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PubMed1997

Limited spatial clustering of individual Plasmodium falciparum alleles in field isolates from coastal Kenya.

We describe Plasmodium falciparum genetic diversity in coastal Kenya, typing S-antigen and the merozoite surface proteins 1 and 2 (MSP-1 and MSP-2) in field isolates by the polymerase chain reaction (PCR). Malaria in coastal Kenya is characterized by low seasonal transmission, and a relatively high incidence of severe disease, which tends to occur in time-space clusters. We chose the highly polymorphic S-antigen as a marker for localized parasite diversity because it has been shown to vary in serotype prevalence in time and space. A total of 261 children (up to nine years of age) in two neighboring locations with different transmission rates were sampled for blood-stage parasites in cross-sectional surveys before and after the main transmission period in 1991, and also in a concomitant one-year longitudinal survey tracing clinical infections. Six major sequence types of S-antigen were identified, which were subdivided into 70 alleles; however, only 50% of isolates were typeable. The S-antigen sequence types varied qualitatively between locations, over time, and between asymptomatic and clinical disease infections, but not between different age groups. The MSP-1 and MSP-2 sequence type prevalences, in contrast, did not differ in any of these comparisons. We describe the use of the Mantel test for assessing clustering of individual parasite alleles at the household level, and demonstrate low-level clustering of MSP-1 and MSP-2 alleles and S-antigen sequence types, at the end of a long period of low transmission.

Age Factors↗
PubMed1999

In vitro sensitivity of Plasmodium falciparum to artesunate in Thailand.

Reported are the in vitro susceptibilities of Plasmodium falciparum to artesunate, mefloquine, quinine and chloroquine of 86 isolates and to dihydroartemisinin of 45 isolates collected from areas of high resistance to mefloquine within Thailand near the borders with Myanmar and Cambodia, and from southern Thailand where P. falciparum is generally still sensitive to mefloquine. All the isolates were highly sensitive to artesunate, but the geometric mean IC50S were higher in isolates from the Thai-Myanmar and Thai-Cambodian borders than in those from southern Thailand. The IC50S for mefloquine and artesunate were strongly correlated (Pearson r = 0.605; n = 86; P < 0.00001). As expected, the in vitro sensitivities to dihydroartemisinin and artesunate were similar and strongly correlated (at IC50, Pearson r = 0.695; n = 45; P < 0.00002). The correlation between the activity of mefloquine and artesunate requires further investigation in order to determine the potential for development of cross-resistance in nature. Our results suggest that combination with mefloquine is not the ideal way of protecting the usefulness of artemisinin and its derivatives. A search for more suitable partner drugs to these compounds and careful regulation of their use are necessary in the interest of ensuring their long therapeutic life span.

Adolescent↗
PubMed1999

[Changes in chloroquine resistance of Plasmodium falciparum in Hainan province].

AIM: To observe the variation in resistance of Plasmodium falciparum after the cessation of chloroquine medication. METHODS: WHO standard in vitro microtest and in vivo test were used. RESULTS: In vitro test showed that the rate of chloroquine-resistant P. falciparum dropped from 97.9% in 1981 to 26.7% in 1997 (P < 0.001). The mean concentration of chloroquine for complete inhibition of schizont formation declined from 10.46 +/- 7.14 pmol/ul blood in 1981 to 1.63 +/- 1.47 pmol/microliter blood in 1997(P < 0.001). In vivo test showed that the rate of chloroquine-resistant P. falciparum decreased from 84.2% in 1981 to 18.4% in 1997(P < 0.001). The proportion of R III cases to the total resistant cases dropped from 53.1% in 1981 to 14.3% in 1997. CONCLUSION: A tendency of progressive decline of resistance of the parasite was revealed after the cessation of chloroquine medication.

Adolescent↗
PubMed2006

Serum antibody levels to glycosylphosphatidylinositols in specimens derived from matched Malian children with severe or uncomplicated Plasmodium falciparum malaria and healthy controls.

