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PubMed1994

Plasmodium vivax merozoite surface protein 1 C-terminal recombinant proteins in baculovirus.

Recombinant proteins derived from the Plasmodium vivax merozoite surface protein 1 have been produced in the baculovirus expression system. These proteins correspond approximately to the Plasmodium vivax analogs of the 42-kDa or 19-kDa C-terminal processing products previously described for Plasmodium falciparum. Each was produced in two versions, either as a membrane-bound entity located on the cell surface and probably carrying a glycosylphosphatidylinositol addition, or as a secreted entity lacking a membrane anchor. Many native conformational epitopes appear to be accurately reproduced in these molecules. Both the 42-kDa and 19-kDa analogs can be N-glycosylated in the baculovirus system and the N-glycosylation appears to be necessary for efficient secretion of both the 42-kDa and 19-kDa recombinant proteins.

Amino Acid Sequence↗
PubMed2005

Biting behavior and Plasmodium infection rates of Anopheles arabiensis from Sille, Ethiopia.

The man-biting behavior and Plasmodium infection rates of anopheline mosquitoes were investigated in Sille, a hyperendemic malarious area in southern Ethiopia. Seven Anopheles species were identified from all night landing collections, conducted from 18:00 to 06:00h between October 2001 and August 2002. The predominant species was Anopheles arabiensis (55.8%), followed by Anopheles coustani (31.5%), Anopheles pharoensis (9.5%), Anopheles funestus (2.2%), Anopheles nili (0.5%), Anopheles marshallii (0.4%) and Anopheles demeilloni (0.2%). Dissection of A. arabiensis showed an average parous rate of 73.2%. A large proportion of the parous mosquitoes were caught biting in the latter part of the night. Malaria sporozoite rates were determined by ELISA for A. arabiensis, with 0.5% (4/796) infective with Plasmodium falciparum and 1.76% (14/796) with Plasmodium vivax; there were no mixed infections. From our small sample of sporozoite positives we found no association between biting behavior and sporozoite infection status.

Animals↗
PubMed2006

Differential gene expression in the ookinete stage of the malaria parasite Plasmodium berghei.

Plasmodium, the malaria parasite, undergoes a complex developmental program in its mosquito vector. The ookinete is the parasite form which invades the mosquito midgut and is an important stage for genetic mixing. To identify genes expressed during ookinete development and mosquito midgut invasion, purified zygotes and ookinetes of the rodent parasite Plasmodium berghei were used to construct a suppression subtractive hybridization cDNA library, enriched in sequences expressed in the ookinete stage. In addition to four genes coding for previously described major ookinete-secreted proteins, we isolated ookinete-expressed sequences representing 18 predicted genes. Their gene products include proteins involved in signal transduction and regulatory processes. For six of these genes our analysis provides the first evidence for expression in the ookinete stage. A majority of the genes are not expressed in the zygote, the preceding developmental stage. Furthermore, four of the genes are also transcribed in sporozoites, and one of these in merozoites, suggesting that they code for proteins with a function common to Plasmodium invasive stages.

Animals↗
PubMed2006

Characterisation of the phosphatidylinositol synthase gene of Plasmodium species.

Phosphatidylinositol (PI) is a versatile lipid that not only serves as a structural component of cellular membranes, but also plays important roles in membrane anchorage of proteins and in signal transduction through distinct phosphorylated derivatives of the inositol head group. PI is synthesised by PI synthase from CDP-diacylglycerol and myo-inositol. The enzymatic activity in Plasmodium falciparum and P. knowlesi has previously been characterised at the biochemical level. Here we characterise the PI synthase gene of P. falciparum and P. knowlesi. The cDNA sequence identified a highly spliced gene consisting of nine exons and encoding a protein of 209 and 207 amino acids, respectively. High sequence conservation enabled the prediction of the PI synthase genes of P. berghei, P. chabaudi and P. vivax. All Plasmodium PI synthase proteins appear to be highly hydrophobic, although no consensus for the number and location of distinct transmembrane domains could be detected. The P. falciparum PI synthase (PfPIS) gene successfully complemented a Saccharomyces cerevisiae PIS1 deletion mutant, demonstrating its enzymatic function. Complementation efficiency was dramatically improved when hybrid constructs between N-terminal S. cerevisiae and C-terminal P. falciparum sequences were used. Determination of in vitro PIS activities of complemented yeast strains confirmed the enzymatic function of the Plasmodium protein.

