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PubMed2006

Transmission-reducing immunity is inversely related to age in Plasmodium falciparum gametocyte carriers.

Immunity to the sexual stages of Plasmodium falciparum is induced during natural infections and can significantly reduce the transmission of parasites to mosquitoes (transmission reducing activity; TRA) but little is known about how these responses develop with increasing age/exposure to malaria. Routinely TRA is measured in the standard membrane feeding assay (SMFA). Sera were collected from a total of 199 gametocyte carriers (median age 4 years, quartiles 2 and 9 years) near Ifakara, Tanzania; 128 samples were tested in the SMFA and generated TRA data classified as a reduction of > 50% and > 90% of transmission. TRA of > 50% was highest in young children (aged 1-2) with a significant decline with age (chi(2) trend = 5.79, P = 0.016) and in logistic regression was associated with prevalence of antibodies to both Pfs230 and Pfs48/45 (OR 4.03, P = 0.011 and OR 2.43 P = 0.059, respectively). A TRA of > 90% reduction in transmission was not age related but was associated with antibodies to Pfs48/45 (OR 2.36, P = 0.055). Our data confirm that antibodies are an important component of naturally induced TRA. However, whilst a similar but small proportion of individuals at all ages have TRA > 90%, the gradual deterioration of TRA > 50% with age suggests decreased antibody concentration or affinity. This may be due to decreased exposure to gametocytes, probably as a result of increased asexual and/or gametocyte specific immunity.

Adolescent↗
PubMed2002

Efficacy of chloroquine in the treatment of uncomplicated, Plasmodium falciparum malaria in northern Ghana.

Chloroquine (CQ) resistance in Plasmodium falciparum contributes to growing malaria-attributable morbidity and mortality in sub-Saharan Africa. However, the extent and degree of such resistance vary considerably between endemic areas. Data on CQ resistance in northern Ghana are almost entirely lacking. The therapeutic efficacy of CQ in uncomplicated malaria was therefore assessed, in a standard, 14-day protocol, in 225 children aged <5 years in Tamale, in the Northern region of Ghana. Early treatment failure (ETF) was observed in 11% of the children and late treatment failure in 18%. High initial parasite density and young age were independent predictors for ETF. Resistant parasitological responses (RI-RIII) were seen in 57% of the cases that could be classified. More than half of these responses occurred in children fulfilling the criteria for adequate clinical response (ACR), indicating a considerable lack of agreement between parasitological and clinical outcome. During the follow-up period, haemoglobin levels increased by approximately 1g/dl not only in patients with ACR but also in those who experienced clinical failure more than 1 week post-treatment. As CQ-treatment failure occurred in >25% of the children and more than half of the parasitological responses indicated resistance, current recommendations for the treatment of uncomplicated malaria in young children in northern Ghana have to be reconsidered.

Age Factors↗
PubMed1992

Characterization of naturally acquired antibodies to the non-repetitive flanking regions of the circumsporozoite protein of Plasmodium falciparum.

Antibody responses to the circumsporozoite (CS) protein of Plasmodium falciparum have previously been reported against the central repeating tetrapeptides of this protein. Segments of the protein flanking the repeat region also contain B-cell epitopes, but specific antibody responses have not been previously characterized. Longitudinal serum sets from 16 Thai adults who developed acute falciparum malaria were selected to represent a spectrum of antibody response to the repeat region (R32). These sera were assayed by enzyme-linked immunosorbent assay using as capture antigen a recombinant fusion protein, NS1(81)RLF, which contains both flanking regions, but lacks the NANP and NVDP repeats of the P. falciparum CS protein. Antibody responses to the repeatless flanking (RLF) regions were observed in all subjects, including five individuals who lacked detectable anti-R32 antibody responses. Anti-RLF antibody responses induced by natural infection appear to be short-lived and of low-to-moderate magnitude. Thus, if anti-RLF antibodies prove to be protective, derived vaccine candidates may require presentation of these epitopes with adjuvants or delivery systems that enhance immunogenicity.

Adult↗
PubMed1997

Daily dynamics of Plasmodium falciparum subpopulations in asymptomatic children in a holoendemic area.