Neutralizing antibodies to glycosylphosphatidylinositols (GPIs), which are Plasmodium falciparum surface protein anchor molecules implicated in malaria pathogenesis, are thought to protect against symptomatic malaria. Index cases of severe malaria in Malian children 3 months to 14 years of age were matched by age and residence to uncomplicated malaria and healthy controls. Serum antibodies to GPI (IgM and IgG) were measured at the time of severe malaria and after the malaria transmission season. The mean optical density values for IgM and IgG antibodies were higher in children with severe or uncomplicated malaria compared with healthy controls. Similarly, higher percentages of children with IgM and IgG antibodies to GPI were observed in the severe malaria group compared with matched healthy controls. IgG antibody levels to GPI were highest among children with cerebral malaria and children who died. The IgG antibody levels to GPI peaked during periods of malaria transmission and decreased after malaria transmission ended. A direct correlation between age and parasitemia and IgG antibodies to GPI was observed. In summary, higher levels of IgM and IgG antibodies to GPI in young children were associated with disease severity and were short-lived.

Adolescent↗
PubMed2006

Structure of ribose 5-phosphate isomerase from Plasmodium falciparum.

The structure of ribose 5-phosphate isomerase from Plasmodium falciparum, PFE0730c, has been determined by molecular replacement at 2.09 angstroms resolution. The enzyme, which catalyzes the isomerization reaction that interconverts ribose 5-phosphate and ribulose 5-phosphate, is a member of the pentose phosphate pathway. The P. falciparum enzyme belongs to the ribose 5-phosphate isomerase A family, Pfam family PF06562 (DUF1124), and is structurally similar to other members of the family.

Aldose-Ketose Isomerases↗
PubMed2006

[In vitro effect of daphnetin on cytochrome C oxidase and ribonucleotide reductase of plasmodium falciparum].

OBJECTIVE: To test the in vitro effect of daphnetin on cytochrome C oxidase (COX) and ribonucleotide reductase (RNR) activity of Plasmodium falciparum. METHODS: P. falciparum (FCC1/HN) was cultured in vitro using the method of Trager and Jensen. The effect of daphnetin and daphnetin-Fe complex on COX and RNR activity of P. falciparum was tested by ultraviolet spectrophotometer and electron spin resonance (ESR) respectively. RESULT: The parasites synchronized with sorbitol in vitro was treated by daphnetin and daphnetin-Fe complex. The inhibition level of the COX activity by daphnetin after being treated for 2, 4, 8 and 12 h were 0.6%, 73% and 80% respectively and the inhibition level by daphnetin at different concentrations (0.1, 1, 100 and 1 mmol/L) for 6h was 3%, 31%, 53% and 84%, respectively. No considerable effect was observed on the COX activity of P. falciparum treated with daphnetin-Fe complex. The tyrosyl free radical was tested to reflect the RNR activity of P. falciparum at various times by ESR. The inhibition level by daphnetin for 1, 2, 3 and 4 h were 7%, 51%, 69% and 75% respectively, while the values treated by daphnetin-Fe complex were 8%, 6%, 11% and 9% respectively. The inhibition level by daphnetin at different concentrations (0.1, 1, 100 and 1 mmol/L) for 6 h was 3%, 31%, 58% and 93% respectively and while the values treated by daphnetin-Fe complex were 8%, 6%, 11% and 9%. CONCLUSION: Daphnetin significantly reduces the COX and RNR activities of Plasmodium falciparum in vitro.

Animals↗
PubMed2004

Transition state analysis for human and Plasmodium falciparum purine nucleoside phosphorylases.

Recent studies have shown that Plasmodium falciparum is sensitive to a purine salvage block at purine nucleoside phosphorylase (PNP) and that human PNP is a target for T-cell proliferative diseases. Specific tight-binding inhibitors might be designed on the basis of specific PNP transition state structures. Kinetic isotope effects (KIEs) were measured for arsenolysis of inosine catalyzed by P. falciparum and human purine nucleoside phosphorylases. Intrinsic KIEs from [1'-(3)H]-, [2'-(3)H]-, [1'-(14)C]-, [9-(15)N]-, and [5'-(3)H]inosines were 1.184 +/- 0.004, 1.031 +/- 0.004, 1.002 +/- 0.006, 1.029 +/- 0.006, and 1.062 +/- 0.002 for the human enzyme and 1.116 +/- 0.007, 1.036 +/- 0.003, 0.996 +/- 0.006, 1.019 +/- 0.005, and 1.064 +/- 0.003 for P. falciparum PNPs, respectively. Analysis of KIEs indicated a highly dissociative D(N)A(N) (S(N)1) stepwise mechanism with very little leaving group involvement. The near-unity 1'-(14)C KIEs for both human and P. falciparum PNP agree with the theoretical value for a 1'-(14)C equilibrium isotope effect for oxacarbenium ion formation when computed at the B1LYP/6-31G(d) level of theory. The 9-(15)N KIE for human PNP is also in agreement with theory for equilibrium formation of hypoxanthine and oxacarbenium ion at this level of theory. The 9-(15)N KIE for P. falciparum PNP shows a constrained vibrational environment around N9 at the transition state. A relatively small beta-secondary 2'-(3)H KIE for both enzymes indicates a 3'-endo conformation for ribose and relatively weak hyperconjugation at the transition state. The large 5'-(3)H KIE reveals substantial distortion at the 5'-hydroxymethyl group which causes loosening of the C5'-H5' bonds during the reaction coordinate.