Amino Acid Sequence↗
PubMed2000

Retrieving parasite specific liver stage gene products in Plasmodium yoelii infected livers using differential display.

Differential display (DD) has been routinely used to identify genes whose expression pattern is altered by changes in the cellular environment and/or at different stages of development. Most reports utilizing DD contain conventional DD primers that have high guanine and cytosine content and would not be expected to be optimal for Plasmodium which has approximately 30-40% G+C. In an attempt to accommodate the high adenine and thymidine rich genome of Plasmodium yoelii, we utilized PCR primers containing 40, 50 and 60% G+C and modified the existing DD technique. Thus 40% G+C appeared to be the most suitable to amplify Plasmodium genome. Gene specific primers were generated from the sequences of selected DD bands amplified using the 40% G+C primers and were used to verify that the DD clones were of parasite origin by PCR and sequence alignment. Additional data on five of the selected DD clones, designated P2T1L5, P2T1L6, P2T6L11, P2T7L12 and P2T7L13, suggested that all are expressed during the P. yoelii liver stage infection. Interestingly, P2T1L5 is also expressed during the sporozoite stage of the life cycle and both P2T1L6 and P2T6L11 are present as blood stage antigens. The results of this study suggest that DD incorporating primers with low G+C content allows the identification of P. yoelii messages from infected mouse livers.

Animals↗
PubMed2001

The Plasmodium falciparum knob-associated PfEMP3 antigen is also expressed at pre-erythrocytic stages and induces antibodies which inhibit sporozoite invasion.

The expression of the pfemp3 gene and the corresponding PfEMP3 knob-associated protein in the pre-erythrocytic stages of Plasmodium falciparum was demonstrated by RT-PCR, Western blots, IFAT and IEM. The antigen was found on the surface of the sporozoite and in the cytoplasm of mature hepatic stage parasites. Immunological cross-reactivity was observed with sporozoites from the rodent malaria parasites Plasmodium yoelii yoelii and Plasmodium berghei and was exploited to assess a potential role of this protein at the pre-erythrocytic stages. Specific antibodies from immune individuals were found to inhibit P. yoelii yoelii and P. berghei sporozoite invasion of primary hepatocyte cultures. PfEMP3 should now be added to the small list of proteins expressed at the pre-erythrocytic stages of P. falciparum, and its vaccine potential now deserves to be investigated.

Animals↗
PubMed2001

Transglutaminase in Plasmodium parasites: activity and putative role in oocysts and blood stages.

Transglutaminase was identified in malaria parasites by immunofluorescence microscopy using alpha-transglutaminase antiserum. Functional enzyme was demonstrated in vivo and in vitro using labeled polyamines that become incorporated into protein substrates through TGase activity. In Plasmodium falciparum intraerythrocytic parasites, transglutaminase activity was stage-dependent: it was weak in ring-forms but much stronger in trophozoites and schizonts. High levels of activity were detected in P. gallinaceum zygotes and ookinetes and in capsules of oocysts developing on mosquito midguts. Unlike most known transglutaminases, the enzymatic activity in Plasmodium was Ca(2+)-independent. Furthermore, levels of activity were similar at 37 and 26 degrees C. Parasite transglutaminase may be responsible for the modification of erythrocytic cytoskeleton in infected cells and it may facilitate the construction of oocyst capsules by cross-linking mosquito-derived basement membrane components with Plasmodium-derived proteins.

Aedes↗
PubMed2001

Comparative genomics in Plasmodium: a tool for the identification of genes and functional analysis.

