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PubMed2000

Correlation of in vivo-resistance to chloroquine and allelic polymorphisms in Plasmodium falciparum isolates from Uganda.

The efficacy of chloroquine in the treatment of uncomplicated falciparum malaria in Africa is heavily compromised by high levels of drug resistance. The occurrence of active site mutations in the Plasmodium falciparum multi drug resistance-gene 1 (pfmdr1) has been associated with development of resistance to chloroquine. This study investigates the occurrence of several mutations at codons 86, 1042 and 1246 of the pfmdr1-gene in infected blood samples taken from Ugandan children before treatment with chloroquine and their relationship to clinical and parasitological resistance. Even though a clear association of CQR to one certain pfmdr1 single point mutation could not be substantiated, the frequency of resistance was consistently higher for samples revealing any of the mutations than among wild type samples, and 90% of the clinically resistant samples did present a mutation. Thus detection of these allelic pfmdr1 polymorphisms is not a decisive factor for prediction of clinical chloroquine resistance, but an interplay of the different mutations with unknown cofactors is to be assumed and the possible role of other genetic alterations remains to be investigated.

ATP-Binding Cassette Transporters↗
PubMed1995

Interleukin-10 inhibits tumor necrosis factor production but not antigen-specific lymphoproliferation in acute Plasmodium falciparum malaria.

In vivo interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma production was measured at the mRNA transcript and protein levels in patients acutely infected with Plasmodium falciparum and during convalescence. Both IL-10 and IFN-gamma but not IL-2 were produced regardless of the patients' clinical severity. IL-4 production was variable. Circulating IFN-gamma and IL-10 were significantly higher in patients with severe disease (P < .01 and .001, respectively). In vitro stimulation of peripheral blood mononuclear cells (PBMC) by malarial antigens during acute infection showed that although there was no lymphoproliferation, the cells could produce IL-10 and IFN-gamma. Recombinant human IL-10 completely abolished in vitro tumor necrosis factor (TNF)-alpha production in response to malarial antigens, as well as the antigen-specific proliferative response of convalescent patients. However, anti-IL-10 was insufficient to restore proliferation of PBMC from acutely infected patients. These findings suggest that IL-10 may have an important negative feedback action on the production of inflammatory cytokines in acute falciparum malaria without contributing to the defect in antigen-specific proliferation.

Adult↗
PubMed2004

Immunoglobulin G isotype responses to variant surface antigens of Plasmodium falciparum in healthy Gabonese adults and children during and after successive malaria attacks.

We assessed immunoglobulin G (IgG) isotype responses with specificity for the variant surface antigens (VSA) of heterologous Plasmodium falciparum isolates by using flow cytometry and plasma from healthy Gabonese adults and from children during and after two consecutive malaria episodes. The individual isolate-specific antibody profiles differed markedly in terms of their isotype content but were similar for healthy adults and healthy uninfected children. In healthy adults, IgG3 and IgG2 responses were the highest, while in healthy children, IgG3 and IgG4 predominated. A transiently elevated IgG1 response was observed during the second of two successive malaria episodes in children, signaling P. falciparum infection-induced cross-reactive anti-VSA responses. Our findings highlight the prominence of IgG3 in the overall profile of these responses but also indicate a marked age-related increase in the prevalence of anti-VSA antibodies of the classically noncytophilic IgG2 isotype, possibly reflecting the high frequency of the histidine-131 variant of FcgammaRIIA in the Gabonese population.

Adolescent↗
PubMed1992

Seroepidemiologic studies of humoral immune response to the Plasmodium falciparum antigens in Thailand.

We have investigated seroreactivity against Plasmodium falciparum crude parasite antigens, the P. falciparum ring-infected erythrocyte surface antigen (Pf155/RESA), as well as against two synthetic peptides (EENV)6 and (EENVEHDA)3 that represent important epitopes of Pf155/RESA. The study population consisted of 421 children and adult Thais living in an area with moderate malaria transmission. We related these serologic findings to some important epidemiologic baseline data collected in the study area. The parasite rate in study subjects was 18.76%. Sixty-two percent were seropositive to crude P. falciparum antigens, 30.3% to the Pf155/RESA antigen, 23.05% to (EENV)6, and 20.17% to (EENVEHDA)3. Antibody responses to crude P. falciparum antigens and to Pf155/RESA were age dependent and increased with exposure. There was evidence that Pf155/RESA antibodies might play a role in protective immunity in this population. Since Pf155/RESA is a potential vaccine candidate antigen, the information obtained from these field studies will provide some seroepidemiologic baseline data for subsequent vaccine trials.