Adenosine Triphosphate↗
PubMed2001

The gametocyte-activating factor xanthurenic acid stimulates an increase in membrane-associated guanylyl cyclase activity in the human malaria parasite Plasmodium falciparum.

Sex is an obligate step in the life cycle of the malaria parasite and occurs in the midgut of the mosquito vector. With both Plasmodium falciparum and Plasmodium berghei, the tryptophan metabolite xanthurenic acid induces the release of motile male gametes from red blood cells (exflagellation), a prerequisite for fertilization. The addition of cGMP or phosphodiesterase inhibitors to cultures of mature gametocytes has also been shown to stimulate exflagellation. Here, we demonstrate that there is a guanylyl cyclase activity associated with mature P. falciparum gametocyte membrane preparations, which is dependent on the presence of Mg(2+)/Mn(2+) but is inhibited by Ca(2+). Significantly, this activity is increased on addition of xanthurenic acid. In contrast, a xanthurenic acid precursor (3-hydroxykynurenine), which is not an inducer of exflagellation, does not induce this guanylyl cyclase activity. These results therefore suggest that xanthurenic acid-induced exflagellation may be mediated by activation of the parasite cGMP signalling pathway.

Animals↗
PubMedDate not supplied

Chloroquine-resistant Plasmodium falciparum malaria in Vanuatu.

Cases of malaria caused by Plasmodium falciparum resistant to chloroquine treatment have been probably occurring in Vanuatu for many years. In this survey, seven patients with P. falciparum malaria were investigated for evidence of resistance to chloroquine. In-vitro resistance to chloroquine was demonstrated in four. Two further patients who had clinical resistance to chloroquine treatment developed cerebral malaria. It is of interest that one of these patients was subsequently successfully treated with mepacrine. Two additional cases are cited as examples of resistance to chloroquine treatment encountered in the past.

Adult↗
PubMed1993

Immunogenicity of the Plasmodium falciparum asexual blood-stage synthetic peptide vaccine SPf66.

The immunogenicity of the cocktail vaccine SPf66 against Plasmodium falciparum was investigated in rabbits, monkeys, and human volunteers. This polymerized peptide vaccine incorporates a portion of each of the 35-kD, 55-kD, and 83-kD blood-stage proteins, linked by an amino acid sequence reproducing one repeat from the circumsporozoite protein of P. falciparum. Results from this study show that vaccination with this vaccine molecule elicited high titers of antibodies to SPf66 and its constituents, but these antibodies did not correlate with regular or sensitive indirect fluorescent antibody (IFA) titers to blood-stage malaria parasites. However, rabbits injected with individual peptides produced antibodies with low affinity to indefinite parasite structures by immunoelectron microscopy, and rabbits injected with SPf66 had high antibody titers against the peptide (NANP)40. Consequently, these anti-SPf66 serum samples recognized P. falciparum sporozoites in the IFA. Such reactivity was not observed in monkeys or human volunteers vaccinated with SPf66. In addition, SPf66 components were recognized by antibodies induced by natural infection in humans and by laboratory-monitored infections in Aotus monkeys. These results suggest that this vaccine candidate merits further developmental work to better define immune response elicited by the copolymer to the parasite.

Adolescent↗
PubMed1993

Characterisation of the gene encoding an unusually divergent TATA-binding protein (TBP) from the extremely A+T-rich human malaria parasite Plasmodium falciparum.