Plasmodium falciparum is the major cause of malaria morbidity and mortality in the world. Biologic and antigenic diversity is a characteristic of this parasite and infections can consist of several genetically diverse parasites. The daily dynamics of these parasite subpopulations were investigated in asymptomatic children in rural Tanzania. Fingerprick blood samples were collected on 14 consecutive days from 20 children. Parasite densities were detected by light microscopy and genotyping of P. falciparum was done using a nested polymerase chain reaction (PCR) assay targeting polymorphic regions on the merozoite surface protein-1 (MSP-1), MSP-2, and glutamine-rich protein (GLURP) genes. In the eight children harboring P. falciparum throughout the study period, infections were found to be highly complex with daily changes in both parasite density and genotypic pattern. A nonrandom. 48-hr periodicity in these fluctuations suggests that P. falciparum infections consist of inherently synchronous subpopulations of parasites. These findings have important biologic and epidemiologic implications since one blood sample may only partly reflect the whole parasite population in an infected individual.

Adolescent↗
PubMed1993

Molecular characterization of the largest subunit of Plasmodium falciparum RNA polymerase I.

Plasmodium species possess developmentally regulated ribosomal RNA (rRNA) genes. This report describes the expression and gene structure of the largest subunit of P. falciparum RNA polymerase I (RNAPI), which is responsible for the synthesis of rRNA. The RNAPI largest subunit gene was present as a single copy gene on chromosome 9. Three exons encode the 2910-amino acid RNAPI polypeptide (340 140 Da). A comparison of Plasmodium, Trypanosoma, and Saccharomyces cerevisiae nuclear RNAP largest subunits identified conserved amino acid positions and class-specific amino acid positions. Novel amino acid insertions were found between RNAPI conserved regions A and B (region A'), D and DE1 (region D'), DE2 and E (region DE2'), and F and G (region F'). Leucine zipper domains were found within regions D', DE2, and DE2'. A novel serine-rich repeat domain, a domain with homology to the C-terminal domain of eukaryotic upstream binding factor (UBF), and 4 highly conserved casein kinase II (CKII) Ser/Thr phosphorylation motifs were found within a 127-amino acid sub-region of enlarged region F'. The novel RNAPI serine-rich repeat contained a conserved motif, Ser-X3-Ser, which was also identified in the serine-rich repeat domains of the P. falciparum RNAPII and RNAPIII largest subunits, as well as within a highly homologous serine-rich repeat from trophozoite antigen R45. The results of this molecular analysis indicate that phosphorylation and dephosphorylation mechanisms regulate the activity of P. falciparum RNAPI.

Amino Acid Sequence↗
PubMed2006

Plasmodium falciparum malaria and ABO blood group: is there any relationship?

There is increasing evidence that Plasmodium falciparum malaria is influenced by ABO blood group but the extent of association between both is yet to be well defined. Studies that investigated association between P. falciparum malaria and ABO blood group were identified using MEDLINE search and were systematically reviewed. There were apparent discrepancies and contradictions in the studies as some reported significant association between both while others observed no significant association. This outcome may reflect the complex interaction between P. falciparum malaria and the host immune responses. However, findings from all studies reviewed suggested that individuals of blood group O are relatively resistant to severe disease caused by P. falciparum infection. It was established that parasitized erythrocytes form rosettes more readily with red blood cells (RBCs) of A, B, or AB groups than with blood group O and this parasite-triggered RBC rosette formation is associated with the severity of clinical disease and with the development of cerebral malaria. Differences in rosetting ability were based on the P. falciparum strain-specific preference of rosetting with non-O blood groups and not only a phenomenon of laboratory-propagated strains, but also exist in wild clinical isolates from all major malarious areas of the world.

ABO Blood-Group System↗
PubMed1991

Plasmodium falciparum: an invasion inhibitory human monoclonal antibody is directed against a malarial glycolipid antigen.

A Plasmodium falciparum malaria blood stage antigen was detected using a human monoclonal antibody (MAb A52A6) obtained from a clinically immune donor. Immunofluorescence analysis showed that the MAb reacted with the intracellular parasite throughout the asexual blood stage cycle as well as with gametocytes. The MAb also reacted with the surface of erythrocytes containing late stage P. falciparum parasites. The antigen seen by the MAb was species- but not strain- or isolate-specific. At rupture of the infected erythrocytes, antigenic material was deposited on the membrane of uninfected cells surrounding the parasite. At merozoite invasion MAb reactive material was present on the invaginating erythrocyte membrane, indicating an involvement of the antigen in the invasion process. This was also indicated by the high capacity of the MAb to inhibit merozoite invasion in vitro. The antigen appears to be a phosphoglycolipid, sensitive to phospholipase and present in lipid extracts of P. falciparum-infected erythrocytes.

