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PubMed2005

Identification, cloning, expression, and characterization of the gene for Plasmodium knowlesi surface protein containing an altered thrombospondin repeat domain.

Proteins present on the surface of malaria parasites that participate in the process of invasion and adhesion to host cells are considered attractive vaccine targets. Aided by the availability of the partially completed genome sequence of the simian malaria parasite Plasmodium knowlesi, we have identified a 786-bp DNA sequence that encodes a 262-amino-acid-long protein, containing an altered version of the thrombospondin type I repeat domain (SPATR). Thrombospondin type 1 repeat domains participate in biologically diverse functions, such as cell attachment, mobility, proliferation, and extracellular protease activities. The SPATR from P. knowlesi (PkSPATR) shares 61% and 58% sequence identity with its Plasmodium falciparum and Plasmodium yoelii orthologs, respectively. By immunofluorescence analysis, we determined that PkSPATR is a multistage antigen that is expressed on the surface of P. knowlesi sporozoite and erythrocytic stage parasites. Recombinant PkSPATR produced in Escherichia coli binds to a human hepatoma cell line, HepG2, suggesting that PkSPATR is a parasite ligand that could be involved in sporozoite invasion of liver cells. Furthermore, recombinant PkSPATR reacted with pooled sera from P. knowlesi-infected rhesus monkeys, indicating that native PkSPATR is immunogenic during infection. Further efficacy evaluation studies in the P. knowlesi-rhesus monkey sporozoite challenge model will help to decide whether the SPATR molecule should be developed as a vaccine against human malarias.

Amino Acid Sequence↗
PubMed2001

Effect of Solanum nudum extracts on the liver of mice infected with Plasmodium berghei.

The plant Solanum nudum has been used by the community of Tumaco (Nariño, Colombia) as a cure for malaria. Our group has confirmed the in vitro antimalarial activity against the strain of Plasmodium falciparum FCB-2. During our in vivo studies on the therapeutic effect of Solanum nudum extracts on mice infected with Plasmodium berghei, we observed yellowish tint in the palms of mice treated with the aqueous extract via i.p. at a concentration of 2.4% w/vol. This finding suggested the need to carry out a histology study of the liver. Plasmodium berghei infection produces liver changes such as the deposit of pigment in sinusoids, leucocytes infiltration, esteatosis and necrosis of hepatocytes. These changes were also observed when the mice were treated with methane and hexane extracts from Solanum nudum; however necrosis of hepatocytes in mice infected with malaria decreased 47-65% when they were administered either with aqueous extract, or tumacoside A and degraded diosgenone, compounds from methane and hexane extracts of Solanum nudum respectively.

Animals↗
PubMed2003

Dependence of Plasmodium falciparum in vitro growth on the cation permeability of the human host erythrocyte.

Intraerythrocyte growth of the malaria parasite Plasmodium falciparum induces a Ca2+-permeable unselective cation conductance in the host cell membrane which is inhibited by ethylisopropylamiloride (EIPA) and is paralleled by an exchange of K+ by Na+ in the host cytosol. The present study has been performed to elucidate the functional significance of the electrolyte exchange. Whole-cell patch-clamp experiments confirmed the Ca2+ permeability and EIPA sensitivity of the Plasmodium falciparum induced cation channel. In further experiments, ring stage-synchronized parasites were grown in vitro for 48 h in different test media. Percentage of Plasmodium-infected and phosphatidylserine-exposing erythrocytes was measured with FACS analysis by staining with the DNA-dye Syto16 and annexin V, respectively. The increase of infected cells was not significantly affected by an 8 h replacement of NaCl in the culture medium with Na-gluconate but was significantly blunted by replacement of NaCl with KCl, NMDG-Cl or raffinose. Half maximal growth was observed at about 25 mM Na+. The increase of infected cells was further inhibited by EIPA (IC50< 10 microM) and at low extracellular free Ca2+. Infected cells displayed significantly stronger annexin binding, an effect mimicked by exposure of noninfected erythrocytes to oxidative stress (1 mM T-butylhydroperoxide for 15 min) or to Ca2+ ionophore ionomycin (1 microM for 60 min). The observations indicate that parasite growth requires the entry of both, Na+ and Ca2+ cations into the host erythrocyte probably through the EIPA sensitive cation channel. Ca2+ entry further induces break-down of the phospholipid asymmetry in the host membrane.

