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At least 1,333 records · Page 74Linked to original sources
PubMed1998

No influence of age on infection complexity and allelic distribution in Plasmodium falciparum infections in Ndiop, a Senegalese village with seasonal, mesoendemic malaria.

We have shown previously that in Dielmo, a Senegalese village with intense perennial Plasmodium falciparum transmission, the infection complexity and the distribution of some allelic types harbored by asymptomatic carriers was age-dependent. We report here an investigation of these parameters in Ndiop, a village located 5 km from Dielmo, where malaria is mesoendemic and seasonal, and where immunity is acquired at a very low rate, as indicated by the lifelong distribution of P. falciparum clinical attacks. Blood was collected from 143 and 125 inhabitants, including 122 individuals sampled in both surveys, during two cross-sectional surveys at one-month intervals during the 1994 transmission season. Plasmodium falciparum parasites were genotyped for three polymorphic single copy genes. Genetic diversity was very large, with 17, 43, and nine distinct alleles detected for the merozoite surface protein-1 (MSP-1), MSP-2, and glutamate-rich protein loci, respectively. These figures, similar to those previously observed in Dielmo, indicate that the parasite genetic diversity is not directly related to the inoculation rate, at least in the range of transmission intensity studied here. The complexity of the asymptomatic infections (average number of distinct genotypes per isolate) was more than two-fold lower in Ndiop than in Dielmo and importantly, did not decrease with age. Likewise, the allele distribution was not influenced by age, contrasting with the observations made in Dielmo. This indicates that the number of parasite types per isolate and the influence of age on complexity and allele distribution depend on the level of endemicity, consistent with the interpretation that they reflect acquired anti-parasite immunity.

Adolescent↗
PubMed1997

Ex vivo antimalarial activity of proguanil combined with dapsone against cycloguanil-resistant Plasmodium falciparum isolates.

The ex vivo antimalarial activity of plasma samples obtained from 20 healthy Caucasian volunteers following daily proguanil (200 mg) plus dapsone (8 mg) for malaria chemoprophylaxis inhibited five cycloguanil-resistant Thai isolates of Plasmodium falciparum. All volunteers were phenotyped as extensive metabolisers (EMs) of proguanil. Three of the five isolates were obtained from Thai soldiers who had failed malaria prophylaxis on daily proguanil (200 mg) plus dapsone (4.0 or 12.5 mg). The Thai soldiers were also classified as EMs, but had relatively lower plasma cycloguanil concentrations compared to values reported in the literature for Caucasians and black Kenyans. Although the high level of parasite resistance to cycloguanil was the most likely explanation for the Thai soldiers failing prophylaxis on proguanil plus dapsone, their low cycloguanil concentrations may have also contributed to their lack of protection. However, in areas where parasites are more susceptible to cycloguanil, such as in certain regions of Africa, proguanil plus dapsone may still be an effective chemoprophylactic drug combination.

Animals↗
PubMed2001

Biosynthesis of glycosphingolipids de-novo by the human malaria parasite Plasmodium falciparum.

Glycolipids are important components of cellular membranes involved in various biological functions. In this report we describe the identification of the de-novo synthesis of glycosphingolipids by intraerythrocytic, asexual stages of the malaria parasite, Plasmodium falciparum. Parasite-specific glycolipids were identified in organic solvent extracts of parasites metabolically labeled with tritiated serine and glucosamine and characterised as sphingolipids based on their insensitivity towards alkaline treatment. While the de-novo synthesis of parasite glycosphingolipids was affected by fumonisin B1, threo-PPMP, cyclo-serine and myriocin, these well established inhibitors of de-novo ceramide biosynthesis were unable to arrest the intraerythrocytic development of the parasites in culture.

Animals↗
PubMed1998

Stage-specific effects of antimalarials on an Indian isolate of Plasmodium falciparum.

In this study, effects of timed sequential exposure to various concentrations of chloroquine and its two metabolites (SA100387/050 B, SA 100487/053 B), quinine, hydroquinine and quinidine were monitored by morphological analyses, using synchronous cultures of Plasmodium falciparum. The trophozoites and schizonts were sensitive to chloroquine and its metabolites. However, quinine and two of its derivatives were lethal without particularly being stage-specific.

Animals↗
PubMed2004

A real-time PCR assay for quantifying Plasmodium falciparum infections in the mosquito vector.

