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PubMed1999

A longitudinal study of human antibody responses to Plasmodium falciparum rhoptry-associated protein 1 in a region of seasonal and unstable malaria transmission.

Rhoptry-associated protein 1 (RAP1) of Plasmodium falciparum is a nonpolymorphic merozoite antigen that is considered a potential candidate for a malaria vaccine against asexual blood stages. In this longitudinal study, recombinant RAP1 (rRAP1) proteins with antigenicity similar to that of P. falciparum-derived RAP1 were used to analyze antibody responses to RAP1 over a period of 4 years (1991 to 1995) of 53 individuals naturally exposed to P. falciparum malaria. In any 1 year during the study, between 23 and 39% of individuals who had malaria developed immunoglobulin G (IgG) antibodies detectable with at least one rRAP1 protein. However, the anti-RAP1 antibody responses were detected only during or shortly after clinical malarial infections. RAP1 antibody levels declined rapidly (within 1 to 2 months) following drug treatment of the infections. No anti-RAP1 antibodies were usually detected a few months after the end of malaria transmission, during the dry season, or by the start of the next malaria season. Thus, RAP1 IgG responses were very short-lived. The short duration of RAP1 antibody response may explain the apparent lack of response in a surprisingly high proportion of individuals after clinical malarial infections. For some individuals who experienced more than one malarial infection, a higher anti-RAP1 antibody response to subsequent infections than to earlier infections was observed. This suggested secondary responses to RAP1 and thus the development of immunological memory for RAP1.

Adult↗
PubMed1999

Point mutations in dihydrofolate reductase and dihydropteroate synthase genes of Plasmodium falciparum isolates from Venezuela.

The present study was designed to characterize mutations in dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) genes of Plasmodium falciparum in the Bolivar region of Venezuela, where high levels of clinical resistance to sulfadoxine-pyrimethamine (SP, Fansidar; F. Hoffman-La Roche, Basel, Switzerland) has been documented. We used a nested mutation-specific polymerase chain reaction and restriction digestion methods to measure 1) the prevalence of DHFR mutations at 16, 50, 51, 59, 108, and 164 codon positions, and 2) the prevalence of mutations in the 436, 437, 581, and 613 codon sites in DHPS gene. In the case of the DHFR gene, of the 54 parasite isolates analyzed, we detected the presence of Asn-108 and Ile-51 in 96% of the isolates and Arg-50 mutation in 64% of the isolates. Each of these mutations has been associated with high level of resistance to pyrimethamine. Only 2 samples (4%) showed the wild type Ser-108 mutation and none showed Thr-108 and Val-16 mutations that are specific for resistance to cycloguanil. In the case of DHPS gene, we found a mutation at position 437 (Gly) in 100% of the isolates and Gly-581 in 96% of the isolates. The simultaneous presence of mutations Asn-108 and Ile-51 in the DHFR gene and Gly-437 and Gly-581 in the DHPS gene in 96% of the samples tested suggested that a cumulative effect of mutations could be the major mechanism conferring high SP resistance in this area.

Animals↗
PubMed1992

Sporozoite transmission by Anopheles freeborni and Anopheles gambiae experimentally infected with Plasmodium falciparum.

A micro-membrane feeding technique was used to evaluate sporozoite transmission for Anopheles freeborni and An. gambiae experimentally infected with Plasmodium falciparum. From cohorts of infected mosquitoes with equivalent sporozoite loads, 75.9% of 29 An. freeborni transmitted a geometric mean (GM) of 4.9 sporozoites and 80% of 30 An. gambiae transmitted a GM of 11.3 sporozoites. Ingested sporozoites, in the blood meal immediately after feeding, were detected in 86.2% of 29 An. freeborni (GM = 9.0) and in 70% of 30 An. gambiae (GM = 44.1). Overall, sporozoites were transmitted and/or ingested by 90% of both species. Most infective mosquitoes transmitted < 1% of the total sporozoites in the salivary glands, and only up to 30% of the variation in transmission, ingestion, or total sporozoite output was related to sporozoite loads. The demonstration that An. gambiae transmitted more than twice as many sporozoites as An. freeborni is the first indication that vector species of anopheline mosquitoes differ in their innate potential for sporozoite transmission.

Animals↗
PubMed1993

Erythrocyte rosetting in Plasmodium falciparum malaria--with special reference to the pathogenesis of cerebral malaria.