Amiloride↗
PubMed1991

Possible involvement of platelets in Plasmodium yoelii nigeriensis malaria infection in mice.

The possible involvement of platelets in the pathogenesis of malaria was examined by monitoring the changes in platelet function (bleeding time [BT] and thrombin time [TT]) concomitantly with changes in packed cell volume (PCV) and erythrocyte infection rate (EIR) in Plasmodium yoelii nigeriensis infection in mice. In untreated plasmodium-infected mice, there was a progressive reduction (day 1-7) in BT from 120.0 +/- 12.6 s to 77.5 +/- 5.9 s (p less than 0.005), a reduction in TT from 26.8 +/- 1.2 s to 17.8 +/- 1.2 s (p less than 0.005), an increase in EIR from 0 to 64.6 +/- 6.3% and a reduction in PCV from 44.9 +/- 1.9% to 21.5 +/- 3.9% (p less than 0.001). Mortality on day 9 was 100%. Antiplatelet serum treatment of plasmodium-infected mice protected against malaria and there was a blunting of the malaria-induced changes in platelet function, EIR and PCV. The values obtained in these rats were significantly higher than those of the untreated malarious mice. The respective values obtained on day 1 were comparable to those of control mice. Data obtained on day 7 were: BT, 106.4 +/- 7.4 s (p less than 0.05), TT, 22.7 +/- 1.1 s (p less than 0.05), EIR, 45.7 +/- 3.2% (p less than 0.01) and PCV, 39.5 +/- 2.0% (p less than 0.01). Mortality on day 9 of infection was 60%. The protection by antiserum was not due to its thrombocytopenic response as busulphan-induced thrombocytopenia did not have the same effect. These results suggest that platelets play an important role in malaria infection as well as in the attendant coagulopathic complications.

Animals↗
PubMed2003

Glutathione is involved in the antimalarial action of chloroquine and its modulation affects drug sensitivity of human and murine species of Plasmodium.

Ferriprotoporphyrin IX (FP) is released inside the food vacuole of the malaria parasite during the digestion of host cell hemoglobin. FP is detoxified by its biomineralization to hemozoin. This process is effectively inhibited by chloroquine (CQ) and amodiaquine (AQ). Undegraded FP accumulates in the membrane fraction and inhibits enzymes of infected cells in parallel with parasite killing. FP is demonstrably degraded by reduced glutathione (GSH) in a radical-mediated mechanism. This degradation is inhibited by CQ and AQ in a competitive manner, thus explaining the ability of increased GSH levels in Plasmodium falciparum-infected cells to increase resistance to CQ and vice versa, and to render Plasmodium berghei that were selected for CQ resistance in vivo sensitive to the CQ when glutathione synthesis is inhibited. Some over-the-counter drugs that are known to reduce GSH in body tissues when used in excess were found to enhance the antimalarial action of CQ and AQ in mice infected either with P. berghei or Plasmodium vinckei. In contrast, N-acetyl-cysteine which is expected to increase the cellular levels of GSH, antagonized the action of CQ. These results suggest that some over-the-counter drugs can be used in combination with some antimalarials to which the parasite has become resistant.

Acetylcysteine↗
PubMed2003

Double-drug development against antioxidant enzymes from Plasmodium falciparum.

New drugs against malaria are urgently and continuously needed. Plasmodium parasites are exposed to higher fluxes of reactive oxygen species and need high activities of intracellular antioxidant systems. A most important antioxidative system consists of (di)thiols which are recycled by disulfide reductases (DR), namely both glutathione reductases (GR) of the malarial parasite Plasmodium falciparum and man, and the thioredoxin reductase (TrxR) of P. falciparum. The aim of our interdisciplinary research is to substantiate DR inhibitors as antimalarial agents. Such compounds are active per se but, in addition, they can reverse thiol-based resistance against other drugs in parasites. Reversal of drug resistance by DR inhibitors is currently investigated for the commonly used antimalarial drug chloroquine (CQ). Our recent strategy is based on the synthesis of inhibitors of the glutathione reductases from parasite and host erythrocyte. With the expectation of a synergistic or additive effect, double-headed prodrugs were designed to be directed against two different and essential functions of the malarial parasite P. falciparum, namely glutathione regeneration and heme detoxification. The prodrugs were prepared by linking bioreversibly a GR inhibitor to a 4-aminoquinoline moiety which is known to concentrate in the acidic food vacuole of parasites. Drug-enzyme interaction was correlated with antiparasitic action in vitro on strains resistant towards CQ and in vivo in Plasmodium berghei-infected mice as well as absence of cytotoxicity towards human cells. Because TrxR of P. falciparum was recently shown to be responsible for the residual glutathione disulfide-reducing capacity observed after GR inhibition in P. falciparum, future development of antimalarial drug-candidates that act by perturbing the redox equilibrium of parasites is based on the design of new double-drugs based on TrxR inhibitors as potential antimalarial drug candidates.

