EHP Malaria Bulletin: May 21-31, 2001

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Br J Haematol 2001 May;113(2):492-9

Growth of Plasmodium falciparum induces stage-dependent haemichrome formation, oxidative aggregation of band 3, membrane deposition of complement and antibodies, and phagocytosis of parasitized erythrocytes.
Giribaldi G, Ulliers D, Mannu F, Arese P, Turrini F.
Department of Genetics, Biology and Biochemistry, University of Torino Medical School, Torino, Italy.

Plasmodium falciparum-parasitized erythrocytes (RBCs) are progressively transformed into non-self cells, phagocytosed by human monocytes. Haemichromes, aggregated band 3 (Bd3) and membrane-bound complement fragment C3c and IgG were assayed in serum-opsonized stage-separated parasitized RBCs. All parameters progressed from control to rings to trophozoites to schizonts: haemichromes, nil; 0.64 0.12; 5.6 1.91; 8.4 2.8 (nmol/ml membrane); Bd3, 1 0.1; 4.3 1.5; 23 5; 25 6 (percentage aggregated); C3c, 31 11; 223 86; 446 157; 620 120 (mOD405/min/ml membrane); IgG, 35 12; 65 23; 436 127; 590 196 (mOD405/min/ml membrane). All increments in rings versus controls and in trophozoites versus rings were highly significant. Parasite development in the presence of 100 &mgr;mol/l beta-mercaptoethanol largely reverted haemichrome formation, Bd3 aggregation, C3c and IgG deposition and phagocytosis. Membrane proteins extracted by detergent C12E8 were separated on Sepharose CL-6B. Haemichromes, C3c and IgG were present exclusively in the high-molecular-weight fractions together with approximately 30% of Bd3, indicating the oxidative formation of immunogenic Bd3 aggregates. Immunoblots of separated membrane proteins with anti-Bd3 antibodies confirmed Bd3 aggregates that, in part, did not enter the gel. Immunoprecipitated antibodies eluted from trophozoites reacted preferentially with aggregated Bd3. Changes in parasitized RBC membranes and induction of phagocytosis were similar to oxidatively damaged, senescent or thalassaemic RBC, indicating that parasite-induced oxidative modifications of Bd3 were per se sufficient to induce and enhance phagocytosis of malaria-parasitized RBC.
PMID: 11380422 [PubMed – in process]

Br J Haematol 2001 May;113(2):486-91

Oxidative stress and erythrocyte damage in Kenyan children with severe Plasmodium falciparum malaria.Griffiths MJ, Ndungu F, Baird KL, Muller DP, Marsh K, Newton CR.
Institute of Child Health, University College London, London, UK, and KEMRI/Wellcome Trust collaborative programme, KEMRI Centre for Geographical Medicine Research Coast, Kilifi, Kenya.

Anaemia causes significant morbidity in children with Plasmodium falciparum malaria, but the mechanism(s) are unclear. During malarial infection, increased reactive oxygen species (ROS) are generated that may contribute to erythrocyte damage and anaemia. This study measured the concentrations of alpha-tocopherol in plasma and erythrocyte membranes, and the percentage polyunsaturated fatty acid composition (%PUFA) (an indirect marker of ROS damage) in erythrocyte membranes in children with severe P. falciparum malaria from Kilifi, Kenya, and asymptomatic children from the same district. Malarial subjects were stratified into complicated malaria and malaria anaemia. Results demonstrated significant reductions in erythrocyte membrane alpha-tocopherol concentration (1.63 0.16 versus 3.38 0.18 &mgr;mol/mg protein; P < 0.001) and total %PUFA (30.7 0.49 versus 32.8 0.44% P < 0.005) for the malarial subjects (non-stratified) compared with controls. Malarial subjects showed a significant positive correlation between membrane alpha-tocopherol and haemoglobin concentrations (P < 0.005 r = 0.63 complicated malaria group; P < 0.05 r = 0.36 non-stratified data). There were no significant differences in plasma alpha-tocopherol concentration between malaria patients and controls. In conclusion, malarial infection may be associated with oxidative damage and reduced alpha-tocopherol reserve in the erythrocyte membrane, suggesting that local antioxidant depletion may contribute to erythrocyte loss in severe malaria. Erythrocyte membrane alpha-tocopherol appeared a better indicator of ROS exposure than plasma.
PMID: 11380421 [PubMed – in process]

J Ethnopharmacol 2001 Jun;76(1):99-103

Antiplasmodial activities of some Ghanaian plants traditionally used for fever/malaria treatment and of some alkaloids isolated from Pleiocarpa mutica; in vivo antimalarial activity of pleiocarpine.
Addae-Kyereme J, Croft SL, Kendrick H, Wright CW.