Spontaneous rosette formation of uninfected erythrocytes around an erythrocyte infected with Plasmodium falciparum is a recently described in vitro phenomenon which is also present in infections with some other malarial species where sequestration of parasite infected erythrocytes is a characteristic. In the present studies, rosetting was established as a P. falciparum virulence factor, the expression of which is modified by a variety of host factors, such as host immunity, ABO blood group and haemoglobin phenotype. The molecules involved in rosetting seem to be distinct from those involved in endothelial cytoadherence, although they are often co-expressed on the same parasitised red cell. Rosette formation was shown not only to be a phenomenon of laboratory-propagated strains, but also to exist in wild clinical isolates from all major malarious areas of the world. In two studies performed in The Gambia, comprising 211 children with uncomplicated or cerebral malaria, a strong association was found between in vitro rosette formation and cerebral malaria, indicating that rosetting plays a role in the pathogenesis of severe P. falciparum disease. Anti-rosetting activity, presumably mediated by antibodies, was found in sera from patients in malaria-endemic areas, and it was demonstrated that such activity was more abundant in individuals with uncomplicated malaria than in those with cerebral disease, suggesting that humoral immunity protects against rosette formation in vivo. It was also demonstrated, by the use of several independent assays, that erythrocytes from individuals with sickle-cell trait, alpha- and beta-thalassaemia trait or with HbE, formed smaller and weaker rosettes than did normal (HbAA) red cells. The results also suggest that microcytosis per se is correlated to impaired rosette formation. Differences in rosetting ability were also seen between red cells of different ABO blood groups, with a diminished rosetting potential in blood group O red cells. Impaired rosette formation may thus contribute to the innate resistance to severe P. falciparum malaria that is known to exist in certain red cell disorders and in individuals of blood group O. Rosette formation was found to be governed by strong adhesive forces, with lectin-like bindings between parasite-derived proteins exposed on the P. falciparum-infected red cell surface, rosettins, and various carbohydrate moieties present on the uninfected erythrocyte. The strongest carbohydrate receptors seem to be contained within the blood group A or B antigens, and the rosettes were abolished by oligosaccharides mimicking these antigens. The binding between infected and uninfected erythrocytes was dependent on divalent cations and was sometimes sensitive to pH.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

A Plasmodium falciparum isolate with a chromosome 9 deletion expresses a trypsin-resistant cytoadherence molecule.

Sequestration of Plasmodium falciparum infected erythrocytes in the cerebral circulation is strongly implicated in the pathogenesis of cerebral malaria. From previous studies it was postulated that genes essential for cytoadherence were located on the right arm of chromosome 9 as P. falciparum isolates with a deletion in this region lost the capacity to cytoadhere in vitro and no longer expressed Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) on the surface of the infected cells. We have selected a P. falciparum isolate from Papua New Guinea for high levels of cytoadherence to human umbilical vein endothelial cells (HUVECs) and have shown that the cloned parasite has several novel properties related to cytoadherence. The cloned parasite adheres to HUVECs, does not bind to melanoma cells, and expresses a surface molecule with most of the properties of PfEMP-1, despite a deletion in the right arm of chromosome 9. Interestingly, the surface expressed PfEMP-1 in this strain is resistant to trypsin treatment and infected cells continue to cytoadhere after trypsin digestion at a concentration of 100 micrograms ml-1. The receptor on HUVECs for the cloned parasite lines is a molecule different from any previously described, as parasitized cells do not adhere to soluble intercellular adhesion molecule 1, thrombospondin, vascular cell adhesion molecule 1, E-selectin or P-selectin, nor to CD36. Our work, taken together with the results from previous studies, suggest that the ability of parasites to cytoadhere is encoded in at least two distinct genomic locations in the parasite, and the diversity of receptor-ligand interaction is greater than previously described.

Animals↗
PubMed2000

Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro.

Gametocytocidal activities of pyronaridine and DNA topoisomerase II inhibitors against two isolates of multidrug-resistant Plasmodium falciparum, KT1 and KT3 were determined. After sorbitol treatment, pure gametocyte cultures of Plasmodium falciparum containing mostly young gametocytes (stage II and III) obtained on day 11 were exposed to the drugs for 48 h. The effect of the drugs on gametocyte development was assessed by counting gametocytes on day 15 of culture. Pyronaridine was the most effective gametocytocidal drug against P. falciparum isolates KT1 and KT3 with 50% inhibitory concentration of 6 and 20 nM, respectively. Moreover, the 50% inhibitory concentration of pyronaridine was lower than that of primaquine which is the only drug used to treat malaria patients harboring gametocytes. Prokaryotic (norfloxacin) and eukaryotic (amsacrine and etoposide) DNA topoisomerase II inhibitors were only effective against asexual but not sexual stages of the malaria parasites. Pyronaridine has both schizontocidal and gametocytocidal activities against the human malaria parasite, P. falciparum.