Animals↗
PubMed1995

Upregulation of ICAM-1, IL-1 and reactive oxygen intermediates (ROI) by exogenous antigens from Plasmodium falciparum parasites in vitro, and of sICAM-1 in the acute phase of malaria.

After 4 hours of stimulation of human mononuclear leukocytes in the presence of 300 ng/ml exogenous Plasmodium falciparum antigens, the ICAM-1 expression increased variably from 15% to 375%. Simultaneously, an increase of IL-1 mRNA production could be observed in Northern blot hybridizations with a specific cDNA gene probe for human IL-1 alpha labelled with digoxigenin. Furthermore, the reactive oxygen intermediates (ROI) production was also found to be enhanced in similar conditions. Additionally, when the levels of soluble ICAM-1 (sICAM-1) in plasma of 122 patients with P. falciparum or Plasmodium vivax malaria were analyzed in an enzyme immunoassay (EIA), significant sICAM-1 increases were found, more pronounced in patients with P. falciparum malaria, in comparison with healthy controls and with the same patients 4 weeks after chemotherapy. The presented results indicate that the expression of ICAM-1 may also be upregulated by exogenous Plasmodium antigens besides cytokines like IL-1 during the acute phase of malaria, with subsequently elevated sICAM-1 concentrations in blood.

Acute Disease↗
PubMed2003

Quantitative trait loci in Anopheles gambiae controlling the encapsulation response against Plasmodium cynomolgi Ceylon.

BACKGROUND: Anopheles gambiae females are the world's most successful vectors of human malaria. However, a fraction of these mosquitoes is refractory to Plasmodium development. L3-5, a laboratory selected refractory strain, encapsulates transforming ookinetes/early oocysts of a wide variety of Plasmodium species. Previous studies on these mosquitoes showed that one major (Pen1) and two minor (Pen2, Pen3) autosomal dominant quantitative trait loci (QTLs) control the melanotic encapsulation response against P. cynomolgi B, a simian malaria originating in Malaysia. RESULTS: We have investigated the response of L3-5 to infection with P. cynomolgi Ceylon, a different but related parasite species, in crosses with the susceptible strain 4Arr. Refractoriness to this parasite is incompletely recessive. Infection and genotyping of F2 intercross females at genome-spanning microsatellite loci revealed that 3 autosomal QTLs control encapsulation of this species. Two loci map to the regions containing Pen2 and Pen3. The novel QTL maps to chromosome 3R, probably to polytene division 32 or 33. Thus the relative contribution of any QTL to oocyst encapsulation varies with the species of parasite. Further, different QTLs were most readily identified in different F2 families. This, like the F1 data, suggests that L3-5 is not genetically homogeneous and that somewhat different pathways may be used to achieve an encapsulation response. CONCLUSION: We have shown here that different QTLs are involved in responses against different Plasmodium parasites.

Animals↗
PubMed2006

Cloning, expression and functional activity of deoxyhypusine synthase from Plasmodium vivax.

