of log dose-response was used to determine effective concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between in vivo and in vitro results was seen in six patients. The results emphasize high levels of P. falciparum resistance to 4-aminoquinolines and suggest an increase in resistance to quinine in the Brazilian Amazon region, reinforcing the need for continuous monitoring of drug sensitivity to adequate chemotherapy according to the most efficacious drug regimens.

Amodiaquine↗
PubMed1987

Regulation of the immune response in Plasmodium falciparum malaria: IV. T cell dependent production of immunoglobulin and anti-P. falciparum antibodies in vitro.

T cells from patients with acute Plasmodium falciparum malaria were investigated for induction of immunoglobulin- or anti-malaria antibody secretion in vitro. Stimulation of autologous T/B cell mixtures (2T:1B) with low concentrations of P. falciparum antigen and cultured for 12 days gave rise to a T-dependent IgG secretion which was significantly elevated over that in medium controls. This was achieved with both a crude P. falciparum antigen and a partially purified preparation enriched in Pf 155, a merozoite-derived antigen deposited in the red cell membrane at invasion (Perlmann et al., 1984). Control antigen (RBC ghosts) induced IgG secretion only when added at high concentrations (greater than 10 micrograms/ml). Neither of the antigens induced IgG secretion at concentrations of less than or equal to 10 micrograms/ml in control cultures of lymphocytes from patients with P. vivax malaria. Supernatants from cultures of P. falciparum patients frequently contained anti-P. falciparum antibodies when nanogram quantities (10-100 ng/ml) of either one of the two malaria antigen preparations was used for stimulation. No anti-P. falciparum antibodies were induced by the control antigen at any concentration. The induced anti-P. falciparum antibodies were directed to intracellular parasites and. at lower frequencies, to Pf 155 as detected on the surface of infected erythrocytes. The induction in vitro of anti-P. falciparum antibodies appeared to be correlated with the presence of such antibodies in the sera of the lymphocyte donors. The lymphocytes of only one out of eight P. vivax patients responded to antigen stimulation by secreting anti-P. falciparum antibodies. However, this donor (but not any of the others), was also P. falciparum seropositive. Taken together, these results indicate that the induction of anti-P. falciparum antibody secretion reflects a secondary response in vitro of cells primed in vivo. The present experimental system should be well suited to map parasite antigen for their capacity to induce T cell dependent responses in P. falciparum malaria.

Acute Disease↗
PubMedDate not supplied

Plasma levels of interleukin-18 and interleukin-12 in Plasmodium falciparum malaria.

Interleukin (IL)-18 produced primarily by mononuclear phagocytes synergizes with IL-12 for interferon-gamma production from T, B and natural killer cells. It has been also demonstrated that, in Plasmodium falciparum malaria, IL-18 could have an immunoregulatory function. The aim of this study was to detect the plasma levels of IL-12 and IL-18, using an enzyme-linked immunosorbent assay, in 105 African children affected by mild and severe Plasmodium falciparum malaria to correlate the production of these cytokines with the severity of the disease. The levels of IL-18 and IL-12 were higher (25.7 +/- 7.6 pg/ml and 17.1 +/- 7.8 pg/ml, respectively) in children with mild malaria than in children with a severe form of the disease (21.5 +/- 10 pg/ml and 13.2 +/- 5.5 pg/ml, respectively). A positive correlation was observed between IL-18 and IL-12. This finding suggests that the production of these two cytokines (IL-18 and IL 12) may be coregulated and both have an immunoregulatory effect on the immune response in Plasmodium falciparum infection.

Animals↗
PubMed2001

Low-complexity regions in Plasmodium falciparum proteins.

Full-sequence data available for Plasmodium falciparum chromosomes 2 and 3 are exploited to perform a statistical analysis of the long tracts of biased amino acid composition that characterize the vast majority of P. falciparum proteins and to make a comparison with similarly defined tracts from other simple eukaryotes. When the relatively minor subset of prevalently hydrophobic segments is discarded from the set of low-complexity segments identified by current segmentation methods in P. falciparum proteins, a good correspondence is found between prevalently hydrophilic low-complexity segments and the species-specific, rapidly diverging insertions detected by multiple-alignment procedures when sequences of bona fide homologs are available. Amino acid preferences are fairly uniform in the set of hydrophilic low-complexity segments identified in the two P. falciparum chromosomes sequenced, as well as in sequenced genes from Plasmodium berghei, but differ from those observed in Saccharomyces cerevisiae and Dictyostelium discoideum. In the two plasmodial species, amino acid frequencies do not correlate with properties such as hydrophilicity, small volume, or flexibility, which might be expected to characterize residues involved in nonglobular domains but do correlate with A-richness in codons. An effect of phenotypic selection versus neutral drift, however, is suggested by the predominance of asparagine over lysine.

Amino Acids↗
PubMed1999

Phenotypic and genotypic characteristics of recently adapted isolates of Plasmodium falciparum from Thailand.