Adolescent↗
PubMed1999

Diagnostic performance of two antigen capture tests for the diagnosis of Plasmodium falciparum malaria in Zimbabwe.

OBJECTIVE: The objective was to compare the diagnostic performance of two antigen capture tests, ParaSight-F test and Immunochromatographic test (ICT), for the diagnosis of Plasmodium falciparum malaria. DESIGN: A comparative study. SETTING: Burma Valley, Mutare District, Manicaland in Zimbabwe. SUBJECTS: Patients attending the local clinic with clinical signs and symptoms associated with malaria infection. A blood film was collected from the patient and at the same time blood for the ParaSight-F test and the ICT was collected too. A total of 123 patients were diagnosed using the ICT test, the ParaSight-F test and microscopy which was used as a "gold" standard. MAIN OUTCOME MEASURES: True positives and negatives, false positives and negatives with reference to microscopy. RESULTS: The results indicate that ICT had a higher sensitivity (100%) than the ParaSight-F test (93.94%) but showing a lower specificity. The specificity for ICT (75%) is lower than the ParaSight-F test (81.2%) because of the presence of circulating P. falciparum histidine-rich protein-2 (PfHRP-2) in blood even after two weeks post treatment. Two slides that were negative for ParaSight-F tests showed positive on microscopy. However, 21 and 12 slides which were negative on microscopy, showed positive with ICT and ParaSight-F respectively. The fact that ICT detects very low quantities of PfHRP-2 puts it at a comparative advantage because it detects positives even at very low parasite rates. CONCLUSION: The availability of these two antigen capture tests, which are easy to perform, will reduce the number of severe cases by providing early diagnosis. The tests will also reduce the number of unnecessary treatments and irrational use of antimalarials.

Animals↗
PubMed2003

Commonly recognised Plasmodium falciparum parasites cause cerebral malaria.

Cerebral malaria (CM) is a devastating form of Plasmodium falciparum malaria, in which adherence and sequestration of infected red blood cells in cerebral blood vessels play a major role. In order to determine whether a distinct parasite phenotype favours the development of this severe complication, P. falciparum isolates from Gabonese children suffering from CM or uncomplicated malaria (UM) were analysed for their binding phenotypes and their recognition in flow cytometry. CM isolates exhibited the ability to form rosettes and to bind ICAM-1, in line with previous studies correlating these phenotypes with CM disease pathology. CM isolates were more reactive with plasma from our cohort than UM parasites. This observation, together with the finding that some CM isolates were highly correlated with each other in their immunoreactivities, confirms that common parasites bearing conserved epitopes, which are capable of inducing cross-reactive antibodies, can cause CM in children.

Animals↗
PubMed2006

Linkage disequilibrium between two distinct loci in chromosomes 5 and 7 of Plasmodium falciparum and in vivo chloroquine resistance in Southwest Nigeria.

Chloroquine (CQ) resistance in Plasmodium falciparum is associated with polymorphisms in loci on pfcrt and pfmdr1 genes. In this study, we determined the association and linkage disequilibrium between in vivo CQ resistance and P. falciparum polymorphisms in pfcrt gene at codon 76 and pfmdr1 gene at codon 86 in isolates obtained from 111 children with acute uncomplicated falciparum malaria in Nigeria. Patients were treated with standard dosage of CQ and followed up for 28 days. Filter paper samples were collected at enrollment and during follow-up for parasites genotypes and identification of pfcrt and pfmdr1 mutations. Association and linkage disequilibrium between mutant pfcrtT76 and pfmdr1Y86 alleles in pretreatment isolates of P. falciparum was determined. Fifty-five out of the 111 patients (49.5%) failed treatment. Single mutant pfcrtT76 or pfmdr1Y86 alleles were found in 55 out of 111 P. falciparum isolates screened at enrollment. Of these 55 isolates, the mutant pfcrtT76 and pfmdr1Y86 alleles were found in 84%. Both mutant pfcrtT76 (p=0.0196) and pfmdr1Y86 (p=0.000042) alleles were associated with in vivo CQ resistance. In addition, the mutant pfcrtT76 (p=0.047) and pfmdr1Y86 (p=0.006) alleles were significantly selected by CQ in patients who failed treatment. Association analysis between paired single alleles at pfcrt and pfmdr1 loci showed a significant association (p=0.0349 and chi(2)=4.45) between the pfcrt T76 allele on chromosome 7 and the pfmdr1Y86 allele on chromosome 5 and that these two mutant alleles were in linkage disequilibrium (p=0.000, D'=0.64, and r(2)=0.28). Considering the high level of CQ resistance and drug use in the study area, the observed linkage disequilibrium between the mutant pfcrtT76 and pfmdr1Y86 alleles is maintained epistatically through directional CQ selective pressure.