BACKGROUND: Plasmodium vivax is the most widespread human malaria parasite. However, genetic information about its pathogenesis is limited at present, due to the lack of a reproducible in vitro cultivation method. Sequencing of the Plasmodium vivax genome suggested the presence of a homolog of deoxyhypusine synthase (DHS) from P. falciparum, the key regulatory enzyme in the first committed step of hypusine biosynthesis. DHS is involved in cell proliferation, and thus a valuable drug target for the human malaria parasite P. falciparum. A comparison of the enzymatic properties of the DHS enzymes between the benign and severe Plasmodium species should contribute to our understanding of the differences in pathogenicity and phylogeny of both malaria parasites. RESULTS: We describe the cloning of a 1368 bp putative deoxyhypusine synthase gene (dhs) sequence from genomic DNA of P. vivax PEST strain Salvador I (Accession number AJ549098) after touchdown PCR. The corresponding protein was expressed and functionally characterized as deoxyhypusine synthase by determination of its specific activity and cross-reactivity to human DHS on a Western blot. The putative DHS protein from P. vivax displays a FASTA score of 75 relative to DHS from rodent malaria parasite, P. yoelii, and 74 relative to that from the human parasite, P. falciparum strain 3D7. The ORF encoding 456 amino acids was expressed under control of IPTG-inducible T7 promoter, and expressed as a protein of approximately 50 kDa (theoretically 52.7 kDa) in E. coli BL21 DE3 cells. The N-terminal histidine-tagged protein was purified by Nickel-chelate affinity chromatography under denaturing conditions. DHS with a theoretical pI of 6.0 was present in both eluate fractions. The specific enzymatic activity of DHS was determined as 1268 U/mg protein. The inhibitor, N-guanyl-1, 7-diaminoheptane (GC7), suppressed specific activity by 36-fold. Western blot analysis performed with a polyclonal anti-human DHS antibody revealed cross-reactivity to DHS from P. vivax, despite an amino acid identity of 44% between the proteins. CONCLUSION: We identify a novel DHS protein in the more benign malaria parasite,P. vivax, on the basis of specific enzymatic activity, cross-reactivity with a polyclonal antibody against human DHS, and amino acid identity with DHS homologs from the rodent malaria parasite, P. yoelii, and human P. falciparum strains.

Amino Acid Sequence↗
PubMed2004

Anti-Plasmodium activity of ceramide analogs.

BACKGROUND: Sphingolipids are key molecules regulating many essential functions in eukaryotic cells and ceramide plays a central role in sphingolipid metabolism. A sphingolipid metabolism occurs in the intraerythrocytic stages of Plasmodium falciparum and is associated with essential biological processes. It constitutes an attractive and potential target for the development of new antimalarial drugs. METHODS: The anti-Plasmodium activity of a series of ceramide analogs containing different linkages (amide, methylene or thiourea linkages) between the fatty acid part of ceramide and the sphingoid core was investigated in culture and compared to the sphingolipid analog PPMP (d,1-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol). This analog is known to inhibit the parasite sphingomyelin synthase activity and block parasite development by preventing the formation of the tubovesicular network that extends from the parasitophorous vacuole to the red cell membrane and delivers essential extracellular nutrients to the parasite. RESULTS: Analogs containing methylene linkage showed a considerably higher anti-Plasmodium activity (IC50 in the low nanomolar range) than PPMP and their counterparts with a natural amide linkage (IC50 in the micromolar range). The methylene analogs blocked irreversibly P. falciparum development leading to parasite eradication in contrast to PPMP whose effect is cytostatic. A high sensitivity of action towards the parasite was observed when compared to their effect on the human MRC-5 cell growth. The toxicity towards parasites did not correlate with the inhibition by methylene analogs of the parasite sphingomyelin synthase activity and the tubovesicular network formation, indicating that this enzyme is not their primary target. CONCLUSIONS: It has been shown that ceramide analogs were potent inhibitors of P. falciparum growth in culture. Interestingly, the nature of the linkage between the fatty acid part and the sphingoid core considerably influences the antiplasmodial activity and the selectivity of analogs when compared to their cytotoxicity on mammalian cells. By comparison with their inhibitory effect on cancer cell growth, the ceramide analogs might inhibit P. falciparum growth through modulation of the endogenous ceramide level.

Animals↗
PubMed2005

An AFLP-based genetic linkage map of Plasmodium chabaudi chabaudi.

BACKGROUND: Plasmodium chabaudi chabaudi can be considered as a rodent model of human malaria parasites in the genetic analysis of important characters such as drug resistance and immunity. Despite the availability of some genome sequence data, an extensive genetic linkage map is needed for mapping the genes involved in certain traits. METHODS: The inheritance of 672 Amplified Fragment Length Polymorphism (AFLP) markers from two parental clones (AS and AJ) of P. c. chabaudi was determined in 28 independent recombinant progeny clones. These, AFLP markers and 42 previously mapped Restriction Fragment Length Polymorphism (RFLP) markers (used as chromosomal anchors) were organized into linkage groups using Map Manager software. RESULTS: 614 AFLP markers formed linkage groups assigned to 10 of 14 chromosomes, and 12 other linkage groups not assigned to known chromosomes. The genetic length of the genome was estimated to be about 1676 centiMorgans (cM). The mean map unit size was estimated to be 13.7 kb/cM. This was slightly less then previous estimates for the human malaria parasite, Plasmodium falciparum CONCLUSION: The P. c. chabaudi genetic linkage map presented here is the most extensive and highly resolved so far available for this species. It can be used in conjunction with the genome databases of P. c chabaudi, P. falciparum and Plasmodium yoelii to identify genes underlying important phenotypes such as drug resistance and strain-specific immunity.