The intergenic regions of the human malaria parasite, Plasmodium falciparum, are extreme in their base composition, averaging approx. 90% A + T. As a first step to investigating whether transcription in this organism follows conventional models based largely on yeast, we have isolated and characterised the gene (TBP) encoding its TATA-binding protein (TBP). The gene is present as a single copy on chromosome 5 and is expressed as a 1.8-kb mRNA encoding a protein of 228 amino acids (aa) (26 164 Da). The inferred protein product has a bipartite structure consisting of a 45-aa species-specific N-terminal domain and a 183-aa C-terminal domain. In the latter, the malarial protein contains two directly repeated, but imperfectly homologous regions, each approx. 78 aa in length, together with a highly basic region located between them. These features are characteristic of all TBPs studied to date. Moreover, hydropathy plots suggest that the overall folding of this C-terminal domain is very similar to that of other TBPs. However, TBP from P. falciparum is much less closely related at the primary sequence level to the archetypal yeast homologue than are all other characterised TBPs (42% identity, compared to 76-93%, respectively). Despite this divergence of the primary sequence, most residues known to be involved in DNA binding are conserved. Those instances where sequence variation at generally conserved residues is observed may reflect functional differences that could ultimately be exploited by selective chemotherapy.

Amino Acid Sequence↗
PubMed1984

Autoantibodies in sera of Thai patients with Plasmodium falciparum infection.

Serum from 98 Thai adults infected with Plasmodium falciparum were examined for the presence of autoantibodies. Malarial containing antibodies sera were also revealed positive for anti-nuclear antibodies with fluorescence speckled pattern, anti-smooth muscle antibodies, anti-mitochondria antibodies and rheumatoid factor. There was no detectable antibody to double stranded DNA. There was a significant relationship between high titre of malarial antibody and high frequency of speckled pattern of anti-nuclear factor or anti-nuclear antibodies. By the ELISA technique determination of serum antibodies against an extractable nuclear antigen (ENA) in patients with P. falciparum infection gave 43.8% (43 of 98) positive result. In addition, sera contained malarial antibodies gave positive antibodies to ENA in 50% (49 of 98) by tanned red cell haemagglutination. Among the positive sera with antibodies to ENA, they showed the presence of antibodies to both ribonucleoprotein RNAase sensitive (RNP) and ribonucleoprotein RNAase resistance (Sm). Also both of antibodies exhibited positive staining of speckled pattern of antinuclear factor. This observation indicated that malaria infection induces autoantibodies which were predominantly anti-nuclear antibodies.

Adult↗
PubMed1994

[Cloning and sequencing of a DNA fragment from Plasmodium falciparum FCC1/HN isolate].

A specific DNA fragment isolated from Plasmodium falciparum FCC1/HN isolate has been cloned in Bam H1 site of pUC18 and first partially sequenced by Sanger's method. The results show: G+C percent of DNA sequence is 26.8%, and the cloned DNA has many restriction sites which are conventional for subcloning. The authors suggest that this clone and sequence may be used as a guide for developing a DNA probe or PCR primers.

Animals↗
PubMed2001

Decoding the language of var genes and Plasmodium falciparum sequestration.

Sequestration and rosetting are key determinants of Plasmodium falciparum pathogenesis. They are mediated by a large family of variant proteins called P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 proteins are multispecific binding receptors that are transported to parasite-induced, 'knob-like' binding structures at the erythrocyte surface. To evade immunity and extend infections, parasites clonally vary their expressed PfEMP1. Thus, PfEMP1 are functionally selected for binding while immune selection acts to diversify the family. Here, we describe a new way to analyse PfEMP1 sequence that provides insight into domain function and protein architecture with potential implications for malaria disease.

Amino Acid Sequence↗
PubMed2003

In vitro activities of piperaquine and other 4-aminoquinolines against clinical isolates of Plasmodium falciparum in Cameroon.