The drug sensitivity characteristics and Plasmodium falciparum pfmdr1 status of five isolates of P. falciparum recently isolated from patients presenting for treatment from the Thailand/Myanmar border have been investigated. The aim of the study was to avoid the criticisms of some earlier studies by focusing on newly collected isolates from a specific geographic location. Three of the isolates studied exhibited clear resistance to chloroquine similar to that observed in the K1 Thai standard isolate obtained in the 1970s, and the other two isolates were of intermediate sensitivity to chloroquine with concentrations of drug that inhibit parasite growth by 50% of 50 and 43 nmol. The sensitivity of all isolates was enhanced by verapamil but we found no clear association between chloroquine sensitivity and gene copy number or intra-allelic variation of pfmdr1. In contrast, clear cross-resistance was seen between mefloquine and halofantrine, with the most sensitive isolates carrying the K1 mutation in pfmdr1.

Animals↗
PubMed1989

Selective antimalarial activity of tetrandrine against chloroquine resistant Plasmodium falciparum.

Antimalarial activity of tetrandrine was studied using a continuous in vitro culture of Plasmodium falciparum. Experimental results showed that tetrandrine has potent antimalarial effect on both chloroquine sensitive and resistant strains of Plasmodium falciparum. Interestingly, tetrandrine is about three times more potent against the chloroquine resistant strain than it is against the sensitive strain based on their IC50 values, which were 5.09 x 10(-7) M for the sensitive strain and 1.51 x 10(-7) M for the resistant strain. In addition, reversal experiments revealed that tetrandrine cannot reverse chloroquine-resistance, although it has verapamil-like, calcium-channel-blocker activity.

Alkaloids↗
PubMed1988

Demonstration of soluble Plasmodium falciparum antigens reactive with Limulus amoebocyte lysate and polymyxin B.

To investigate whether soluble Plasmodium falciparum antigens possess endotoxin-like properties, the interaction of Limulus amoebocyte lysate (LAL) with defined soluble antigens from Plasmodium falciparum was studied by various crossed immunoelectrophoretic methods and immunoblotting. The soluble P. falciparum antigens were purified by affinity chromatography using human IgG from malaria-immune adults as ligand. Of eight possible antigens, at least three were affected by LAL, as indicated by disappearance of these antigens in the precipitation pattern, after the reaction with LAL. One of the LAL-reactive antigens is a heat-stable glycoprotein with the presence of both hydrophilic and hydrophobic regions in its structure. This antigen shows a strong reaction with polymyxin B, and antibodies against it have been shown to be inhibitory to the growth of P. falciparum in culture. It is concluded that LAL reacts with several soluble antigens from P. falciparum and it is suggested that these antigens participate in the induction of protective immunity to malaria, and consequently that one or more of the soluble antigens are candidates for a malaria vaccine.

Animals↗
PubMed1998

[Cloning and sequence analysis of the gene encoding the partial region CS protein of a Plasmodium falciparum isolate from Yunnan].

AIM: Determining nucleotide sequence of the circumsporozoite protein partial gene of the Plasmodium falciparum PFD-3/YN (Yunnan of China) and finding out the differences of the CS gene sequence between Chinese Plasmodium falciparum isolate and other isolates. METHODS: The circumsporozoite protein gene fragment was amplified by polymerase chain reaction and cloned into M13 bacteriophage. M13-CSP single strand DNAs of the three positive clones were extracted respectively. Then, the nucleotide sequence of the CS gene fragment was determined by the dideoxy chain termination method. PCGENE software was used to compare and analyze the CS gene sequence of the six isolates. RESULTS: Different degrees of diversity of the CS gene sequences were found among P. falciparum PFD-3/YN and other isolates(T4, Wellcome, NF54, 3D7 and 7G8). A non-silent substitution at the nucleotide level being found in the P. f Th/Tc antigenic epitope region. CONCLUSION: There were differences in the CS gene sequence among P. falciparum PFD-3/YN and those of other isolates.

Amino Acid Sequence↗
PubMed1999

Sequence analysis of the MSP 1 gene of Plasmodium falciparum isolates from Hainan, China.

AIM: To obtain the complete sequence and analyze the diversity of the MSP 1 molecule from the Chinese isolates of Plasmodium falciparum. METHODS: Genomic DNA was prepared directly from blood samples spotted on filter papers from 2 malaria patients from Baoting County, Hainan Province. PCR amplification of the target gene was carried out using 5 pairs of oligonucleotides specific for the MSP 1 gene. Direct sequencing of the target gene fragments was performed using ABI PRISM Dye Terminator Cycle Sequencing Ready Reaction Kit (Perkin Elmer) in a automatic ABI PRISM 310 Genetic Analyzer. RESULTS: For the first time, two complete sequences of the MSP1 gene from two Chinese isolates of Plasmodium falciparum were obtained. A comparison with the previously reported sequences identified them as members of the MAD20 allelic family. The deduced amino acid sequences of the MSP1 from this two Chinese isolates were identical with each other except for Blocks 2, 4 and 8. CONCLUSION: The sequences of the MSP 1 from two Chinese isolates of P. falciparum belong to the MAD20 allelic family. Minor variations through the whole sequences exist compared with the MAD20 sequence. The results provide the first evidence of the diversity of the MSP 1 molecule from Chinese isolates of Plasmodium falciparum.

Amino Acid Sequence↗