Amsacrine↗
PubMed2000

Plasmodium vivax polymorphs and Plasmodium falciparum circumsporozoite proteins in Anopheles (Diptera: Culicidae) from Belize, Central America.

Eight species of Anopheles mosquitoes from indoor/outdoor human landing collections in Belize, Central America, were examined for human Plasmodium circumsporozoite protein (CSP) using an enzyme-linked immunosorbent assay (ELISA). A total of 14 of 9,104 females tested were positive from general surveys throughout Belize and three of 11,966 were positive from a longitudinal study in Caledonia, northern Belize. ELISA results, using pooled head-thorax preparations and species-specific monoclonal antibodies directed against the circumsporozoite proteins of Plasmodium falciparum and two Plasmodium vivax polymorphs (210 and VK247), found four species reactive: Anopheles vestitipennis (3 pools), Anopheles darlingi (2 pools), Anopheles albimanus (10 pools), and Anopheles gabaldoni (2 pools). The minimum field infection rates (MFIR) for combined Plasmodium species from the general survey were 0.282% for An. vestitipennis, 0.271% for An. darlingi, 0.126% for An. albimanus, and 0.395% for An. gabaldoni. MFIRs for combined Plasmodium species from the longitudinal study in the village of Caledonia were 0.018% for both An. vestitipennis and An. albimanus and 1.66% for An. gabaldoni. Positive CSP pools were collected from the Cayo, Corozal, Orange Walk, Stann Creek, and Toledo political districts. No CSP positive pools were detected from collections in the Belize District. The study provides valuable information on the spatial distribution and species type of Plasmodium positive mosquitoes. This information, in combination with other vector data, suggest that An. vestitipennis and An. darlingi are commonly involved in malaria transmission. Additionally, these species appear to be much more efficient vectors than An. albimanus in Belize.

Animals↗
PubMed1986

The efficacy of artemether (qinghaosu) in Plasmodium falciparum and P. vivax in Burma.

Seven sulfadoxine-pyrimethamine resistant Plasmodium falciparum infected patients and 2 patients with mixed (P. falciparum and P. vivax) infection were given Artemether. The results showed that Artemether is effective in sulfadoxine-pyrimethamine resistant malaria. The mean fever clearance time and parasite clearance time of patients treated with Artemether is shorter than those treated with chloroquine, quinine or sulfadoxine/pyrimethamine. In one patient with mixed infection all parasites disappeared but P. vivax reappeared on day 11 and on day 14 after two consecutive courses. In another P. vivax reappeared on day 21.

Antimalarials↗
PubMed2000

Plasmodium falciparum infection in the pregnant patient.

Malaria should be considered a risk factor in women who are pregnant, principally when the infection is Plasmodium falciparum. Moreover, the risk is greater if the woman is pregnant for the first time; if she has no immunity for malaria; if the diagnosis is made late; or if P. falciparum shows resistance to antimalarial drugs. This article presents the most significant aspects of P. falciparum malaria during pregnancy, including information about treatments and prophylaxis.

Animals↗
PubMed1992

Relationship between body size of adult Anopheles gambiae s.l. and infection with the malaria parasite Plasmodium falciparum.

The influence of adult female body size of Anopheles gambiae s.l. on development of midgut and salivary gland infections by the parasite Plasmodium falciparum was investigated in a field study carried out in Tanzania. The proportion of mosquitoes infected during a blood meal was independent of size. However, the number of oocysts harboured by infected mosquitoes increased with size of the mosquito. The proportion of mosquitoes with sporozoites, and thus potentially infective to humans, was highest in intermediate-sized mosquitoes, whereas the largest and smallest mosquitoes were less likely to have sporozoites. This pattern is interpreted as a combination of high survival rate of large, uninfected mosquitoes and of low survival rate of mosquitoes infected with many oocysts.

Animals↗
PubMed1998

The early sporogonic cycle of Plasmodium falciparum in laboratory-infected Anopheles gambiae: an estimation of parasite efficacy.

