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PubMed1989

Immune response to a synthetic peptide corresponding to an epitope of a parasitophorous vacuole membrane antigen from Plasmodium falciparum.

The parasitophorous vacuole membrane antigen QF 116 from Plasmodium falciparum contains a defined epitope, DNNLVSGP, proximal to the carboxyl-terminus which binds to the inhibitory monoclonal antibody 8E7/55. A synthetic peptide containing this epitope was constructed and coupled to diphtheria toxoid as carrier. Mice and rabbits were inoculated with this conjugate using CFA, SAF-1, or aluminum phosphate as adjuvants. The peptide conjugate was highly immunogenic in both animal species, giving rise to polyclonal antibodies with a similar epitope specificity as the original mAb. Antibody titers were dependent on the route of immunization. Rabbit antibodies produced in sufficient quantity for biologic assays inhibited parasite growth in vitro. This synthetic peptide thus shows promise as an immunogen for use in synthetic vaccine design.

Amino Acid Sequence↗
PubMed1981

Reaction of immune sera with components of the human malarial parasite, Plasmodium falciparum.

Human and monkey sera from individuals exposed to Plasmodium falciparum were characterized by indirect immunofluorescence, in vitro parasite growth inhibition, and immunoprecipitation of 125I-labeled parasite antigens followed by analytical sodium dodecyl-sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In general there was a good correlation between fluorescence titer and the ability of a serum to inhibit parasite growth in vitro. Exceptions were found, however. Some variance was seen in the ability of a given serum to inhibit different strains of the parasite. The significance of this is unknown. The proteins bound by human sera with high and low in vitro inhibitory capacities were compared by SDS-PAGE. The human sera which did not inhibit parasite growth in vitro well differed from those which did by failing to efficiently bind certain parasite components having molecular weights in the range of 200,000, 70,000-85,000, and 45,000.

Animals↗
PubMed1988

Effect of carrier selection on immunogenicity of protein conjugate vaccines against Plasmodium falciparum circumsporozoites.

Conjugate vaccines against the sporozoite stage of Plasmodium falciparum were synthesized by covalently coupling the recombinant protein R32 [with the one-letter amino acid code of MDP-[(NANP)15NVDP]2LR] to tetanus toxoid, cholera toxin, choleragenoid, and Pseudomonas aeruginosa toxin A. Conjugates were produced by using adipic acid dihydrazide as a spacer molecule and carbodiimide as a coupling agent. The molar ratio of R32 to carrier protein ranged from 2.5:1 to 8.4:1. These conjugates were found to be stable, nontoxic, and nonpyrogenic. When adsorbed onto Al(OH)3, all conjugates were capable of inducing anti-R32 antibody. Conjugates made with either cholera toxin or Pseudomonas aeruginosa toxin A were significantly more immunogenic than those constructed with tetanus toxoid or choleragenoid. However, the magnitude of the immune response to the R32 moiety was not governed by the antibody response to the carrier protein.

Amino Acid Sequence↗
PubMed2004

Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents.

Chloroquine resistance in Plasmodium falciparum is primarily conferred by mutations in pfcrt. Parasites resistant to chloroquine can display hypersensitivity to other antimalarials; however, the patterns of crossresistance are complex, and the genetic basis has remained elusive. We show that stepwise selection for resistance to amantadine or halofantrine produced previously unknown pfcrt mutations (including S163R), which were associated with a loss of verapamil-reversible chloroquine resistance. This was accompanied by restoration of efficient chloroquine binding to hematin in these selected lines. This S163R mutation provides insight into a mechanism by which PfCRT could gate the transport of protonated chloroquine through the digestive vacuole membrane. Evidence for the presence of this mutation in a Southeast Asian isolate supports the argument for a broad role for PfCRT in determining levels of susceptibility to structurally diverse antimalarials.

Alanine↗
PubMed1991

In vitro and clinical correlates of mefloquine resistance of Plasmodium falciparum in eastern Thailand.