Transmission-blocking vaccines prevent the development of Plasmodium parasite within the mosquito vector, thereby thwarting the spread of malaria through a community. The gold standard for determining the efficacy of a transmission-blocking vaccine is the standard membrane feeding assay. This assay requires the dissection of mosquitoes and microscopic counting of oocysts present on the mosquito mid-gut, typically at 7-10 days p.i. Here we describe a real-time quantitative PCR assay that is rapid, target-specific and robust, with a sensitive detection threshold and which may be employed earlier p.i. than the standard membrane feeding assay and is applicable to preserved material. The real-time PCR assay utilises the LightCycler platform and SYBR Green I detection system to amplify 180 bp of the asexual form of the Plasmodium falciparum rRNA gene. It has a quantitative range of greater than four orders of magnitude and a detection threshold of 10 parasites. Validation experiments using a monoclonal antibody of known blocking activity revealed the real-time PCR assay to give equivalent results to the standard membrane feeding assay. In addition, the PCR assay can establish the effect of such a monoclonal antibody on the parasites' development within the oocyst and on the sporozoite (the transmissible stage) yield, providing a more pertinent assessment of transmission blocking activity than is possible by the standard membrane feeding assay. This assay may also be employed to monitor the sporogonic development of P. falciparum parasites within the mosquito vector.

Animals↗
PubMedDate not supplied

Possible prognostic significance of a brief rise in parasitaemia following quinine treatment of severe Plasmodium falciparum malaria.

An increase in parasitaemia is not uncommon after initiation of treatment for Plasmodium falciparum malaria, but its exact significance is unknown. The time-course of parasitaemia was assessed retrospectively in 33 patients with severe imported malaria. In 19 patients (group 1) mean parasitaemia (+/- SEM) fell promptly after starting quinine treatment, from 24.9 +/- 4.1% on day 0 to 9.7 +/- 2.3% on day 1 and 1.8 +/- 0.7% on day 2. In 14 other patients (group 2), parasitaemia did not change significantly or increased, with mean parasitaemia (+/- SEM) of 9.5 +/- 2.1% on day 0, 17.2 +/- 2.6% on day 1, and 3.7 +/- 1.8% on day 2. Simplified acute physiology scores on admission (mean +/- SEM) were 17.4 +/- 1.4 in group 1 and 11.7 +/- 1.0 in group 2 (P = 0.006). The mean number of complications of malaria per patient (+/- SEM) was 2.9 +/- 0.5 in group 1 and 1.6 +/- 0.3 in group 2 (P = 0.046). Two group 1 patients died. Initially, more than 95% of peripheral blood parasites were tiny and small rings in both groups, and this distribution was unchanged on day 1, suggesting that the parasitaemia increase in group 2 was not due to release of sequestered mature parasites. In severe falciparum malaria, a rise in parasitaemia after treatment initiation may be of favourable prognostic significance and should not lead to aggressive therapeutic approaches such as exchange transfusion.

Adult↗
PubMed1997

Plasmodium falciparum chloroquine and quinine sensitivity in asymptomatic and symptomatic children in São Tomé Island.

Plasmodium falciparum sensitivity to quinine in São Tomé was determined by in vivo and in vitro tests in 56 children with mild or cerebral malaria. Chloroquine sensitivity was assessed by in vitro tests in 105 parasitaemic asymptomatic children from the same community as the cases. The WHO standard methodology was used. No resistance to quinine was found by in vivo or in vitro tests in either group of patients or in asymptomatic children, although some degree of chloroquine resistance was found with the in vitro test. This was more common in patients than in asymptomatic children. Chloroquine resistance may be explained by the recent history of malaria in São Tomé Island, which caused an important decrease of immunity among the population and consequently the emergence of resistant strains. Implications of the use of in vivo/in vitro tests for determining the antimalarial drug policy within the primary health care system are discussed.

Adolescent↗
PubMed2003

Plasmodium falciparum multiplicity correlates with anaemia in symptomatic malaria.

In 366 Ghanaian children with symptomatic Plasmodium falciparum malaria, low haemoglobin levels and severe anaemia were associated with a high multiplicity of infection (MOI) and with distinct merozoite surface protein alleles. High MOI not only reflects premunition but may also contribute to anaemia in symptomatic malaria.

Alleles↗
PubMed2000

HLA-DQB1*0501-restricted Th1 type immune responses to Plasmodium falciparum liver stage antigen 1 protect against malaria anemia and reinfections.

Protective immunity against Plasmodium falciparum requires constant exposure to the pathogen. T cell-mediated immune responses are induced by T cell epitopes of pre-erythrocytic stage antigens of P. falciparum and involve HLA-restricted CD4 and CD8 cells. Cytotoxic T cell responses to a conserved epitope of P. falciparum liver stage antigen (LSA) type 1 are restricted by the HLA class I allele Bw53. The role of HLA class II alleles in mediating cellular responses against P. falciparum LSA-1 has not yet been demonstrated. In a longitudinal study performed for >4 years, associations were found between the HLA class II allele DQB1*0501 and protection from malaria anemia and malarial reinfections in Gabonese children. Children carrying DQB1*0501 had a higher frequency of interferon-gamma responses to LSA-1 T cell epitopes, compared with noncarriers.

Alleles↗
PubMed2004

Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote.