The School of Pharmacy, University of Bradford, BD7 1DP, West Yorkshire, UK

Fourteen Ghanaian plants used in folk medicine to treat fever/malaria were screened for activity against Plasmodium falciparum (strain K1) and were tested for general toxicity to the brine shrimp. Extracts from three of the plants, Pleiocarpa mutica, Cleistopholis patens and Uvaria chamae were found to have significant antiplasmodial activity. The extract of U. chamae was toxic to brine shrimps. These findings lend support to the use of these plants in traditional medicine. Possible toxicity due to U. chamae is a cause for concern. Five known alkaloids, pleiocarpine (1), kopsinine (2), pleiocarpamine (3), eburnamine (4) and pleiomutinine (5) were isolated from the roots of P. mutica. This is the first report of the occurrence of (4) in P. mutica. Compound (5) was the most active against P. falciparum (IC(50)=5 &mgr;M). Although (1) was inactive against malaria parasites in vitro, it was moderately active against P. berghei in mice (25 mg kg(-1) daily for 4 days reduced parasitaemia by 28.5% compared to untreated controls).PMID: 11378289 [PubMed – in process]

Mol Biochem Parasitol 2001 May;114(2):227-37

Multiple var gene transcripts are expressed in Plasmodium falciparum infected erythrocytes selected for adhesion.Noviyanti R, Brown GV, Wickham ME, Duffy MF, Cowman AF, Reeder JC.
Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Melbourne, Australia

Adherence of Plasmodium falciparum-infected erythrocytes to the post-capillary endothelium is an important characteristic of malaria infection. The adhesion is mediated predominantly by P. falciparum Erythrocyte Membrane Protein-1 (PfEMP1), a clonally variant protein expressed on the surface of infected red blood cells that appears to be a target of protective immunity. A multi-membered var gene family encodes PfEMP1 and switching expression of different var genes conveys different antigenic and adhesive properties to infected red blood cells. Knowledge about transcriptional control of phenotypic expression, or the mechanisms that allow multiple binding specificities, is very limited. Here, we describe a series of phenotypic selection experiments, which resulted in the expression of different PfEMP1 and the detection of multiple full-length var gene transcripts in the mature trophozoite stage. However, a dominant form of PfEMP1 appeared to be expressed, which suggested that most var transcripts do not lead to a surface expressed PfEMP1 molecule. Parasites bound to specific receptors still expressed multiple full-length var genes and mature trophozoites selected for increased adhesion to a specific receptor retained the ability to bind to multiple receptors. Our findings suggest that a defined adhesive phenotype can be associated with expression of multiple var genes.
PMID: 11378202 [PubMed – in process]

Mol Biochem Parasitol 2001 May;114(2):217-26

Merozoite surface protein 8 of Plasmodium falciparum contains two epidermal growth factor-like domains.Black CG, Wu T, Wang L, Hibbs AR, Coppel RL.
Department of Microbiology, PO Box 53, Monash University, 3800, Victoria, Australia