Comparative genomics allows inferences to be drawn about the coding potential of related genomes, and the evolutionary forces that have influenced genome organisation. Early comparisons have indicated that there is significant synteny (conserved physical association of genes) between the human parasite Plasmodium falciparum and the malaria parasites of rodents, such as Plasmodium berghei. The various Plasmodium genome initiatives have now provided the opportunity to perform comparative genomics within different species of malaria parasites in more detail, allowing the discovery of orthologues and paralogues of less well conserved genes and addressing questions of conservation, evolution and structure of multi-gene families. A remarkable level of conservation is being revealed, illustrated here by a comparison of members of one of the first conserved gene families to emerge from the sequencing initiatives, the P48/45 gene family. We have identified two additional members in this family, Pf36p and Pfs38, and shown that all members are conserved in P. falciparum and P. berghei, opening the way for functional analyses in the latter more accessible rodent malaria model. In addition, it has been shown that direct comparison of a 13.6 kb contig of a chromosome of P. berghei and the orthologous region in P. falciparum reveals an unexpected high level of conservation of gene organisation and complexity. The results of this comparison highlight the value of a comparative approach to elucidate the gene content of complex loci and improve its annotation

Amino Acid Sequence↗
PubMed2003

A gene-family encoding small exported proteins is conserved across Plasmodium genus.

A gene-family, named sep, encoding small exported proteins conserved across Plasmodium species has been identified. SEP proteins (13-16 kDa) contain a predicted signal peptide at the NH(2)-terminus, an internal hydrophobic region and a polymorphic, low-complexity region at the carboxy-terminus. One member of the Plasmodium berghei family, Pbsep1, encodes an integral membrane protein expressed along the entire erythrocytic cycle. Immunolocalisation results indicated that PbSEP1 is targeted to the membrane of the parasitophorous vacuole up to the early phases of schizogony, while, in late schizonts, it re-locates in structures within the syncitium. After erythrocyte rupture, PbSEP1 is still detectable in free merozoites thus suggesting its involvement in the early steps of parasite invasion. Seven members of the sep-family in Plasmodium falciparum have been identified. Two of them correspond to previously reported gene sequences included in a family of early transcribed membrane proteins (etramp). Structural, functional and phylogenetic features of the sep family, shown in the present work, supercede this previous classification. PfSEP proteins are exported beyond the parasite membrane and translocated, early after invasion, to the host cell compartment in association with vesicle-like structures. Colocalisation results indicated that PfSEP-specific fluorescence overlaps, at the stage of trophozoite, with that of Pf332, a protein associated with Maurer's clefts, membranous structures in the cytosol of parasitised red blood cells, most probably involved in trafficking of parasite proteins. The specific signals necessary to direct SEP proteins to the vacuolar membrane in P. berghei or to the host cell compartment in P. falciparum remain to be determined.

Amino Acid Sequence↗
PubMed2002

Plasmodium sex determination and transmission to mosquitoes.

In order to be transmitted by their mosquito vector, malaria parasites undergo sexual reproduction, which occurs between specialized male and female parasites (gametes) within the blood meal in the mosquito. Nothing was known about how Plasmodium determines the sex of its gametocytes (gamete precursors), which are produced in the vertebrate host. Recently, erythropoietin, the vertebrate hormone controlling erythropoiesis in response to anaemia, was implicated in Plasmodium sex determination in animal models of malaria. This review examines the available information and addresses the relevance of such a sex determining mechanism for Plasmodium falciparum transmission to mosquitoes, with special reference to low gametocytaemias.

Anemia↗
PubMed1991

Mitochondria of mammalian Plasmodium spp.