A series of isolates of Plasmodium falciparum from eastern Thailand was collected prior to and after treatment failure with mefloquine. Patterns of drug sensitivity to standard and new antimalarials were characterized by using an in vitro assay based on the inhibition of schizont maturation. In vitro levels of mefloquine sensitivity of isolates were correlated with clinical treatment failures. In vitro parasite resistance to mefloquine is defined as an inhibitory dose-50 value greater than 20 nM. For isolates collected prior to treatment, there was no significant difference in mefloquine sensitivity patterns between subsequent successes and failures, suggesting that mefloquine treatment failures could not be predicted based on in vitro sensitivity of pretreatment isolates. A series of paired isolates were collected both prior to treatment with mefloquine and after recrudescence. Recrudescent isolates showed significant decreases in sensitivity to mefloquine, WR 194965, enpiroline, and halofantrine; no significant changes in sensitivity to amodiaquine, qinghaosu, and pyrimethamine; and an increase in sensitivity to chloroquine.

Amodiaquine↗
PubMed1993

Immune response in mouse and malaria-exposed humans to peptides derived from Pf11-1, a highly repetitive megadalton protein of Plasmodium falciparum.

We have investigated the immune response against the Plasmodium falciparum gametocyte-specific antigen Pf11-1. This megadalton parasite molecule has been implicated in the process of erythrocyte rupture during gametogenesis. The molecule is composed in great part of degenerated nonapeptide motifs which are tandemly repeated several hundred times. A computer algorithm searching for T sites predicted that the entire repeat region of the Pf11-1 represents potential T cell antigenic major histocompatibility complex class II-binding sites. To test this hypothesis, synthetic peptides corresponding to two nonamer subtype repeats, differing only at two amino acid positions, were used to immunize congenic mouse strains. Both peptides were shown to contain both B and T cell epitopes. The immune response is restricted to the H-2d and H-2k haplotypes. The T cell response against the peptides appeared to be highly specific, clearly discriminating between the two similar nonamer repeat sequences, whereas the humoral response produced cross-reacting antibodies. We also investigated the humoral and T cell reactivities of P. falciparum-primed individuals in West Africa against the synthetic Pf11-1 peptides. Among 51 individuals 35 had antibodies to at least one of the two peptides and a majority of them (28) had antibodies reacting with both peptides. The cellular response was analyzed by [3H]thymidine incorporation or interferon-gamma release. There was considerable variation in the response to the two peptides. Among the human samples 36% responded to one repeat subtype, while only 13% responded to the second subtype. Interestingly, in individual donors the T cell response to both peptides are associated, suggesting that, as shown for mice, the response is restricted by a genetic element. The data obtained on the two subtypes of the nonamer repeat region suggest that the entire Pf11-1 molecule might induce an unusually heterogenous B and T cell response during natural infection in man.

Adolescent↗
PubMed1998

Microtubules in Plasmodium falciparum merozoites and their importance for invasion of erythrocytes.

Plasmodium falciparum merozoites have an array of 2-3 subpellicular microtubules, designated f-MAST. We have previously shown that colchicine inhibits merozoite invasion of erythrocytes, indicating a microtubular involvement in this process. Colchicine inhibition of invasion was reduced by the Taxol-stabilization of merozoite microtubules prior to colchicine exposure. Immunofluorescence assays showed that the number and length of f-MASTs were reduced in colchicine-treated merozoites, confirming that microtubules were the target of colchicine inhibition. The dinitroaniline drugs, trifluralin and pendimethalin, were shown by immunofluorescence to depolymerize the f-MAST and both drugs were inhibitory in invasion assays. These results demonstrate that the integrity of the f-MAST is important for successful invasion. Fluorescence imaging demonstrated the alignment of mitochondria to f-MAST, suggesting that mitochondrial transport might be perturbed in merozoites with disorganized f-MAST. Depolymerizing mt in late-stage schizonts did not affect the allocation of mitochondria to merozoites.

Aniline Compounds↗
PubMed2005

Ultrastructural assessment of Plasmodium falciparum in age-fractionated thalassaemic erythrocytes.