By motif searching of the unfinished sequences in the Malaria Genome Sequencing Project databases we have identified a novel EGF-like domain-containing protein of Plasmodium falciparum. The sequence lies within a single open reading frame of 1791 bp and is predicted to encode a polypeptide of 597 amino acids. There are hydrophobic regions at the extreme N- and C-termini, which could represent secretory signal peptide and GPI attachment sites, respectively. Similar to MSP1, there are two EGF-like domains located near the C-terminus. RT-PCR analysis of the novel gene shows that it is transcribed in asexual stages of the malaria parasite. We have expressed portions of the protein as recombinant GST fusions in Escherichia coli and raised antisera in rabbits. Antibodies to the EGF-like domains of the novel protein are highly specific and do not cross-react with the EGF-like domains of MSP1, MSP4 or MSP5 expressed as GST fusion proteins. Antiserum raised to the most C-terminal region of the protein reacts with four bands of 98, 50, 25 and 19 kDa in P. falciparum parasite lysates whereas antisera to the N-terminal fusion proteins recognise the 98 and 50 kDa bands, suggesting that the novel protein may undergo processing in a similar way to MSP1. Immunoblot analysis of stage-specific parasite samples reveals that the protein is present throughout the parasite asexual life cycle and in isolated merozoites, with the smaller fragments present in ring stage parasites. The protein partitions in the detergent-enriched phase after Triton X-114 fractionation and is localized to the surfaces of trophozoites, schizonts and free merozoites by indirect immunofluorescence. Antisera to the C-terminus stain the surface of rings, whereas antisera to the N-terminus do not, suggesting that a fragment of the protein is carried into the developing ring stage parasite. Based on the accepted nomenclature in the field we designate this protein MSP8. We have shown that the MSP8 fusion proteins are in a conformation that can be recognised by human immune sera and that there is very limited diversity in the MSP8 gene sequences from various P. falciparum laboratory isolates. MSP8 shows significant similarity to the recently reported sequence of the protective P. yoelii merozoite surface protein pypAg-2 [Burns JM, Belk CC, Dunn PD. Infect Immun 2000;68:6189-95.] suggesting that the two proteins are homologues. Taken together, these findings suggest that MSP8/pypAg-2 may play an important role in the process of red cell invasion and is a potential malaria vaccine candidate.
PMID: 11378201 [PubMed – in process]

Mol Biochem Parasitol 2001 May;114(2):197-208

Distribution and characterisation of the 235 kDa rhoptry multigene family within the genomes of virulent and avirulent lines of Plasmodium yoelii.Khan SM, Jarra W, Bayele H, Preiser PR.
Division of Parasitology, The National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, London, UK

In the rodent malaria species, Plasmodium yoelii, a multi-gene family (Py235) encodes a 235 kDa rhoptry protein. This protein is believed to be involved in merozoite attachment and invasion of red blood cells. Only two members of Py235 have been sequenced so far. Using genomic DNA from the virulent P. yoelii YM line we have PCR amplified additional members of this gene family. These >8 kb full length clones have been cloned and sequenced. Based on differences within the tri-amino acid repeat structure at the C-terminal end of the Py235 protein, it has been possible to divide the multi-gene family into subtypes. The protein translations of five full-length genes (representing four different subtypes) were compared. While there was a high level of amino acid identity at the C-terminal end of these proteins, the N-terminal region revealed a great deal of sequence diversity. Critically, certain residues appeared to be conserved notably seven out of eight cysteines. Comparison of two full-length genes of a particular sub-type shows >99% amino acid identity at the protein level, implying that very closely related genes exist within the parasite genome. We have used this new sequence information to compare the distribution of Py235 in the virulent YM and avirulent 17X lines of P. yoelii. Our results indicate that while the overall distribution of Py235 genes is broadly conserved between the two lines, significant differences exist when individual subtypes are compared.
PMID: 11378199 [PubMed – in process]

 Mol Biochem Parasitol 2001 May;114(2):183-95

Two classes of plant-like vacuolar-type H()-pyrophosphatases in malaria parasites.McIntosh MT, Drozdowicz YM, Laroiya K, Rea PA, Vaidya AB.
Department of Microbiology and Immunology, MCP Hahnemann University, 2900 Queen Lane, 19129, Philadelphia, PA, USA

In plants, cytosolic inorganic pyrophosphate (PP(i)) is hydrolyzed by energy-conserving vacuolar-type H()-pyrophosphatases (V-PPases) that harness the free energy of PP(i) hydrolysis to establish transmembrane H() gradients. Here we describe the identification and cloning of two genes, PfVP1 and PfVP2, from the malaria parasite Plasmodium falciparum. Inferred to encode type I (K()-dependent) and type II (K()-independent) V-PPases, respectively, PfVP1 and PfVP2 appeared more sequence divergent from each other than from their type I and type II counterparts in plants. The steady state levels of PfVP1 mRNA were high in comparison to PfVP2 mRNA throughout the erythrocytic phases of infection. Western analyses of trophozoite membranes using generic V-PPase antibodies (PAB(HK) and PAB(TK)) demonstrated appreciable amounts of a Mr 67000 polypeptide whose associated aminomethylenediphosphonate- (AMDP) inhibitable PPase activity was markedly stimulated by K(). Immunofluorescence microscopy of infected erythrocytes revealed PfVP antigen associated with both the parasite plasma membrane and punctate intracellular inclusions. Transient transfection of a PfVP1-GFP fusion further supported the localization of PfVP1 to the parasite plasma membrane. Based on these findings and the growth-retarding effects of AMDP, P. falciparum is concluded to possess both type I and type II V-PPases of which the former has the greatest potential for contributing to the establishment of H() gradients across the parasite plasma membrane under conditions of energy limitation.
PMID: 11378198 [PubMed – in process]