Highly purified mitochondrial fractions have been isolated from the intraerythrocytic stages of two mammalian Plasmodium spp., Plasmodium yoelii of rodents and Plasmodium falciparum of man. Mitochondria of the former parasite are cristate whereas those of the latter are essentially acristate. Isolated mitochondria from both parasite species were heterogeneous with respect to size, shape, density of matrix staining and extent of internal structure. Respiratory assay, by reduction of exogenous cytochrome c, showed NADH, alpha-glycerophosphate and succinate to be the substrates with the greatest potential for metabolism. Additionally, proline, dihydroorotate and glutamate (P. falciparum only) were oxidized at low rates. A number of NAD(+)-linked substrates were not utilized. The NADH-dependent reduction of cytochrome c was insensitive to rotenone and antimycin A. Fumarate inhibited the NADH-dependent reduction of cytochrome c and stimulated the oxidation of NADH, suggestive of an NADH-fumarate reductase pathway. Oxidation of either alpha-glycerophosphate or succinate was fully inhibited by standard mitochondrial electron transport inhibitors, including a number of Complex III inhibitors, although the concentrations required of such inhibitors (notably myxothiazol) were relatively high compared to mammalian mitochondria. Dithionite-reduced minus oxidized difference spectra indicated the presence of cytochromes aa3, b, c and c1 in mitochondria of both parasite species, but at a higher cytochrome to protein ratio in P. yoelii. Freshly isolated mitochondria from either species exhibited only low respiratory control ratios with alpha-glycerophosphate or succinate as substrates. The apparent absence of a respiratory chain 'Site I' in such mitochondria may mean that NADH-fumarate reductase serves to reoxidize mitochondrial NADH.

Animals↗
PubMed2000

Genetic diversity and dynamics of plasmodium falciparum and P. vivax populations in multiply infected children with asymptomatic malaria infections in Papua New Guinea.

We describe the dynamics of co-infections of Plasmodium falciparum and P. vivax in 28 asymptomatic children by genotyping these species using the polymorphic loci Msp2 and Msp3alpha, respectively. The total number of Plasmodium spp. infections detected using 3 day sampling over 61 days varied between 1 and 14 (mean 6.6). The dynamics of P. falciparum and P. vivax genotypes varied greatly both within and amongst children. Periodicity in the detection of P. falciparum infections is consistent with the synchronous replication of individual genotypes. Replication synchrony of multiple co-infecting genotypes was not detected. In 4-year-old children P. falciparum genotype complexity was reduced and episodes lasted significantly longer (median duration > 60 days) when compared to children aged 5-14 years (median duration 9 days). P. vivax genotype complexity was not correlated with age but the episode duration was also longer for this species in 4-year-olds than in older children but was not as long as P. falciparum episodes. Recurrence of P. falciparum and P. vivax genotypes over weeks was observed. We interpret these major fluctuations in the density of genotypes over time as the result of the mechanism of antigenic variation thought to be present in these Plasmodium species.

Adolescent↗
PubMed2002

Genome sequence and comparative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii.

Species of malaria parasite that infect rodents have long been used as models for malaria disease research. Here we report the whole-genome shotgun sequence of one species, Plasmodium yoelii yoelii, and comparative studies with the genome of the human malaria parasite Plasmodium falciparum clone 3D7. A synteny map of 2,212 P. y. yoelii contiguous DNA sequences (contigs) aligned to 14 P. falciparum chromosomes reveals marked conservation of gene synteny within the body of each chromosome. Of about 5,300 P. falciparum genes, more than 3,300 P. y. yoelii orthologues of predominantly metabolic function were identified. Over 800 copies of a variant antigen gene located in subtelomeric regions were found. This is the first genome sequence of a model eukaryotic parasite, and it provides insight into the use of such systems in the modelling of Plasmodium biology and disease.

Animals↗
PubMed1997

Phospholipid metabolism of serine in Plasmodium-infected erythrocytes involves phosphatidylserine and direct serine decarboxylation.