Alleles↗
PubMed2006

Plasmodium diversity in non-malaria individuals from the Bioko Island in Equatorial Guinea (West Central-Africa).

BACKGROUND: In this paper we analyse the Plasmodium sp. prevalence in three villages with different isolation status on the island of Bioko (Equatorial Guinea) where malaria is a hyper-endemic disease. We also describe the genetic diversity of P. falciparum, using several plasmodia proteins as markers which show a high degree of polymorphism (MSP-1 and MSP-2). The results obtained from three different populations are compared in order to establish the impact of human movements and interventions. METHODS: Plasmodium sp. were analysed in three villages on Bioko Island (Equatorial Guinea), one of which (Southern) is isolated by geographical barriers. The semi-nested multiplex polymerase chain reaction (PCR) technique was used to determine the prevalence of the four human plasmodia species. The genotyping and frequency of P. falciparum populations were determined by PCR assay target polymorphism regions of the merozoite surface proteins 1 and 2 genes (MSP-1 and MSP-2). RESULTS: The data obtained show that there are no differences in plasmodia population flow between the Northwest and Eastern regions as regards the prevalence of the different Plasmodium species. The Southern population, on the other hand, shows a minor presence of P. malariae and a higher prevalence of P. ovale, suggesting some kind of transmission isolated from the other two. The P. falciparum genotyping in the different regions points to a considerable allelic diversity in the parasite population on Bioko Island, although this is somewhat higher in the Southern region than the others. There was a correlation between parasitaemia levels and the age of the individual with the multiplicity of infection (MOI). CONCLUSION: Results could be explained by the selection of particular MSP alleles. This would tend to limit diversity in the parasite population and leading up to the extinction of rare alleles. On the other hand, the parasite population in the isolated village has less outside influence and the diversity of P. falciparum is maintained higher. The knowledge of parasite populations and their relationships is necessary to study their implications for control intervention.

Alleles↗
PubMed2004

Developmental-stage-specific triacylglycerol biosynthesis, degradation and trafficking as lipid bodies in Plasmodium falciparum-infected erythrocytes.

Triacylglycerol (TAG) serves as a major energy storage molecule in eukaryotes. In Plasmodium, however, this established function of TAG appears unlikely, despite detecting previously considerable amount of TAG associated with intraerythrocytic parasites, because plasmodial cells have very little capacity to oxidize fatty acids. Thus, it is plausible that TAG and its biosynthesis in Plasmodium have other functions. As a first step in understanding the biological significance of TAG and its biosynthesis to the intraerythrocytic proliferation of Plasmodium falciparum, we performed detailed characterization of TAG metabolism and trafficking in parasitized erythrocyte. Metabolic labeling using radiolabeled-oleic and palmitic acids in association with serum albumin, which have been shown to be among the serum essential factors for intraerythrocytic proliferation of P. falciparum, revealed that accumulation of TAG was strikingly pronounced from trophozoite to schizont, whereas TAG degradation became active from schizont to segmented schizont; the consequent products, free fatty acids, were released into the medium during schizont rupture and/or merozoite release. These results were further supported by visualization of lipid bodies through immunofluorescence and electron microscopy. At the schizont stages, there is some evidence that the lipid bodies are partly localized in the parasitophorous vacuole. Interestingly, the discrete formation and/or trafficking of lipid bodies are inhibited by brefeldin A and trifluoperazine. Inhibition by trifluoperazine hints at least that a de novo TAG biosynthetic pathway via phosphatidic acid contributes to lipid body formation. Indeed, biochemical analysis reveals a higher activity of acyl-CoA:diacylglycerol acyltransferase, the principal enzyme in the sn-glycerol-3-phosphate pathway for TAG synthesis, at trophozoite and schizont stages. Together, these results establish that TAG metabolism and trafficking in P. falciparum-infected erythrocyte occurs in a stage-specific manner during the intraerythrocytic cycle and we propose that these unique and dynamic cellular events participate during schizont rupture and/or merozoite release.

Animals↗
PubMed2003

Rheumatoid factor-like IgM in Plasmodium berghei (Apicomplexa: Haemosporida) infections of BALB/c mice.