Animals↗
PubMed2005

Fragmented population structure of plasmodium falciparum in a region of declining endemicity.

BACKGROUND: The population genetic structure of Plasmodium falciparum differs between endemic regions, but the characteristics of a population recently fragmented by effective malaria control have been unknown. METHODS: Genotypic analysis of 10 microsatellite loci widely separated in the parasite genome was conducted on 288 P. falciparum isolates from 8 foci in Malaysian Borneo, a region in which malaria incidence has been progressively reduced. RESULTS: Within all P. falciparum foci, moderate levels of allelic diversity were found, but levels of multilocus linkage disequilibrium were extremely variable. The population with the highest proportion of mixed-clone infections also had the highest allelic diversity and nonsignificant linkage disequilibrium. In contrast, several populations showed evidence of clonal expansion, and one offshore island population had exceptionally high levels of linkage disequilibrium. Genetic differentiation between many populations was very high and strongly associated with the geographical distance between them. CONCLUSIONS: High levels of differentiation and contrasting population structure among P. falciparum populations in Malaysian Borneo indicate that they are genetically independent. This supports the feasibility of individually eradicating the remaining P. falciparum foci.

Animals↗
PubMed2006

Analysis of human antibodies to erythrocyte binding antigen 175 peptide 4 of Plasmodium falciparum.

BACKGROUND: The IgG1 and IgG3 antibodies are considered cytophilic and protective against Plasmodium falciparum, whereas IgG2 and IgG4 are thought to block protective mechanisms. OBJECTIVES: The main objective was to measure antibodies directed against erythrocyte binding antigen-175 (EBA-175) peptide 4 and analyze the relationship between such antibodies and clinical malaria attack. METHODS: Using an enzyme-linked immunosorbent assay, a retrospective analysis of naturally acquired antibodies to synthetic peptide from EBA-175 peptide 4 has been carried out in 158 school children from the village of Dienga in Gabon. RESULTS: The overall prevalence rates of antibodies to EBA-175 peptide 4 were 85.2%, 66.8%, 52.6%, 71.6% and 64.0% for total IgG, IgG1, IgG2, IgG3 and IgG4, respectively. Protection from clinical malaria, determined after a prospective 1-year study, was associated with the levels of IgG and IgG1 antibodies that increased with age. CONCLUSION: Together, these data suggest that age/exposure-related acquisition of anti-EBA-175 antibodies may contribute to the development of clinically protective immunity and could be taken into account in malaria control strategies when they are confirmed.

Adolescent↗
PubMed1998

The in vivo sensitivity of Plasmodium falciparum to chloroquine in the Red River basin, Yunnan, China.

The sensitivity of Plasmodium falciparum to chloroquine in vivo was examined out in a small town in the Red River basin from 1995 to 1996. forty cases were recruited into the present study, 32 cases were completely followed-up. The results of the in vivo study revealed that only 3 (9%) cases were sensitive to chloroquine, 29 (90.6%) showed resistance to chloroquine, among whom 7 cases (22%) showed resistance at RI, 12 cases (38%) at RII, and 10 cases (31%) at RIII. It is suggested that P. falciparum endemic areas should stop using chloroquine and other 4-aminoquinolines in the Red River basin now. Qinhaosu and pyronaridine were recommended to use as the first line antimalarial drugs of P. falciparum infection in the basin.