BACKGROUND: Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. Eukaryotic protein kinases (ePKs) form a large family of enzymes with crucial roles in most cellular processes; hence malarial ePKS represent potential drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB) aimed at identifying and classifying all ePKs in this organism. RESULTS: Using a variety of bioinformatics tools, we identified 65 malarial ePK sequences and constructed a phylogenetic tree to position these sequences relative to the seven established ePK groups. Predominant features of the tree were: (i) that several malarial sequences did not cluster within any of the known ePK groups; (ii) that the CMGC group, whose members are usually involved in the control of cell proliferation, had the highest number of malarial ePKs; and (iii) that no malarial ePK clustered with the tyrosine kinase (TyrK) or STE groups, pointing to the absence of three-component MAPK modules in the parasite. A novel family of 20 ePK-related sequences was identified and called FIKK, on the basis of a conserved amino acid motif. The FIKK family seems restricted to Apicomplexa, with 20 members in P. falciparum and just one member in some other Apicomplexan species. CONCLUSION: The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the kinome of malaria parasites and that of yeast or mammalian cells.

Animals↗
PubMed1997

The Malayan IV strain of Plasmodium falciparum in Aotus monkeys.

Forty-nine infections with the Malayan IV strain of Plasmodium falciparum were induced in different species of Aotus monkeys. The parasite was shown to be infective to four different species of Aotus monkeys via the inoculation of parasitized erythrocytes. Sporozoite transmission was obtained to A. lemurinus griseimembra, A. vociferans, and hybrid monkeys with A. azarae boliviensis x A. nancymai and A. lemurinus griseimembra x A. nancymai parentage. Anopheles freeborni and An. stephensi mosquitoes fed readily on animals and through membranes; both supported the development of infective sporozoites. Markedly increased levels of mosquito infection were routinely obtained by membrane feeding, indicating the presence of serum factors inhibitory to infection. The Malayan IV strain appears suitable for blood-stage and transmission-blocking vaccine trials.

Animals↗
PubMed1998

Relationships of malaria morbidity with exposure to Plasmodium falciparum in young children in a highly endemic area.

To study incidence of clinical Plasmodium falciparum malaria in relation to exposure to parasites, attendance of children less than eighteen months old at a village dispensary in a highly endemic area of Tanzania was recorded. Entomologic inoculation rates (EIRs), estimated as a function of time period and place of residence, exceeded one sporozoite positive bite per adult per night in some village neighborhoods during the wet season. Incidence of clinical P. falciparum malaria, defined either as fever with parasitemia or as fever with hyperparasitemia, increased with the EIR over the whole range of exposures. Each 10-fold increase in the EIR corresponded to a 1.6-fold increase in incidence of fever plus parasitemia (95% confidence interval = 1.4-2.0). Therefore reduction of human-vector contacts will probably reduce morbidity incidence even at very high exposures. Incidence showed little relationship to estimated cumulative numbers of inoculations since birth, but decreased steeply with estimated cumulative time infected with trophozoites. This suggests that clinical immunity depends mainly on the extent of exposure to blood-stage antigens, not on the diversity of inocula seen, and thus temporary reductions in human-vector contacts are unlikely to result in subsequent increases in morbidity.

Animals↗
PubMed1993

Sensitive detection of Plasmodium falciparum in blood and mosquito by DNA amplification.

By means of enzymatic amplification of Plasmodium falciparum DNA using the polymerase chain reaction (PCR), we have been able to detect as little as 20 parasites in 20 ml infected human blood based on the visualization of a 206 bp fragment in ethidium bromide-stained agarose gel. Comparison, through microscopic examination of 2030 blood samples collected from various endemic areas in Thailand, indicates that the PCR-based detection system is 96% specific and 81% sensitive, with a disagreement of 6.6%. The same protocol can be applied to detect a minimum of 10 sporozoites or a single oocyst dissected from P. falciparum-infected mosquito.

Animals↗
PubMedDate not supplied

Detection of extracellular forms of babesia in the blood by electron microscopy: a diagnostic method for differentiation from Plasmodium falciparum.

Light microscopic examination of blood smears is the traditional approach for the diagnosis of babesiosis, but there is morphological overlap with Plasmodium falciparum. The authors describe 3 patients with babesial infection in whom the diagnosis was made by identifying extracellular merozoites in a buffy coat preparation using electron microscopy. This method resulted in a high yield of extracellular babesia, even in a case where virtually no extracellular babesia were detectable in the blood smear. The test had a reasonably fast turnaround time and allowed detailed visualization of the organisms and reliable distinction from Plasmodium falciparum.

Aged↗
PubMed1989

The mature erythrocyte surface antigen of Plasmodium falciparum is not required for knobs or cytoadherence.