Animals↗
PubMedDate not supplied

Ciprofloxacin does not achieve radical cure of Plasmodium falciparum infection in Sierra Leone.

Recently, activity in vivo of norfloxacin has been reported against Plasmodium falciparum and, in vitro, ciprofloxacin has been found to be even more potent than norfloxacin. We therefore treated one patient infected with chloroquine-resistant P. falciparum at relatively low parasite density with ciprofloxacin, 200 mg intravenously twice daily for 3 d. This treatment failed to produce radical cure, although some suppressive effect was probably obtained. The growth of the P. falciparum isolate in vitro was inhibited at 12.5 micrograms/ml, whereas the plasma concentration recorded 1 h after infusion was only 1.2 microgram/ml. It is concluded that, if ciprofloxacin is to be used for treatment of malaria, a higher dose than that normally used for bacterial infections is necessary.

Animals↗
PubMed2005

Interaction between Plasmodium falciparum and human immunodeficiency virus type 1 on the central nervous system of African children.

Plasmodium falciparum and human immunodeficiency virus type 1 (HIV-1) infections are common in children living in sub-Saharan Africa (SSA). Both of these pathogens affect the central nervous system (CNS). Most HIV-1 infection of children in this region is acquired from infected mothers, particularly during breast-feeding and at the time of delivery. Over a third of children infected by birth will have died before their first birthday, before overt CNS manifestations have developed. The most common manifestations of primary CNS infection include neurodevelopmental delay, impaired brain growth, motor deficits, and behavioral problems. These deficits may also result from infections, neoplasm, or stroke. Cognitive impairments become more evident if the child survives for longer, but in Africa, children rarely survive past their fifth birthday. In malaria endemic areas, severe falciparum malaria usually develops after 6 months of age, and most of the CNS manifestations are more common in children over 1 year old. About 11% of children develop neurological deficits following cerebral malaria, most of which improve within 2 years of the insult. However, up to 24% of children may have neurocognitive impairments following severe malaria. The effect of milder malaria and coincidental parasitization on cognitive function is unknown. Other comorbidities that are common in SSA, such as malnutrition or micronutrient deficiencies, may influence children's neurodevelopment. The coinfection of malaria and HIV-1 may aggravate the neurodevelopmental impairments documented in these children. However, to date there are little published data, although it may have a profound effect of children living in SSA.

Africa↗
PubMed1992

Immunogenicity and efficacy trials in Aotus nancymai monkeys with model compounds representing parts of a 75-kD merozoite surface antigen of Plasmodium falciparum.

We tested the ability of a recombinant DNA-encoded fragment (C7Ag) of a Plasmodium falciparum merozoite protein (p75) and of two carrier-free peptide models (28-mer and 76-mer) to stimulate boostable antibody responses in Aotus nancymai monkeys. In addition, we evaluated protection against challenge with the Uganda Palo Alto (FUP) strain of this parasite. The data indicate that C7Ag elicited a strong and boostable IgG antibody response in all the monkeys immunized. However, studies with the peptide models demonstrated that various animals produce antibodies to different portions of this structure. When the post-boost sera from monkeys immunized with C7Ag were analyzed for reactivity against two major portions of C7Ag, most of the antibody response was observed against the disulfide-bonded 76-residue region that forms a conformational immunogenic epitope. In the same sera, antibody levels against the charged helical region modeled with a 28-mer were generally low. Immunization with synthetic peptides revealed that the 76-mer stimulated an antibody response almost as strong as C7Ag, with substantial cross-reactivity against the parasite antigen. The 28-mer evoked a response that was not efficient or uniform, and showed little reactivity with the authentic parasite antigen. Aotus nancymai was shown to be susceptible to infection with the Uganda Palo Alto strain of P. falciparum; however, maximum parasitemia varied markedly in both immunized and control monkeys. Statistical analysis failed to recognize differences in maximum parasitemia between the vaccine and control groups. The variation in maximum parasitemia suggests that the FUP strain in this species of Aotus is a poor model for the detection of differences in efficacy based on maximum parasitemia. This initial study with structures based on parts of the 75-kD merozoite surface antigen of P. falciparum indicated that both the recombinant-produced protein C7 and the 76-mer synthetic peptide, when combined with a Syntex adjuvant formulation, were safe and immunogenic in A. nancymai monkeys. However, the data emphasize the problems of using animal models to evaluate the potential effects of immunogens in humans.