Trends Parasitol 2001 Jun;17(6):292-6

Chemokines in host-protozoan-parasite interactions.Brenier-Pinchart M, Pelloux H, Derouich-Guergour D, Ambroise-Thomas P.
Interactions Cellulaires Parasite-Hote, CNRS-ER2014, Faculte de Medecine, Universite J. Fourier, Domaine de la Merci, 38706 La, Tronche, France

Here, we review the interactions between parasites and chemokines and chemokine receptors in toxoplasmosis, trypanosomiasis, leishmaniasis, malaria and other diseases caused by protozoan parasites. The potential roles of chemokines after infection by these intracellular pathogens include host defence functions such as leukocyte recruitment, participation in cell-mediated immunity and antiprotozoal activity. However, these interactions can also help the parasite in, for example, the penetration of host cells.
PMID: 11378037 [PubMed – in process]

Trends Parasitol 2001 Jun;17(6):269-72

Plasmodium ookinete-secreted chitinase and parasite penetration of the mosquito peritrophic matrix.Langer RC, Vinetz JM.
WHO Collaborating Center for Tropical Diseases, University of Texas Medical Branch, Keiller 2.138, 301 University Blvd, 77555-0609, Galveston, TX, USA

Malaria transmission-blocking strategies aimed at disrupting parasite-mosquito interactions have the potential to make important contributions to global malaria control. It has been suggested that Plasmodium-secreted chitinase plays a crucial role in allowing the ookinete to initiate its invasion of the mosquito midgut, which suggests that this enzyme is a candidate target for blocking malaria transmission. In this review, the authors discuss Plasmodium chitinases from the molecular, biochemical and cell biology viewpoints. Future directions of study could involve developing strategies for interrupting the function of Plasmodium chitinases within the mosquito midgut, including transmission-blocking drugs or vaccines, or the development of chitinase-inhibitor-producing transgenic mosquitoes.
PMID: 11378031 [PubMed – in process]

Trends Parasitol 2001 Jun;17(6):253-4

Case-control studies on host factors in severe malaria.Nacher M, Singhasivanon P, Gay F, Silachamroon U, Looareesuwan S.
Unite INSERM U511, Immunobiologie Cellulaire et Moleculaire des Infections Parasitaires, Faculte de Medecine Pitie-Salpetriere, 91 Boulevard de l’Hopital, 75634, Cedex 13, Paris, France

Although molecular biology has illustrated the phenotypic heterogeneity of Plasmodium falciparum, there are still no specific markers of virulence. As parasite virulence is an important determinant of severe malaria, the choice of comparison groups in the study of host factors influencing severity is a delicate issue. Ignoring parasite factors in the selection of controls potentially leads to biased comparisons between a majority of cases with virulent parasites and a majority of controls with non-virulent parasites. This article discusses how to avoid this virulence bias in the absence of specific markers of virulence.
PMID: 11378013 [PubMed – in process]

Mol Biochem Parasitol 2001 Jun;115(1):77-86

Histidine-rich protein 2 of the malaria parasite, Plasmodium falciparum, is involved in detoxification of the by-products of haemoglobin degradation.Papalexis V, Siomos M, Campanale N, Guo X, Kocak G, Foley M, Tilley L.
Department of Biochemistry, La Trobe University, Bundoora, 3083, Victoria, Australia