Adult↗
PubMed1999

Blood-stage dynamics and clinical implications of mixed Plasmodium vivax-Plasmodium falciparum infections.

We present a mathematical model of the blood-stage dynamics of mixed Plasmodium vivax-Plasmodium falciparum malaria infections in humans. The model reproduces features of such infections found in nature and suggests several phenomena that may merit clinical attention, including the potential recrudescence of a long-standing, low-level P. falciparum infection following a P. vivax infection or relapse and the capacity of an existing P. vivax infection to reduce the peak parasitemia of a P. falciparum superinfection. We simulate the administration of antimalarial drugs, and illustrate some potential complications in treating mixed-species malaria infections. Notably, our model indicates that when a mixed-species infection is misdiagnosed as a single-species P. vivax infection, treatment for P. vivax can lead to a surge in P. falciparum parasitemia.

Animals↗
PubMed2001

Plasmodium falciparum signal sequences: simply sequences or special signals?

The malaria parasite, Plasmodium falciparum, synthesises and exports several proteins inducing morphological and biochemical modifications of erythrocytes during the erythrocytic cycle. The protein trafficking machinery of the parasite is similar to that of other eukaryotic cells in several ways. However, some unusual features are also observed. The secretion of various polypeptides was inhibited when P. falciparum-infected erythrocytes were incubated with Brefeldin A. Immunoelectron microscopy studies revealed substantial morphological changes in the endoplasmic reticulum following exposure of parasitised erythrocytes to the drug. Immunofluorescence studies of Brefeldin A-treated parasites suggest that polypeptide sorting to different intracellular destinations begins at the endoplasmic reticulum. The parasite also secretes polypeptides by a Brefeldin A-insensitive route that bypasses the classical endoplasmic reticulum-Golgi complex pathway.

Animals↗
PubMedDate not supplied

Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data.

Plasmodium falciparum malaria is one of mankind's main killers. Part of the parasite's life-cycle is spent in human blood, mainly as asexual stages. A fraction of the asexual parasites develops into gametocytes (gamete precursors) while sequestered in deep tissues. After re-entering the circulation, gametocytes can be picked up by a mosquito to continue the parasite's life-cycle. We present estimates of the conversion probability from asexual parasites to circulating gametocytes and of the gametocytes' sequestration and circulation times, obtained for the first time by fitting a dynamic model to individual patients' histories (daily records of 113 neurosyphilitic patients undergoing malariatherapy). The model assumes that the conversion probability can vary among the successive waves of asexual parasitaemia of a patient, and that gametocytes die at an age-dependent rate which increases under high asexual parasite densities. On average, 1 gametocyte per 156 asexual parasites (range 7.4-3700) is produced. The most remarkable findings are the large individual variation of conversion probabilities and circulation times, the average gametocyte circulation time of 6.4 days (range 1.3-22.2 days) which is more than twice the currently accepted value, and the large variation of conversion probabilities among successive waves of asexual parasitaemia without any particular time pattern. The latter finding could be explained by an association between conversion probability and variation of PfEMP1.

Animals↗
PubMedDate not supplied

ParaSight-F test for the detection of treatment failure in multidrug resistant Plasmodium falciparum malaria.

The ParaSight-F test for the detection of Plasmodium falciparum was evaluated for its accuracy and usefulness in predicting treatment outcome in 75 patients (70 males, 5 females) with acute uncomplicated malaria who attended a malaria clinic in Mae Sot, Tak province, on the Thai-Myanmar border. All patients were admitted to the clinic for 28 d to exclude reinfection. The test was performed using blood samples collected into ethylenediaminetetraacetic acid from the patients on admission, and on days 1, 2, 7, and 14. The presence of microscopically detectable parasitaemia was used as the reference for sensitivity and specificity of the test. The reappearance of parasites on day 28 was used to determine the accuracy of predicting the outcome of artemether treatment on day 14. The sensitivity of the ParaSight-F test on admission, and on days 1, 2, 7, and 14, was 98.7%, 96.7%, 100%, 100% and 100%, respectively, with corresponding specificities of 50%, 24.2%, 47.1% and 72.9%. The sensitivity for predicting recrudescence by using the test on day 14 was 100%, with 97.7% specificity, and the sensitivity of predicting a sensitive response on day 14 was 97.7%, with 100% specificity. The test seems to permit more precise detection of treatment failure under 'field' conditions if used on day 14 after the start of treatment.