This study investigated the successive losses in the parasite densities of Plasmodium falciparum stages during the early sporogony in laboratory-reared Anopheles gambiae infected by membrane feeding with blood from naturally infected gametocyte carriers (>50 gametocytes/mm3). The developmental stages of P. falciparum in the mosquito were studied from zygote to oocyst, by immunofluorescent method using monoclonal antibodies against the Pfs25 protein present on the surface of newly formed gametes. This method allows for assessment of the various sporogonic stages before, during and after passage of the midgut wall. Parasite densities were determined within the entire blood meal at 3 h (zygotes and macrogametes) and 24 h (ookinetes) post-infection. At 48 h after the mosquito blood meal, midguts were checked for the presence of early oocysts. For the mid-size oocysts count, classic microscopy examination was used at day 7 postinfection. The parasite efficacy was estimated by following successive losses in parasite densities between different early stages of the sporogonic cycle in A. gambiae. Thirty-seven experimental infections were realized with high gametocyte densities, ranging from 64 to 2392 gametocytes/mm3. All gametocyte carriers showed infection with round forms 100%; ookinetes were found in 91.9%. The prevalences of infections with oocysts were 48.6% at day 2 (young oocyst) and 37.8% at day 7 (mid-size oocyst). The mean densities per mosquito for each parasite stage were 12.6 round forms, 5.5 ookinetes, 1.8 young oocyst and 2 mid-size oocysts. Significant correlations were found between two consecutive parasite stages (round forms/ookinetes, ookinetes/young oocysts, young oocysts/mid-size oocysts) and between round forms and mid-size oocysts. The mean parasite density significantly decreased between round forms and ookinetes (yield Y1 = 41.6%) and between ookinetes and young oocysts (Y2 = 61.4%). By contrast, no significant decrease was observed between young oocysts and mid-size oocysts (Y3 = 91.2%). The overall yield of the early sporogonic cycle (from round form to oocyst at day 7) was equal to 25.7%, indicating that almost 3/4 of the total parasites were lost during the early step of the sporogonic cycle, from 3 h post-infection to day 7.

Animals↗
PubMed2005

In vivo selection of Plasmodium falciparum pfmdr1 86N coding alleles by artemether-lumefantrine (Coartem).

Artemisinin derivative-based combination therapy is expected to suppress the development of Plasmodium falciparum drug resistance in Africa. We have performed an artemether-lumefantrine (Coartem; Novartis) follow-up clinical trial in Zanzibar, in which pfcrt K76T and pfmdr1 N86Y frequencies were determined before drug administration and in all recurrent parasites during a follow-up period of 42 days. A significant increase in pfmdr1 86N was observed after exposure to the drug. This points to 86N as a potential marker of lumefantrine resistance in vivo, while suggesting that Coartem is not robust enough to avoid selection of resistance-associated mutations in some malarial settings.

ATP-Binding Cassette Transporters↗
PubMed1998

Kenyan Plasmodium falciparum field isolates: correlation between pyrimethamine and chlorcycloguanil activity in vitro and point mutations in the dihydrofolate reductase domain.

Sixty-nine Kenyan Plasmodium falciparum field isolates were tested in vitro against pyrimethamine (PM), chlorcycloguanil (CCG), sulfadoxine (SD), and dapsone (DDS), and their dihydrofolate reductase (DHFR) genotypes were determined. The in vitro data show that CCG is more potent than PM and that DDS is more potent than SD. DHFR genotype is correlated with PM and CCG drug response. Isolates can be classified into three distinct groups based on their 50% inhibitory concentrations (IC50s) for PM and CCG (P < 0.01) and their DHFR genotypes. The first group consists of wild-type isolates with mean PM and CCG IC50s of 3.71 +/- 6.94 and 0.24 +/- 0.21 nM, respectively. The second group includes parasites which all have mutations at codon 108 alone or also at codons 51 or 59 and represents one homogeneous group for which 25- and 6-fold increases in PM and CCG IC50s, respectively, are observed. Parasites with mutations at codons 108, 51, and 59 (triple mutants) form a third distinct group for which nine- and eightfold increases in IC50s, respectively, of PM and CCG compared to the second group are observed. Surprisingly, there is a significant decrease (P < 0.01) of SD and DDS susceptibility in these triple mutants. Our data show that more than 92% of Kenyan field isolates have undergone at least one point mutation associated with a decrease in PM activity. These findings are of great concern because they may indicate imminent PM-SD failure, and there is no affordable antimalarial drug to replace PM-SD (Fansidar).

Animals↗
PubMedDate not supplied

Standardization of procedures of Plasmodium falciparum antigen preparation for serologic tests.