The histidine-rich protein 2 (PfHRP2) of Plasmodium falciparum has been implicated in the detoxification of ferriprotoporphyrin IX (FP) moieties that are produced as by-products of the digestion of haemoglobin. In this work, we have used a spectroscopic analysis to confirm that recombinant PfHRP2 binds FP. A monoclonal antibody that recognises both recombinant and authentic PfHRP2 was used in immunofluorescence microscopy studies. We found that PfHRP2 is mainly located in the erythrocyte cytosol of infected erythrocytes, however, dual labelling studies suggest that the location of a sub-population of the PfHRP2 molecules overlaps with that of the food vacuole-associated protein, P-glycoprotein homologue (Pgh-1). A semi-quantitative analysis of the level of PfHRP2 in infected erythrocytes suggests a concentration of a few micromolar in the food vacuole. Under conditions designed to mimic the parasite food vacuole, we found that 1.2 &mgr;M PfHRP2 is sufficient to catalyse the conversion of about 30% of a 100 &mgr;M sample of FP to beta-haematin within 24 h. Moreover, PfHRP2 is capable of promoting the H(2)O(2)-induced degradation of FP at pH 5.2. PfHRP2 also efficiently enhances the ability of FP to catalyse the H(2)O(2)-mediated oxidation of the model co-factor, ortho-phenylene diamine (OPD). These data suggest that PfHRP2 may promote the detoxification of FP and reactive oxygen species within the food vacuole. By contrast, PfHRP2 inhibits the destruction of FP by glutathione (GSH) at pH 7.4. This suggests that PfHRP2 is not a catalyst of FP degradation outside the food vacuole.
PMID: 11377742 [PubMed – in process]

Mol Biochem Parasitol 2001 Jun;115(1):29-39

Characterization of a novel serine/threonine protein phosphatase (PfPPJ) from the malaria parasite, Plasmodium falciparum.Dobson S, Bracchi V, Chakrabarti D, Barik S.
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, 307 University Blvd., 36688, Mobile, AL, USA

A novel protein phosphatase cDNA of the PPP superfamily was identified from the malaria parasite, Plasmodium falciparum (Pf), and tentatively named PfPPJ. The predicted primary structure of the phosphatase contained all the known conserved motifs of the PPP superfamily essential for catalytic activity. The enzyme was specific for dephosphorylation of phosphoserine and phosphothreonine residues with very little activity against phosphotyrosine residues. However, the sequence at its C-terminal end was unique, and was consistent with its resistance to the classical PP2A-specific inhibitors such as okadaic acid and microcystin-LR, and the PP1-specific inhibitor, mammalian heat-stable inhibitor-2 (I-2). Even the catalytic core of PfPPJ had a sequence substantially different from the other PPPs such that PfPPJ could be placed in an apparently separate phylogenetic branch. At 294 amino acids residues, PfPPJ was one of the smallest okadaic acid-resistant PPP phosphatases known. By Northern blot analysis, the expression of the PfPPJ mRNA showed the following pattern: schizont>ring>trophozoite, which closely paralleled the expression of the protein, as determined by immunofluorescence. Together, these results suggested a parasitic stage-specific transcriptional regulation of this novel and potentially unique protozoan phosphatase.
PMID: 11377737 [PubMed – in process]

Lancet 2001 May 12;357(9267):1502-3

A non-sense mutation in Cd36 gene is associated with protection from severe malaria.Pain A, Urban BC, Kai O, Casals-Pascual C, Shafi J, Marsh K, Roberts DJ.
We sought genetic evidence for the importance of host-parasite interactions involving CD36 in severe malaria. We identified a non-sense mutation in Cd36 gene and looked at the influence of this mutation on the outcome of malaria infection in 693 African children with severe malaria and a similar number of ethnically matched controls. We showed that heterozygosity for this mutation is associated with protection from severe disease (OR 0.74, 95% CI 0.55-0.99; p=0.036). These findings suggest that this Cd36 mutation might have a complex effect on malaria infection by decreasing parasite sequestration, and also by decreasing host immune responses.
PMID: 11377606 [PubMed – in process]

 Lancet 2001 May 12;357(9267):1471-7

Intermittent treatment for malaria and anaemia control at time of routine vaccinations in Tanzanian infants: a randomised, placebo-controlled trial.Schellenberg D, Menendez C, Kahigwa E, Aponte J, Vidal J, Tanner M, Mshinda H, Alonso P.
Unidad de Epidemiologia, Hospital Clinic, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Villarroel 170, 08036, Barcelona, Spain.