Culture of Plasmodium falciparum in age-fractionated thalassaemic red blood cells (RBC) has shown evidence of parasite damage on light microscopy in older cells during the third culture cycle (96-144 h). In this report, parasites growing in thalassaemic trait and normal RBC were examined ultrastructurally from 96 to 144 h. All parasite stages in old thalassaemic RBC showed evidence of damage worsening with culture duration. There were cytoplasmic alterations with ribosomal damage, and parasite cytoplasm became increasingly loose and grainy, with multiple fissures. Discontinuity of the nuclear membrane with an abnormal nucleolus was seen at l20 h. Cytosomes remained normal, but damage to the food vacuole and shrunken disintegrating parasites were observed at 144 h. These changes are compatible with cellular degeneration and developmental retardation and would account for the schizont maturation arrest and reduced reinvasion rates previously reported. Increased free radicals associated with thalassaemic erythrocytes would explain these changes, further supporting the role for oxidant stress in the protective mechanism.

Animals↗
PubMed1999

The fragmented mitochondrial ribosomal RNAs of Plasmodium falciparum have short A tails.

The mitochondrial genome of Plasmodium falciparum encodes highly fragmented rRNAs. Twenty small RNAs which are putative rRNA fragments have been found and 15 of them have been identified as corresponding to specific regions of rRNA sequence. To investigate the possible interactions between the fragmented rRNAs in the ribosome, we have mapped the ends of many of the small transcripts using primer extension and RNase protection analysis. Results obtained from these studies revealed that some of the rRNA transcripts were longer than the sequences which encode them. To investigate these size discrepancies, we performed 3' RACE PCR analysis and RNase H mapping. These analyses revealed non-encoded oligo(A) tails on some but not all of these small rRNAs. The approximate length of the oligo(A) tail appears to be transcript-specific, with some rRNAs consistently showing longer oligo(A) tails than others. The oligoadenylation of the rRNAs may provide a buffer zone against 3' exonucleolytic attack, thereby preserving the encoded sequences necessary for secondary structure interactions in the ribosome.

3' Untranslated Regions↗
PubMed1992

Longitudinal study of Plasmodium falciparum polymorphic antigens in a malaria-endemic population.

Plasmodium falciparum merozoite surface antigens MSP1 and MSP2 and an exported antigen, Exp-1, exhibit allelic polymorphism in natural populations. To explain this, one hypothesis is that antigen polymorphisms are maintained by frequency-dependent immune selection. An expectation of the hypothesis is that rare variants have an advantage over common variants because of a lower level of acquired immunity against them and thus increase in frequency until an equilibrium is attained. To test this hypothesis, the frequencies of polymorphic epitopes of MSP1, MSP2, and Exp-1 were determined among isolates from malaria patients in an urban area of The Gambia, during different periods of one transmission season (1988) and in different years (1982, 1983, 1988, and 1989). The frequencies remained very stable throughout the period of study, alternative epitope variants remaining either rare or common, without shifts in relative frequencies. These results are discussed with reference to the immune-selection hypothesis, with the conclusion that frequencies of the major dimorphic serological classes of MSP1 are probably not maintained by immune selection.

Animals↗
PubMed1991

Localization and stage specific phosphorylation of Plasmodium falciparum phosphoproteins during the intraerythrocytic cycle.

Fifty-nine Plasmodium falciparum specific phosphoproteins with molecular weights between 15,000 and 192,000 were analyzed by SDS-PAGE and two-dimensional gel electrophoresis. 40 phosphoproteins were identified by [gamma-32P]ATP labeling of cell lysates, 19 by [32P]orthophosphate labeling of parasitic cultures in vivo. Changes in the phosphorylation pattern during the infectious erythrocytic cycle were determined for all proteins. In parallel, cell fractionation studies were done to follow up possible changes in the cellular distribution of these proteins. Several phosphoproteins are associated with the membrane fraction of infected erythrocytes. One pair of proteins of approx. 88 kDa and a pI of about 5.0 was further characterized. Both proteins are located in the parasitic fractions as well as in the membrane of infected erythrocytes during the entire cycle. Phosphorylation of these proteins, however, is restricted to the trophozoite and schizont stages. Peptide mapping studies demonstrated that both proteins are identical with the exception of minor modifications which are probably not the result of differences in phosphorylation.

Animals↗
PubMed1985

Characterization of permeation pathways in the plasma membrane of human erythrocytes infected with early stages of Plasmodium falciparum: association with parasite development.