Erythrocytes infected with Plasmodium falciparum or Plasmodium knowlesi efficiently incorporated radioactive serine into phosphatidylserine (PtdSer), phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho). Serine was also metabolized into ethanolamine (Etn) and phosphorylethanolamine (P-Etn) via direct serine decarboxylation; this is a major phenomenon since together these metabolites represent 60% of total radioactive water-soluble metabolites. They were identified by reverse-phase HPLC and two TLC-type analyses and confirmed by alkaline phosphatase treatment, which depleted the radioactive P-Etn peak completely with a concomitant increase in that of Etn. In the presence of 5 microM labelled serine, radioactivity appeared in Etn and P-Etn after a 25 min lag period, and isotopic equilibrium was reached at 40 and 95 min respectively. There was a similar lag period for PtdEtn formation, which accumulated steadily for at least 180 min. Incorporation of serine into phospholipids and water-soluble metabolites increased in the presence of up to 500 microM external serine. An apparent plateau was then reached for all metabolites except intracellular serine and Etn. Exogenous Etn (at 20 microM) induced a concomitant dramatic decrease in serine incorporation into P-Etn and all phospholipids, but not into Etn. Increasing exogenous serine to 100 microM decreased the incorporation of radioactive Etn into PtdEtn by only 30%, and the PtdCho level was not affected. 2-Hydroxyethylhydrazine significantly decreased serine incorporation into P-Etn and PtdEtn, whereas Etn was accumulated. No concomitant inhibition of PtdSer or PtdCho labelling from serine occurred, even when PtdEtn formation was decreased by 95%. This indicates that the PtdEtn pool derived from direct serine decarboxylation differed from that derived from PtdSer decarboxylation, and the latter appeared to be preferentially used for PtdCho biosynthesis. Hydroxylamine also inhibited phosphorylation of serine-derived Etn but not that of exogenous Etn. The rate of PtdSer synthesis from 10 microM L-serine was 3.1+/-0.5 and 2.95+/-1.3 nmol/5 h per 10(10) infected cells, whereas L-serine decarboxylation accounted for 7.1+/-1.5 and 9.9+/-3 nmol/5 h per 10(10) infected cells for P. falciparum and P. knowlesi respectively (means+/-S.E.M.). The serine decarboxylating reaction was not detected in other higher eukaryotic cells such as mouse fibroblasts and human lymphocytes. Finally, these results also indicate compartmentalization of phospholipid metabolism in Plasmodium-infected erythrocytes.

Animals↗
PubMed2000

Apical membrane antigen 1 plays a central role in erythrocyte invasion by Plasmodium species.

Apical membrane antigen 1 (AMA1) is an asexual blood-stage protein expressed in the invasive merozoite form of Plasmodia species, which are the causative agent of malaria. We have complemented the function of Plasmodium falciparum AMA1 (PfAMA1) with a divergent AMA1 transgene from Plasmodium chabaudi (PcAMA1). It was not possible to disrupt the PfAMA1 gene using 'knock-out' plasmids, although we demonstrate that the PfAMA1 gene can be targeted by homologous recombination. These experiments suggest that PfAMA1 is critical, perhaps essential, for blood-stage growth. Importantly, we showed that PcAMA1 expression in P. falciparum provides trans-species complementation to at least 35% of the function of endogenous PfAMA1 in human red cells. Furthermore, expression of this transgene in P. falciparum leads to more efficient invasion of murine erythrocytes. These results indicate an important role for AMA1 in the invasion of red blood cells (RBCs) across divergent Plasmodium species.

Animals↗
PubMed1991

Plasmodium falciparum appears to have arisen as a result of lateral transfer between avian and human hosts.

It has been proposed that the acquisition of Plasmodium falciparum by man is a relatively recent event and that the sustained presence of this disease in man is unlikely to have been possible prior to the establishment of agriculture. To establish phylogenetic relationships among the Plasmodium species and to unravel the mystery of the origin of P. falciparum, we have analyzed and compared phylogenetically the small-subunit ribosomal RNA gene sequences of the species of malaria that infect humans as well as a number of those sequences from species that infect animals. Although this comparison confirmed the three established major subgroups, broadly classed as avian, simian, and rodent, we find that the human pathogen P. falciparum is monophyletic with the avian subgroup, indicating that P. falciparum and avian parasites share a relatively recent avian progenitor. The other important human pathogen, P. vivax, is very similar to a representative of the simian group of Plasmodium. The relationship between P. falciparum and the avian parasites, and the overall phylogeny of the genus, provides evidence of an exception to Farenholz's rule, which propounds synchronous speciation between host and parasite.