BACKGROUND: Clinical malaria and severe anaemia are major causes of paediatric hospital admission and death in many malaria-endemic settings. In the absence of an effective and affordable vaccine, control programmes continue to rely on case management while attempting the large-scale deployment of insecticide-treated nets. We did a randomised, placebo-controlled trial to assess the efficacy and safety of intermittent sulphadoxine-pyrimethamine treatment on the rate of malaria and severe anaemia in infants in a rural area of Tanzania. METHODS: We randomly assigned 701 children living in Ifakara, southern Tanzania, sulphadoxine-pyrimethamine or placebo at 2, 3, and 9 months of age. All children received iron supplementation between 2 and 6 months of age. The intervention was given alongside routine vaccinations delivered through WHO’s Expanded Program on Immunisation (EPI). The primary outcome measures were first or only episode of clinical malaria, and severe anaemia in the period from recruitment to 1 year of age. Morbidity monitoring through a hospital-based passive case-detection system was complemented by cross-sectional surveys at 12 and 18 months of age. Results were expressed in terms of protective efficacy (100 [1-hazard ratio]%) and analysis was by intention to treat. FINDINGS: 40 children dropped out (16 died, 11 migrated, 12 parents withdrew consent, and one for other reasons). Intermittent sulphadoxine-pyrimethamine treatment was well tolerated and no drug-attributable adverse events were recorded. During the first year of life, the rate of clinical malaria (events per person-year at risk) was 0.15 in the sulphadoxine-pyrimethamine group versus 0.36 in the placebo group (protective efficacy 59% [95% CI 41-72]), and the rate of severe anaemia was 0.06 in the sulphadoxine-pyrimethamine group versus 0.11 in the placebo group (50% [8-73]). Serological responses to EPI vaccines were not affected by the intervention. INTERPRETATION: This new approach to malaria control reduced the rate of clinical malaria and severe anaemia by delivering an available and affordable drug through the existing EPI system. Data are urgently needed to assess the potential cost-effectiveness of intermittent treatment in areas with different patterns of malaria endemicity.
PMID: 11377597 [PubMed – in process]

J Biol Chem 2001 May 25; [epub ahead of print]

Luciferase when fused to an N-terminal signal peptide is secreted from transfected Plasmodium falciparum and transported to the cytosol of infected erythrocytes.Burghaus PA, Lingelbach K.
FB Biologie/Zoologie, Abt. Parasitologie, Philipps Universitaet Marburg, Marburg 35032.

Plasmodium falciparum, a unicellular parasite that causes human malaria infects erythrocytes where it develops within a vacuole. The vacuolar membrane separates the parasite from the erythrocyte cytosol. Some secreted parasite proteins remain inside the vacuole and others are transported across the vacuolar membrane. To identify protein sequences responsible for this distribution we investigated the suitability of the green fluorescent protein (GFP)1 and of luciferase as reporters in transiently transfected parasites. Owing to the higher sensitivity of the enzymatic assay, luciferase was quantified 3 days after transfection, whereas reliable detection of GFP required prolonged drug selection. Luciferase was confined to the parasite cytosol in subcellular fractions of infected erythrocytes. When parasites were transfected with a hybrid gene coding for the cleavable N-terminal signal peptide of a secreted parasite protein fused to luciferase, the reporter protein was secreted. It was recovered with the vacuolar content and with the erythrocyte cytosol. The results suggest that no specific protein sequences are required for translocation across the vacuolar membrane. The high local concentration of luciferase within the vacuole argues against free diffusion and thus, transport into the erythrocyte cytosol must involve a rate limiting step.
PMID: 11375978 [PubMed – as supplied by publisher]

J Med Entomol 2001 May;38(3):451-4

Use of circumsporozoite protein enzyme-linked immunosorbent assay compared with microscopic examination of salivary glands for calculation of malaria infectivity rates in mosquitoes (Diptera: Culicidae) from Cameroon.
Fontenille D, Meunier JY, Nkondjio CA, Tchuinkam T.

Organisation de Coordination pour la Lutte Contre les Endemies en Afrique Centrale, Yaounde, Cameroon.