Human intraerythrocytic malarial parasites (Plasmodium falciparum) induce permeability changes in the membrane of their host cells. The differential permeability of infected erythrocytes at various stages of parasite growth, in combination with density gradient centrifugation, was used to fractionate parasitized cells according to their developmental stage. By this method it was possible to obtain cell fractions consisting essentially of erythrocytes infected with the youngest parasite stage (i.e., rings). These preparations were used for the measurement of transport of various solutes. It is shown that permeabilization of host erythrocyte membrane appears as early as 6 h after parasite invasion of the erythrocyte and increases gradually with parasite maturation. Since the selectivity for several different solutes and the enthalpy of activation of transport remain unaltered with maturation-related increase of permeability, it is concluded that the number of transport agencies in the host cell membrane increases with parasite maturation. Evidence is presented to indicate the need for parasite protein synthesis as an essential factor for the generation of the new permeability pathways.

Alanine↗
PubMed1982

Studies on the Cambodian I strain of Plasmodium falciparum in Aotus monkeys.

The Cambodian I strain of Plasmodium falciparum, originally from Kampuchea was adapted for development in three different types of Aotus monkeys. High-level parasitemias were readily produced in splenectomized Colombian A. trivirgatus griseimembra monkeys. Initially, only minimal parasitemias developed in A. t. trivirgatus monkeys from Colombia. However, in one animal, adaptation occurred and high-level parasitemias were obtained during the second recrudescence of the infection. Passage to other A. t. trivirgatus monkeys indicated that the parasite was well adapted for development in splenectomized animals; low to moderate parasitemias were still produced in intact animals. This line of the parasite produced high level parasitemias when inoculated into splenectomized Aotus monkeys from Peru. Infections in Anopheles freeborni mosquitoes were obtained as late as the 7th passage in A. t. griseimembra monkeys and as late as the 7th recrudescence of the infection in an individual monkey (348 days after inoculation). The sporogonic cycle was completed in An. freeborni mosquitoes, and one transmission to an A. t. griseimembra monkey via the bites of infected mosquitoes was obtained.

Animals↗
PubMed1991

Selective internalization of choline-phospholipids in Plasmodium falciparum parasitized human erythrocytes.

We have incubated control and Plasmodium falciparum parasitized human erythrocytes with lipid vesicles containing radiolabeled long-chain phosphatidylcholine and sphingomyelin, in the presence of a nonspecific lipid transfer protein. Most of the radiolabeled phospholipids were, immediately thereafter, available for extracellular phospholipases, suggesting that uptake of vesicles as such did not occur. In time, the amount of phosphatidylcholine inserted in the outer leaflet of the host cell membrane of parasitized erythrocytes decreased, indicating that phosphatidylcholine was being internalized in parasitized erythrocytes. The exclusion of sphingomyelin from the internalization process suggests that the removal of phosphatidylcholine from the outer leaflet of the erythrocyte membrane is caused by transbilayer migration, rather than by endocytosis. The extent of phosphatidylcholine internalization indicates that part of it does not remain in the inner leaflet of the host cell membrane, but is taken up by the intraerythrocytic parasite. Individual phosphatidylcholine species, containing 16:0/18:1-, 16:0/18:2- and 16:0/20:4-fatty acids, showed similar extents of internalization, after being incorporated in parasitized erythrocytes by a phosphatidylcholine specific transfer protein.

Animals↗
PubMed1991

Studies on Pf155/RESA and other soluble antigens from in vitro cultured Plasmodium falciparum.

Spent culture medium from in vitro cultures of Plasmodium falciparum was used as the source for immunoadsorbent enrichment of soluble parasite antigens. IgG obtained from P. falciparum-hyperimmune Liberian serum was used as the ligand in the immunoadsorbent. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of the immunoadsorbent isolated material revealed the presence of at least 15 antigenic and parasite-derived polypeptides. Immunoblotting after SDS-PAGE showed greater than 20 antigenic polypeptides in the molecular weight range of 15-250 kDa. Several of these were heat-stable (100 degrees C for 5 min), and six of them were detected even after heating for 60 min. Among the latter antigens was Pf155/RESA, a merozoite antigen deposited in the erythrocyte membrane at invasion. Pf155/RESA can be detected using a modified erythrocyte membrane immunofluorescence (EMIF) assay. Inhibition of EMIF with heated parasite material showed that the antigenic activity was intact after heating for up to 30 min. The immunofluorescence-inhibitory activity was separated into two fractions, one containing Pf155/RESA and one containing polypeptides with molecular weights of 135 and 120 kDa. All three of these antigenic polypeptides bound selectively, albeit nonspecifically, to aminoethyl-BioGel resins.