Groups of female BALB/c mice infected by intravenous injection with 50 erythrocytes containing Plasmodium berghei Vincke et Lips, 1948 were sacrificed on days 3 through 12 after infection. Rheumatoid factor-like IgM (RF-IgM) and parasite-specific IgG levels were determined by enzyme-linked immunosorbent assay in serum specimens and in culture medium removed from spleen cell cultures established at sacrifice. All four mouse IgG subisotypes were recognized by RF-IgM molecules induced by Plasmodium berghei infection, and in this regard, the parasite-induced RF-IgM response resembled that induced by lipopolysaccharide polyclonal activation. Plasmodium berghei infection resulted in a biphasic RF-IgM response, with infected animals demonstrating significantly increased levels of RF-IgM early in the infection and significantly decreased levels late in the infection, compared to uninfected control mice. The decreased levels of RF-IgM observed late in infection correlated with increasing parasitaemia levels, and were primarily due to a decrease in RF-IgM specific for mouse IgG2a. Late infection levels of RF-IgM specific for IgGI, IgG2b, and IgG3 were not significantly different from those of control animals.

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↗
PubMed2006

Studies in a co-infection murine model of Plasmodium chabaudi chabaudi and Leishmania infantum: interferon-gamma and interleukin-4 mRNA expression.

This work aimed to study the T helper type 1/2 (Th1/Th2) cytokine profile in a co-infection murine model of Plasmodium chabaudi chabaudi and Leishmania infantum. Expression of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) was analyzed, in spleen and liver of C57BL/6 mice, by reverse transcriptase-polymerase chain reaction. High levels of IFN-gamma expression did not prevent the progression of Leishmania in co-infected mice and Leishmania infection did not interfere with the Th1/Th2 switch necessary for Plasmodium control. The presence of IL-4 at day 28 in co-infected mice, essential for Plasmodium elimination, was probably a key factor on the exacerbation of the Leishmania infection.

Animals↗
PubMed2003

Interruption of the blood-stage cycle of the malaria parasite, Plasmodium chabaudi, by protein tyrosine kinase inhibitors.

Malaria is a devastating disease caused by a unicellular protozoan, Plasmodium, which affects 3.7 million people every year. Resistance of the parasite to classical treatments such as chloroquine requires the development of new drugs. To gain insight into the mechanisms that control Plasmodium cell cycle, we have examined the effects of kinase inhibitors on the blood-stage cycle of the rodent malaria parasite, Plasmodium chabaudi. In vitro incubation of red blood cells for 17 h at 37 degrees C with the inhibitors led to a decrease in the percent of infected cells, compared to control treatment, as follows: genistein (200 microM - 75%), staurosporine (1 microM - 58%), R03 (1 microM - 75%), and tyrphostins B44 (100 microM - 66%) and B46 (100 microM - 68%). All these treatments were shown to retard or prevent maturation of the intraerythrocytic parasites. The diverse concentration ranges at which these inhibitors exert their effects give a clue as to the types of signals that initiate the transitions between the different developmental stages of the parasite. The present data support our hypothesis that the maturation of the intraerythrocytic cycle of malaria parasites requires phosphorylation. In this respect, we have recently reported a high Ca2+ microenvironment surrounding the parasite within red blood cells. Several kinase activities are modulated by Ca2+. The molecular identification of the targets of these kinases could provide new strategies against malaria.

Animals↗
PubMed2006

Plasmodium development in white-eye (kh(w)) and transformed strains (kh43) of Aedes aegypti (Diptera: Culicidae).

Xanthurenic acid (XA) has been implicated as an inducer in vivo of exflagellation in Plasmodium spp. Consequently, the development of Plasmodium gallinaceum was assessed in a white-eye mosquito strain, kh(w), of Aedes aegypti (L.), which is deficient in XA because of a mutation of the gene encoding the enzyme kynurenine hydroxylase, and in a transformed line of kh(w) mosquitoes that carry the wild-type cn+ gene of Drosophila melanogaster Meigen and express a functional enzyme necessary for XA production. Although XA was not detectable in kh(w) mosquitoes by using high-pressure liquid chromatography with electrochemical detection, parasites were able to develop. Transformed kh(w) mosquitoes failed to consistently support parasite development at higher prevalences and mean intensities than did the nontransformed kh(w) lines, even though XA was detectable. These data suggest that factors other than XA may play a role in initiating Plasmodium development in vivo.

Aedes↗