Animals↗
PubMed2003

Clearance of drug-resistant parasites as a model for protective immunity in Plasmodium falciparum malaria.

Residents of malaria-endemic areas sometimes spontaneously clear Plasmodium falciparum infection without drug treatment, implying an important role for host factors such as immunity in this clearance. Host factors may also contribute to clearance of parasites resistant to a treatment drug. Chloroquine resistance is caused by point mutations in P. falciparum chloroquine resistance transporter (pfcrt) gene. We investigated the clearance of malaria parasites carrying the key chloroquine resistance-conferring PfCRT mutation K76T in patients treated with chloroquine. We found that the ability to clear these resistant parasites is strongly dependent on age (the best surrogate for protective immunity in endemic areas), suggesting that host immunity plays a critical role in the clearance of resistant P. falciparum infections. Age-adjusted comparison of subjects able to clear resistant parasites and those unable to do so provides a new phenotype for identifying host immune and genetic factors responsible for protective immunity against malaria.

Adolescent↗
PubMed1997

Large scale culture technique for pure Plasmodium falciparum gametocytes.

A large scale technique for pure gametocyte cultures of Plasmodium falciparum was established in culture flasks by using treated erythrocytes and RPMI medium supplemented with 15% human plasma instead of serum. Pure gametocyte cultures were successfully obtained following treatment with 5% sorbitol on day 8 and 9 of cultivation. This method resulted in approximately 97% reduction of asexual parasites and provided pure gametocytes in culture. The highest numbers of gametocytes were obtained from cultures starting with 2% parasitemia and 2% erythrocyte suspension. On day 12 of cultivation, approximately 35 x 10(6) gametocytes per 100 ml of cell suspension could be harvested.

Animals↗
PubMed1994

[Molecular recognition between GlcNAc and Plasmodium falciparum merozoites].

In this study p-aminophenyl-2-acetamido-2-deoxy-beta-D-glucopyranoside was bound covalently to bovine serum albumin (BSA) to form neoglycoprotein (GlcNAc-BSA). The antigenicity of BSA and the pyranose structure of the sugar was preserved. By using the neoglycoprotein antibody against BSA and staphylococcal protein A-gold (SPA-gold), Plasmodium falciparum FCC-1/HN merozoites were immunolabeled. The labelled sample was observed under transmission electron microscope (TEM). The TEM pictures showed that colloidal gold pellets were distributed all over the merozoite surface. This is the first report on the direct experimental evidence of molecular recognition between GlcNAc-BSA (or GlcNAc) and Plasmodium falciparum merozoites. But free GlcNAc or even GlcN can inhibit the immunolabeleation. The results support the hypothesis that, besides N-acetylneuraminic acid, GlcNAc is involved as another recognized site on GPA for Plasmodium falciparum. Thus we further confirmed that N-acetyl of GlcNAc is not necessary for the recognition.

Acetylglucosamine↗
PubMed2003

Prevalence of the K76T mutation in the pfcrt gene of Plasmodium falciparum among chloroquine responders in India.

Chloroquine-resistant Plasmodium falciparum needs to be monitored in the field for effective malaria control strategies. A point mutation K76T in the P. falciparum chloroquine resistance transporter (Pfcrt) protein has recently been proposed as a molecular marker for the faster detection of chloroquine-resistant falciparum malaria in field. We describe here the evaluation of this marker in Indian P. falciparum isolates. A total of 274 Indian P. falciparum isolates were analyzed for the K76T mutation. This mutation was detected in all the clinical isolates obtained from the in vivo chloroquine non-responders. But majority of the clinical isolates from chloroquine responders (71 of 74 patients, i.e. 96%) also harbored this mutation. The K76T mutation was indeed highly prevalent (91%) among 213 clinical isolates. There was a significant association between K76T mutation and the in vitro chloroquine response (P<0.05) but six isolates showed discordant results. In conclusion, the K76T mutation fails to differentiate majority of the chloroquine responders from that of the non-responders and thus will be of limited use in the field in India.

Adolescent↗