Animals↗
PubMed1999

The transport of the histidine-rich protein I from Plasmodium falciparum is insensitive to brefeldin A.

During its intraerythrocytic development, Plasmodium falciparum synthesizes several proteins that are exported beyond its membrane. Some of these secreted antigens are involved in the formation of protuberances or knobs, a major virulence factor, at the erythrocyte membrane. Various secreted malarial polypeptides, the transport of which is sensitive to brefeldin A, are translocated in vitro into dog pancreatic microsomes. We present evidence that the histidine-rich protein I (PfHRPI) is secreted by the parasite via a novel pathway, independent of the ER/Golgi apparatus. The secretion of PfHRPI was not blocked by incubation of parasite cultures at 15 degrees C and 20 degrees C or 37 degrees C in the presence of brefeldin A. PfHRPI was not translocated into microsomes in an in vitro translation-translocation cell-free system. Unlike other polypeptides from eukaryotic cells that bypass the ER/Golgi pathway and do not have a signal peptide, PfHRPI has an atypical signal sequence consisting of 21 amino acids, including eight positively charged residues followed by 11 hydrophobic residues. We also found that the unusually charged PfHRPI signal sequence diverts Exp-1, which is usually exported, away from the translocation machinery of microsomal membranes.

Animals↗
PubMed1989

Decreased sensitivity of artesunate and chloroquine of Plasmodium falciparum infecting hemoglobin H and/or hemoglobin constant spring erythrocytes.

Plasmodium falciparum infecting hemoglobin (Hb) H and/or Hb Constant Spring erythrocytes in vitro was relatively more resistant than that infecting normal erythrocytes to artesunate and chloroquine, while the sensitivity to pyrimethamine was unchanged. The 50% inhibitory concentrations (IC50) for artesunate in HbH (alpha-thal 1/alpha-thal 2), HbH (alpha-thal 1/Hb Constant Spring), and homozygous Hb Constant Spring erythrocytes were 4.5 +/- 2.8, 8.5 +/- 3.2, and 2.6 +/- 1.6 nM compared with 0.82 +/- 0.35 nM in normal erythrocytes (P less than 0.002 for all three cases). The IC50 for chloroquine were 97 +/- 46, 162 +/- 67, and 93 +/- 36 nM, respectively, in the variant erythrocytes, compared with 48 +/- 13 nM in normal erythrocytes (P less than 0.002, 0.002, and 0.02, respectively). The differences in sensitivity to artesunate and chloroquine of the parasite infecting HbH erythrocytes are probably related to their oxidative mode of action and relatively high amounts of antioxidant enzymes in the host erythrocytes. This novel example of dependence on the host of the malarial parasite drug sensitivity may have implications for chemotherapy of malaria in patients with genetically variant erythrocytes.

Animals↗
PubMed1994

Allelic variation in the circumsporozoite protein of Plasmodium falciparum from Thai field isolates.

Allelic variation in the Plasmodium falciparum circumsporozoite (CS) protein gene has been examined by sequencing the entire gene in 15 isolates from an endemic area of Thailand. The isolates contain a total of six new allelic forms of the tetrapeptide repeats and eight variants of the T cell epitope (TCE) region of the CS gene. All nucleotide substitutions in the TCE are nonsynonymous. There is no apparent association between the sequence patterns in the repeats and in the TCE. Comparison of the TCE with published sequences has shown that most variants of our isolates are not identical to those found in different geographic areas, suggesting geographic variation in genetic diversity of the CS protein. In a phylogenetic tree, the new Thai alleles did not cluster together, suggesting a considerable heterogeneity within some geographic areas. Furthermore, analyses of tetrapeptide repeats from a number of isolates and strains showed evidence of three genetic mechanisms for the generation of variation in the repeats of the CS gene: point mutation, duplication of one or more repeat units, and intragenic recombination.

Alleles↗