Adjuvants, Immunologic↗
PubMed1998

Follow-up of the susceptibility of Plasmodium falciparum to antimalarials in Gabon.

The sensitivity of Plasmodium falciparum to chloroquine, mefloquine, quinine, quinidine, halofantrine, artemisinin, and sulfadoxine/pyrimethamine was investigated in Lambarene, Gabon in 1994. The development of in vitro susceptibility has been traced from 1983 or 1992 to 1994 for chloroquine, mefloquine, halofantrine, and quinine. Standard in vitro microtests according to World Health Organization methodology were performed. Of 33 isolates tested for susceptibility to chloroquine, 31 were resistant, one was borderline, and one isolate was sensitive (mean 50% effective concentration [EC50] = 1.38 micromol/L of blood). With mefloquine, all isolates were fully inhibited below the threshold of resistance (mean EC50 = 0.51 micrmol/L of blood). Of 32 isolates tested with quinine, six had borderline resistance (mean EC50 = 0.54 micromol/L of blood medium mixture). Susceptibility to quinidine was higher with a mean EC50 of 0.15 micromol/L of blood medium mixture. With halofantrine, 26 of 32 isolates matured at 3 nmol/L of blood medium mixture (mean EC50 = 1.64 nmol/L of blood medium mixture), indicating a steep decrease in susceptibility in comparison with 1992. For artemisinin, the mean EC50 was 97.92 nmol/L of blood medium mixture. Sulfadoxine/pyrimethamine showed five of 16 resistant isolates with a mean EC50 of 2.46 nmol/L of blood medium mixture. Whereas chloroquine resistance remained stable with a tendency to decrease, susceptibility to mefloquine and quinine was slightly decreased. A significant increase in the mean EC50 and EC90 in comparison with our previous data from Gabon was found for halofantrine.

Animals↗
PubMed1991

Changing response of Plasmodium falciparum to chloroquine in West Bengal during 1980-1988.

A total of 314 cases of Plasmodium falciparum malaria studied during 1980-88 in nine times monitoring revealed three RIII foci i.e. two in Jalpaiguri and one in Purulia districts. The studies showed a parasite clearance of 40 per cent and 32 per cent of P. falciparum cases within seventh day in Purulia and Jalpaiguri districts respectively, with a dosage of 25 mg per kg body weight, spread over three days in divided doses. Increase in transmission potential and prolonged drug pressure with single drug have been noted in association with development of resistance. Malaria parasite clearance time (MPCT) value of sensitive and resistant cases reach parallelism and malaria parasite recrudescence time (MPRT) value starts declining, giving an indication of stabilisation of genetic change in the parasite.

Animals↗
PubMed1997

Precursor frequency analysis of cytotoxic T lymphocytes to pre-erythrocytic antigens of Plasmodium falciparum in West Africa.

Some individuals living in malaria-endemic areas have CTL to Plasmodium falciparum liver stage Ags. We have quantified these CTL responses using limiting dilution analysis studies on the peripheral blood cells of naturally exposed Gambian donors. CTL precursor frequencies were determined to a wide range of epitopes derived from different liver stage Ags (liver stage protein 1, circumsporozoite protein, thrombospondin-related anonymous protein, and sporozoite threonine/asparagine-rich protein) restricted through common HLA alleles present in this population (HLA-A2.1, -A2.2, -B7, -B8, -B35, and B53). Precursor frequencies were between 17 and 98/million PBMC and correlated with the levels of specific lysis in parallel bulk cultures. The quantitative nature of limiting dilution assay analysis revealed varying degrees of immunodominance in the CTL responses to different epitopes within single proteins (thrombospondin related anonymous protein: tr42, tr43, tr26, tr29, and tr39; circumsporozoite protein: cp6, cp26, and cp29) and within individual donors. The temporal stability of some of these CTL responses was determined over a 4-yr period. This is the first quantitative study of CTL specific for any plasmodial species or nonviral pathogen in humans and provides a basis for a multiepitope approach to malaria vaccination.