The spread of chloroquine-resistant Plasmodium falciparum calls for a constant search for new drugs. The in vitro activity of piperaquine, a new Chinese synthetic drug belonging to the bisquinolines, was evaluated in 103 fresh clinical isolates of P. falciparum in Cameroon, Central Africa, and compared with that of other 4-aminoquinoline and Mannich base derivatives and dihydroartemisinin. Piperaquine was highly active (geometric mean 50% inhibitory concentration, 38.9 nmol/liter; range, 7.76 to 78.3 nmol/liter) and equally active (P > 0.05) against the chloroquine-sensitive and the chloroquine-resistant isolates. There was a significant but low correlation of response between chloroquine and piperaquine (r = 0.257, P < 0.05). These results suggest that further development of piperaquine, in combination with dihydroartemisinin, holds promise for use in chloroquine-resistant regions of endemicity.

Aminoquinolines↗
PubMed2003

Identification and characterization of heme-interacting proteins in the malaria parasite, Plasmodium falciparum.

The degradation of hemoglobin by the malaria parasite, Plasmodium falciparum, produces free ferriprotoporphyrin IX (FP) as a toxic by-product. In the presence of FP-binding drugs such as chloroquine, FP detoxification is inhibited, and the build-up of free FP is thought to be a key mechanism in parasite killing. In an effort to identify parasite proteins that might interact preferentially with FP, we have used a mass spectrometry approach. Proteins that bind to FP immobilized on agarose include P. falciparum glyceraldehyde-3-phosphate dehydrogenase (PfGAPDH), P. falciparum glutathione reductase (PfGR), and P. falciparum protein disulfide isomerase. To examine the potential consequences of FP binding, we have examined the ability of FP to inhibit the activities of GAPDH and GR from P. falciparum and other sources. FP inhibits the enzymic activity of PfGAPDH with a Ki value of 0.2 microm, whereas red blood cell GAPDH is much less sensitive. By contrast, PfGR is more resistant to FP inhibition (Ki > 25 microm) than its human counterpart. We also examined the ability of FP to inhibit the activities of the additional antioxidant enzymes, P. falciparum thioredoxin reductase, which exhibits a Ki value of 1 microm, and P. falciparum glutaredoxin, which shows more moderate sensitivity to FP. The exquisite sensitivity of PfGAPDH to FP may indicate that the glycolytic pathway of the parasite is particularly susceptible to modulation by FP stress. Inhibition of this pathway may drive flux through the pentose phosphate pathway ensuring sufficient production of reducing equivalents to counteract the oxidative stress induced by FP build-up.

Animals↗
PubMed1990

Cloning and expression in Escherichia coli of a hypoxanthine-guanine phosphoribosyltransferase-encoding cDNA from Plasmodium falciparum.

The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) of Plasmodium falciparum plays a key role in the salvage of preformed purine nucleotides from parasite-infected erythrocytes. Since P. falciparum cannot synthesize purines de novo, development of inhibitors specific for the parasite HGPRT should be an effective method of chemotherapy. To provide sufficient amounts of HGPRT for biochemical and crystallographic analysis, we have isolated the P. falciparum HPRT cDNA sequence and expressed it in an Escherichia coli strain deficient for both de novo purine synthesis and guanine utilization (strain GP120). GP120 cells containing the P. falciparum HPRT plasmid vector (pRD500), when grown in the presence of isopropyl-beta-D-thiogalactopyranoside (IPTG) which induces the tac promoter of the expression vector, produce a novel protein of 26 kDa, which is in agreement with the predicted Mr deduced from the HPRT cDNA open reading frame. In addition, we have demonstrated significant HGPRT activity in cell-free extracts of GP120[pRD500] cultures grown in minimal medium containing xanthine, as the sole source of purines, and IPTG.

Amino Acid Sequence↗
PubMed2002

Identification of a conserved Plasmodium falciparum var gene implicated in malaria in pregnancy.

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family is a highly polymorphic class of variant surface antigens encoded by var genes that play an important role in malaria pathogenesis. This report describes the unexpected finding that 1 of the var genes encoding a PfEMP1 variant that binds to the host receptor chondroitin sulfate A (CSA) and is implicated in malaria in pregnancy is well conserved among P. falciparum isolates worldwide. The N-terminal domains of this PfEMP1 variant are especially highly conserved, whereas the functional CSA binding domain is more variable. Analysis of var gene expression in placental parasites from primigravid women in Malawi did not support a role for this conserved gene in placental infection but identified a second commonly occurring var gene. These results indicate the need for reevaluation of previous assumptions of a minimal overlap between var gene repertoires from different parasite isolates.

Animals↗