Animals↗
PubMed2003

Analysis of the Plasmodium and Anopheles transcriptomes during oocyst differentiation.

Understanding the life cycle of the malaria parasite in its mosquito vector is essential for developing new strategies to combat this disease. Subtractive hybridization cDNA libraries were constructed that are enriched for Plasmodium berghei and Anopheles stephensi genes expressed during oocyst differentiation on the midgut. Sequencing of 1485 random clones led to the identification of 1137 unique expressed sequence tags. Of the 608 expressed sequence tags with data base hits, 320 (53%) had significant matches to the non-redundant protein data base, whereas 288 (47%) with matches only to genomic data bases represent novel Plasmodium and Anopheles genes. Transcription of six novel parasite genes and two previously identified asexual stage genes was up-regulated during oocyst differentiation. In addition, the mRNA for an Anopheles fibrinogen domain gene was induced on day 2 after an infectious blood meal, at the time of ookinete to oocyst differentiation. The subcellular distribution of MAEBL, a sporozoite surface protein, is developmentally regulated from presumed storage organelles in day 15 oocysts to uniform distribution on the surface in day 22 oocysts. This redistribution may reflect a sporozoite maturation program in preparation for salivary gland invasion. Furthermore, apical membrane antigen 1, another parasite surface molecule, is translationally regulated late in sporozoite development, suggesting a role during infection of the vertebrate host. The present results and those of an accompanying report (Abraham, E. G., Islam, S., Srinivasan, P., Ghosh, A. K., Valenzuela, J., Ribeiro, J. M., Kafatos, F. C., Dimopoulos, G., & Jacobs-Lorena, M. (2003) J. Biol. Chem. 279, 5573-5580) provide the foundation for studies seeking to understand at the molecular level Plasmodium development and its interactions with the mosquito.

Amino Acid Sequence↗
PubMed2004

Plasmodium ookinete-secreted proteins secreted through a common micronemal pathway are targets of blocking malaria transmission.

The mosquito midgut ookinete stage of the malaria parasite, Plasmodium, possesses microneme secretory organelles that mediate locomotion and midgut wall egress to establish sporogonic stages and subsequent transmission. The purpose of this study was 2-fold: 1) to determine whether there exists a single micronemal population with respect to soluble and membrane-associated secreted proteins; and 2) to evaluate the ookinete micronemal proteins chitinase (PgCHT1), circumsporozoite and TRAP-related protein (CTRP), and von Willebrand factor A domain-related protein (WARP) as immunological targets eliciting sera-blocking malaria parasite infectivity to mosquitoes. Indirect immunofluorescence localization studies in Plasmodium gallinaceum using specific antisera showed that all three proteins are distributed intracellularly with a similar granular cytoplasmic appearance and with focal concentration of PgCHT1 and PgCTRP, but not PgWARP, at the ookinete apical end. Immunogold double-labeling electron microscopy, using antisera against the membrane-associated protein CTRP and the soluble WARP, showed that these two proteins co-localized to the same micronemal population. Within the microneme CTRP was associated peripherally at the microneme membrane, whereas PgCHT1 and WARP were diffuse within the micronemal lumen. Sera produced against Plasmodium falciparum WARP significantly reduced the infectivity of P. gallinaceum to Aedes aegypti and P. falciparum to Anopheles mosquitoes. Antisera against PgCTRP and PgCHT1 also significantly reduced the infectivity of P. gallinaceum for A. aegypti. These results support the concept that ookinete micronemal proteins may constitute a general class of malaria transmission-blocking vaccine candidates.

Amino Acid Sequence↗