Adult↗
PubMed2007

Independent evolution of pyrimethamine resistance in Plasmodium falciparum isolates in Melanesia.

Pyrimethamine resistance in Plasmodium falciparum has previously been shown to have emerged once in Southeast Asia, from where it spread to Africa. Pyrimethamine resistance in this parasite is known to be conferred by mutations in the gene encoding dihydrofolate reductase (dhfr). We have analyzed polymorphisms in dhfr as well as microsatellite haplotypes flanking this gene in a total of 285 isolates from different regions of Melanesia (Papua New Guinea, Vanuatu, and the Solomon Islands) and Southeast Asia (Thailand and Cambodia). Nearly all isolates (92%) in Melanesia were shown to carry a dhfr double mutation (CNRNI [underlining indicates the mutation]) at positions 50, 51, 59, 108, and 164, whereas 98% of Southeast Asian isolates were either triple (CIRNI) or quadruple (CIRNL) mutants. Microsatellite analysis revealed two distinct lineages of dhfr double mutants in Melanesia. One lineage had the same microsatellite haplotype as that previously reported for Southeast Asia and Africa, suggesting the spread of this allele to Melanesia from Southeast Asia. The other lineage had a unique, previously undescribed microsatellite haplotype, indicative of the de novo emergence of pyrimethamine resistance in Melanesia.

Animals↗
PubMed1986

Stage-specific sensitivity of Plasmodium falciparum to antifolates.

Highly synchronous cultures of Plasmodium falciparum were exposed to therapeutic concentrations of sulfadoxine or pyrimethamine at different developmental stages to investigate the effect on subsequent growth. Morphological observations showed that schizont formation from uninuclear trophozoites was the only process inhibited by the drugs. Segmentation of mature schizonts, merozoite invasion and development of the ring stage remained unaffected. These results support earlier reports suggesting that DNA synthesis is most pronounced in 32-42 h old trophozoites. The possible relevance of our results to the metabolism of P. falciparum is discussed.

Animals↗
PubMed2001

Functional genomic technologies applied to the control of the human malaria parasite, Plasmodium falciparum.

Infection with any of the four species of Plasmodium single cell parasites that infects humans causes the clinical disease, malaria. Of these, it is Plasmodium falciparum that is responsible for the majority of the 1.5-2.3 million deaths due to this disease each year. Worldwide there are between 300-500 million cases of malaria annually. To date there is no licensed vaccine and resistance to most of the available drugs used to prevent and/or treat malaria is spreading. There is therefore an urgent need to develop new and effective drugs and vaccines against this devastating parasite. We have outlined a strategy using a combination of DNA-based vaccines and the data derived from the soon-to-be completed P. falciparum genome and the genomes of other species of Plasmodium to develop new vaccines against malaria. Much of the technology that we are developing for vaccine target identification is directly applicable to the identification of potential targets for drug discovery. The publicly available genome sequence data also provides a means for researchers whose focus may not be primarily malaria to leverage their research on cancer, yeast biology and other research areas to the biological problems of malaria.

Animals↗
PubMed2005

Prevalence of pfcrt point mutations and level of chloroquine resistance in Plasmodium falciparum isolates from Africa.

The development in Plasmodium falciparum of the resistance to chloroquine (CQ) constitutes a public health priority, due to its direct influence in childhood mortality. The molecular basis for CQ resistance (CQR) is still unclear but, recently, a new relevant gene, named pfcrt, with several point mutations was identified in P. falciparum. Two mutations, K76T and A220S, have been considered crucial for CQR in further studies, making the pfcrt a good candidate as determinant for CQR in P. falciparum. To contribute to this topic, we have undertaken a molecular screening on 164 P. falciparum isolates from Africa: 120 isolates were Italian imported malaria cases, 27 and 17 isolates were from a school-children survey from Congo and Tanzania, respectively. In vitro tests (pLDH and WHO-Mark III tests) for CQ sensitivity have been also carried out on 28 plasmodial isolates and results compared to those obtained by molecular analysis in the same isolates. The SVIET pfcrt haplotype has been identified in the samples from Congo, and this is the first time that this haplotype is detected in Africa. Our results give further evidence to the reliability of the 76T (and the linked 74I-75E) pfcrt point mutation as molecular marker for CQR.

Adolescent↗