A survey in Cameroon compared the usefulness of the circumsporozoite protein enzyme-linked immunosorbent assay (CSP ELISA) to dissection and microscopic examination of anopheline salivary glands for measuring infectivity rates in anopheline mosquitoes. The salivary glands of 375 females, belonging to four species were examined for sporozoites. After microscopic examination, the glands as well as all the remaining heads and thoraces were tested by ELISA. The sensitivity of ELISA was 100% (18/18), confidence interval (CI) (78.1-100) and the specificity was 99.7% (357/358), CI (98.2 100). The Kappa value, agreement between examination of the glands and salivary gland ELISA, was 0.97. The head thorax CSP ELISA overestimated the true salivary gland infection rate by 12.0%. The results obtained in Central Africa in a village with perennial transmission highly justified the use of the ELISA for measuring the entomological inoculation rate.
PMID: 11372973 [PubMed – in process]

J Med Entomol 2001 May;38(3):388-92

Anopheline mosquito survival strategies during the dry period in western Kenya.Minakawa N, Githure JI, Beier JC, Yan G.
Department of Biological Sciences, State University of New York at Buffalo, 14260, USA.

The dry season survival mechanism of Anopheles gambiae Giles is one of the most vexing deficiencies in our understanding of the biology of the major malaria vectors. In this study, we examined the dynamics of anopheline adult mosquitoes, their larval habitats, and egg survival potential during the dry season in the basin region of Lake Victoria, western Kenya. Through field surveys, we demonstrated two survival strategies of An. gambiae sensu stricto during the dry season: continuous reproduction throughout the year and embryo dormancy in moist soil for at least several days. We further demonstrated that An. gambiae shows a strong preference for moist soil as an oviposition substrate rather than dry soil substrate under the insectary conditions. The observation that anopheline eggs remain a dormant stage to resist desiccation clearly contrasts the conventional wisdom that anopheline eggs hatch shortly after they are laid. Our results from western Kenya are consistent with the suggestion that anopheline mosquitoes do not necessarily suffer a severe population bottleneck during the dry season and thus maintain a large effective population size.
PMID: 11372963 [PubMed – in process]

J Biol Chem 2001 May 22; [epub ahead of print]

Stage-dependent localization of a novel gene product of the malaria parasite, Plasmodium falciparum.Nguyen TV, Fujioka H, Kang AS, Rogers WO, Fidock DA, James AA.
Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900.

A novel Plasmodium falciparum gene, MB2, was identified by screening a sporozoite cDNA library with the serum of a human volunteer protected experimentally by the bites of P. falciparum-infected and irradiated mosquitoes. The single-exon, single-copy MB2 gene is predicted to encode a protein with an Mr of 187,000. The MB2 protein has an amino-terminal basic domain, a central acidic domain and a carboxyl-terminal domain with similarity to the GTP-binding domain of the prokaryotic translation initiation factor 2. MB2 is expressed in sporozoites, the liver and blood-stage parasites and gametocytes. The MB2 protein is distributed as a ~120 kDa1 moiety on the surface of sporozoites and is imported into the nucleus of blood-stage parasites as a ~66 kDa species. Proteolytic processing is favored as the mechanism regulating the distinct subcellular localization of the MB2 protein. This differential localization provides multiple opportunities to exploit the MB2 gene product as a vaccine or therapeutic target.
PMID: 11371568 [PubMed – as supplied by publisher]

Protein Sci 2001 Jun;10(6):1150-1159

Structure of a malaria parasite antigenic determinant displayed on filamentous bacteriophage determined by NMR spectroscopy: Implications for the structure of continuous peptide epitopes of proteins.Monette M, Opella SJ, Greenwood J, Willis AE, Perham RN.
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, England, UK.

The NANP repeating sequence of the circumsporozoite protein of Plasmodium falciparum was displayed on the surface of fd filamentous bacteriophage as a 12-residue insert (NANP)(3) in the N-terminal region of the major coat protein (pVIII). The structure of the epitope determined by multidimensional solution NMR spectroscopy of the modified pVIII protein in lipid micelles was shown to be a twofold repeat of an extended and non-hydrogen-bonded loop based on the sequence NPNA, demonstrating that the repeating sequence is NPNA, not NANP. Further, high resolution solid-state NMR spectra of intact hybrid virions containing the modified pVIII proteins demonstrate that the peptides displayed on the surface of the virion adopt a single, stable conformation; this is consistent with their pronounced immunogenicity as well as their ability to mimic the antigenicity of their native parent proteins.
PMID: 11369853 [PubMed – as supplied by publisher]

Microbes Infect 2001 Apr;3(5):363-7

Antibodies specific for heat shock proteins in human and murine malaria.Zhang M, Hisaeda H, Kano S, Matsumoto Y, Hao Y, Looaresuwan S, Aikawa M, Himeno K.
Department of Parasitology and Immunology, The University of Tokushima School of Medicine, Kuramoto-cho, 770-8503, Tokushima, Japan