Intraerythrocytic Plasmodium falciparum parasites at the trophozoite and schizont stages synthesize a greater than 200-kDa protein, the mature erythrocyte surface antigen (MESA), that is localized at the membrane of infected red blood cells and manifests size polymorphism and antigenic diversity among parasite isolates. Because MESA is localized in the host cell membrane, we examined parasites with differing knob and cytoadherence phenotypes to determine whether MESA expression correlated with knob formation and cytoadherence. A cloned line of P. falciparum that was cultured with repeated selection for the knobbed and cytoadherent phenotypes did not express MESA, due to at least partial deletion of the single-copy MESA gene. In contrast, parasites from the same clone that were cultured without this selection lost the knobbed and cytoadherent phenotypes, but continued to express MESA. These results indicate that MESA is apparently not required for differentiation and multiplication of erythrocyte stage P. falciparum parasites in vitro, or for knob formation and cytoadherence. We speculate that MESA may have a role in evasion of the host immune response by P. falciparum.

Animals↗
PubMed1997

Developmentally regulated expression of pfs16, a marker for sexual differentiation of the human malaria parasite Plasmodium falciparum.

Sexual differentiation is essential for the transmission of Plasmodium to mosquitoes and therefore, for the spread of malaria. The molecular mechanisms underlying sexual differentiation are poorly understood but may be elucidated by a detailed study of the regulation of expression of sexual stage specific genes. In the present work we describe the differential expression of the gene encoding the sexual stage specific protein, Pfs16. We have conducted a comparative analysis of pfs16 promoter activity, RNA levels and the rate of de novo protein synthesis during development of Plasmodium falciparum. Furthermore, we have determined the pattern of expression of pfs16 transcripts at the single cell level by in situ hybridisation. We show that the expression of pfs16 is induced immediately following the invasion of a red blood cell in sexually committed ring stage parasites and continues throughout gametocytogenesis and in macrogametes. The expression of pfs16 is regulated at the level of transcription initiation and modulated by a post-transcriptional process. These results demonstrate that the expression of the pfs16 gene is the earliest event in the sexual differentiation process of P. falciparum described to date.

Animals↗
PubMed2001

New class of small nonpeptidyl compounds blocks Plasmodium falciparum development in vitro by inhibiting plasmepsins.

Malarial parasites rely on aspartic proteases called plasmepsins to digest hemoglobin during the intraerythrocytic stage. Plasmepsins from Plasmodium falciparum and Plasmodium vivax have been cloned and expressed for a variety of structural and enzymatic studies. Recombinant plasmepsins possess kinetic similarity to the native enzymes, indicating their suitability for target-based antimalarial drug development. We developed an automated assay of P. falciparum plasmepsin II and P. vivax plasmepsin to quickly screen compounds in the Walter Reed chemical database. A low-molecular-mass (346 Da) diphenylurea derivative (WR268961) was found to inhibit plasmepsins with a K(i) of 1 to 6 microM. This compound appears to be selective for plasmepsin, since it is a poor inhibitor of the human aspartic protease cathepsin D (K(i) greater than 280 microM). WR268961 inhibited the growth of P. falciparum strains W2 and D6, with 50% inhibitory concentrations ranging from 0.03 to 0.16 microg/ml, but was much less toxic to mammalian cells. The Walter Reed chemical database contains over 1,500 compounds with a diphenylurea core structure, 9 of which inhibit the plasmepsins, with K(i) values ranging from 0.05 to 0.68 microM. These nine compounds show specificity for the plasmepsins over human cathepsin D, but they are poor inhibitors of P. falciparum growth in vitro. Computational docking experiments indicate how diphenylurea compounds bind to the plasmepsin active site and inhibit the enzyme.

Animals↗
PubMed1992

A fourth family of the Plasmodium falciparum S-antigen.

The S-antigen of Plasmodium falciparum is a highly diverse heat stable protein that is located in the parasitophorous vacuole of the mature asexual intraerythrocytic parasite. The gene for S-antigen exists within the parasite population as multiple alleles at a single locus. Its sequence contains a large central block of tandemly arranged peptides that are identical or very similar in one allele but differ widely in sequence, repeat length and number among different alleles, and consequently antigenic specificity. Thus, antibodies directed against the repeat region can be used to define the serotype of an S-antigen. Flanking this repeat block are 2 short regions of non-repetitive sequence which have been described as occurring in three different forms, each of which is used to define a single S-antigen family. We present the S-antigen sequence for the isolate 3D7 which defines not only a novel serotype but also a novel S-antigen family. The central repeat block is composed of 57 copies of an 8-residue peptide with consensus sequence ED(E/K)VSNG(R/G). Comparison of the four S-antigen families reveals that they differ considerably from each other with variation being most pronounced in the carboxy terminal-flanking region. This pattern of sequence variation differs considerably from that found for MSA-1 and MSA-2, the only other diverse proteins of P. falciparum for which sequence information is available.

Amino Acid Sequence↗