The objective of the present study is to standardize the technical variables for preparation and storage of Plasmodium falciparum and of antigen components extracted with the amphoteric detergent Zwittergent. P. falciparum obtained from in vitro culture was stored at different temperatures and for different periods of time. For each variable, antigen components of the parasite were extracted in the presence or absence of protease inhibitors and submitted or not to later dialysis. Products were stored for 15, 30 and 60 days at different temperatures and immunological activity of each extract was determined by SDS-PAGE and ELISA using positive or negative standard sera for the presence of IgG directed to blood stage antigens of P. falciparum. Antigen extracts obtained from parasites stored at -20 degrees C up to 10 days or at -70 degrees C for 2 months presented the best results, showing well-defined bands on SDS-PAGE and Western blots and presenting absorbance values in ELISA that permitted safe differentiation between positive and negative sera.

Animals↗
PubMed1992

[Stability and chemosensitivity of Plasmodium falciparum to chloroquine in 1990 and 1991 in Ankazobe, a village in high plateau Madagascar].

The in vivo and in vitro response of Plasmodium falciparum to chloroquine was conducted in Ankazobe, a village located in the high plateau area. These studies confirmed the low level of chloroquine-resistance. The in vivo data indicate the absence of increase resistance during the 2 years study. Chloroquine is still the drug of choice for the treatment of malaria attack in this area.

Animals↗
PubMed1994

Chloroquine resistant Plasmodium falciparum in coastal Tanzania. A challenge to the continued strategy of village based chemotherapy for malaria control.

An in vivo study to assess Plasmodium falciparum sensitivity to chloroquine was conducted in two villages of the Bagamoyo District, Tanzania in December 1992. The WHO standard field test (7 days) and the extended test (28 days) were carried out on symptom free children. The presence of chloroquine resistance was confirmed with 59% of infections being found resistant. Fifty-three percent were RI, 2% were at RII and 4% at RIII levels of resistance. Dosage was 25 mg/kg chloroquine base delivered over three days.

Animals↗
PubMed1998

[Cloning and sequencing of the gene coding the sexual stage antigen Pfs48/45 of Plasmodium falciparum].

AIM: To express the antigen Pfs48/45 in vitro and provide an antigen for the development of the transmission-blocking vaccine. METHODS: According to the published nucleotide sequence of Pfs48/45 of Plasmodium falciparum isolate NF54, a pair of oligonucleotides was designed and used as primers(P1, P2). The gene encoding the gametocyte/gamete-specific membrane protein Pfs48/45 of P. falciparum isolate FCC1/HN has been amplified by using polymerase chain reaction (PCR) technique. The PCR product was purified and directly sequenced by the dideoxynucleotide terminator method with 5'-end primer P1. At the same time, the purified PCR product was digested with BamHI and EcoRI and cloned into the plasmid pcDNA3, then the recombinant clones were transformed into E. coli strain TG1. The recombinant plasmid pcDNA3-Pfs48/45 was screened and identified by PCR amplification and restriction analysis. RESULTS: 1. The gene fragment Pfs48/45 was specifically amplified from the genomic DNA of Plasmodium falciparum isolate FCC1/HN; 2. The sequence demonstrated that the that the 5'-end nucleotide and predicted aminoacid sequence of Pfs48/45 from FCC1/HN isolate was basically identical with that from NF54 isolate. We found that the sequence of the Pfs48/45 gene from the isolate FCC1/HN differs from the published sequence(isolate NF54) only at positions 307 and 372(T-->C). The substitution of T-->C at the position of 372 generates a new restriction site Taq I. The PCR product digested by Taq I generates DNA fragment of 984 bp and 379 bp, suggesting that the PCR product is the gene encoding the transmission blocking antigen Pfs48/45; 3. The gene fragment of Pfs48/45 was directly inserted into the BamHI and EcoRI site of plasmid pcDNA3. CONCLUSION: The nucleotide sequence of Pfs48/45 of Plasmodium falciparum isolate FCC1/HN from south China was similar to that of isolate NF54. The recombinant plasmid pcDNA3-Pfs48/45 was successfully constructed, providing a means to evaluate the role and biological function of this sexual-stage-specific protein of Pfs48/45.

Amino Acid Sequence↗
PubMedDate not supplied

Cryptic Plasmodium falciparum parasites in clinical P. vivax blood samples from Thailand.

Polymerase chain reaction detection revealed cryptic Plasmodium falciparum infections in 21 of 160 samples collected from Thai patients diagnosed (by microscopy) with vivax malaria. The clinical and biological significance of these mixed infections is discussed in the context of chloroquine resistance and the low inoculation rates which characterize malaria epidemiology in Thailand.

Animals↗