Heat shock proteins (HSPs) are immunodominant antigens recognized by the host immune system in various infectious diseases. We analyzed HSP-specific antibodies, including immunoglobulin G (IgG), IgM and IgA, in sera from malaria patients in Thailand by using an enzyme-linked immunosorbent assay. All of the antibodies to HSP90 were remarkably increased in the patients compared with those in controls, while only IgM to HSP70 or IgA to HSP65 was significantly elevated. Further experiments showed that anti-HSP IgG was significantly increased in C57BL/6 mice infected with a non-lethal strain of Plasmodium yoelii, with anti-HSP90 IgG being the most elevated. These results suggest that the antigenic potential of HSP90 is higher than those of HSP70 and HSP65 in malaria infection.
PMID: 11369272 [PubMed – in process]

Pharmacogenomics 2001 May;2(2):137-42

Functional genomic technologies applied to the control of the human malaria parasite, Plasmodium falciparum.Carucci DJ.
Malaria Program, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.

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 [1]. 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.
PMID: 11368752 [PubMed – in process]

Nucleic Acids Res 2001 May 15;29(10):2059-68

Interspecies conservation of gene order and intron-exon structure in a genomic locus of high gene density and complexity in Plasmodium.van Lin LH, Pace T, Janse CJ, Birago C, Ramesar J, Picci L, Ponzi M, Waters AP.
Department of Parasitology, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands and Laboratorio di Biologia Cellulare, Istituto Superiore di Sanita, Rome, Italy.

A 13.6 kb contig of chromosome 5 of Plasmodium berghei, a rodent malaria parasite, has been sequenced and analysed for its coding potential. Assembly and comparison of this genomic locus with the orthologous locus on chromosome 10 of the human malaria Plasmodium falciparum revealed an unexpectedly high level of conservation of the gene organisation and complexity, only partially predicted by current gene-finder algorithms. Adjacent putative genes, transcribed from complementary strands, overlap in their untranslated regions, introns and exons, resulting in a tight clustering of both regulatory and coding sequences, which is unprecedented for genome organisation of PLASMODIUM: In total, six putative genes were identified, three of which are transcribed in gametocytes, the precursor cells of gametes. At least in the case of two multiple exon genes, alternative splicing and alternative transcription initiation sites contribute to a flexible use of the dense information content of this locus. The data of the small sample presented here indicate the value of a comparative approach for Plasmodium to elucidate structure, organisation and gene content of complex genomic loci and emphasise the need to integrate biological data of all Plasmodium species into the P.falciparum genome database and associated projects such as PlasmodB to further improve their annotation.
PMID: 11353075 [PubMed – in process]

J Immunol 2001 Jun 1;166(11):6742-8

Peroxisome Proliferator-Activated Receptor gamma-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis of Plasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-alpha Secretion by Monocytes/Macrophages.Serghides L, Kain KC.
Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Tropical Disease Unit, Toronto General Hospital, Toronto, Ontario, Canada.

Severe and fatal malaria is associated with the failure of host defenses to control parasite replication, excessive secretion of proinflammatory cytokines such as TNF-alpha, and sequestration of parasitized erythrocytes (PEs) in vital organs. The identification of CD36 as a major sequestration receptor has led to the assumption that it contributes to the pathophysiology of severe malaria and has prompted the development of antiadherence therapies to disrupt the CD36-PE interaction. This concept has been challenged by unexpected evidence that individuals deficient in CD36 are more susceptible to severe and cerebral malaria. In this study, we demonstrate that CD36 is the major receptor mediating nonopsonic phagocytosis of PEs by macrophages, a clearance mechanism of potential importance in nonimmune hosts at the greatest risk of severe malaria. CD36-mediated uptake of PEs occurs via a novel pathway that does not involve thrombospondin, the vitronectin receptor, or phosphatidylserine recognition. Furthermore, we show that proliferator-activated receptor gamma-retinoid X receptor agonists induce an increase in CD36-mediated phagocytosis and a decrease in parasite-induced TNF-alpha secretion. Specific up-regulation of monocyte/macrophage CD36 may represent a novel therapeutic strategy to prevent or treat severe malaria.

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