EHP Library Malaria Bulletin – February 10-23, 2003

Social Sciences and Malaria Control

WHO/TDR – Economics of malaria control in China: cost, performance and effectiveness of Henan’s consolidation programme. Social, Economic and Behavioural Research. Report Series No. 1 Full-text at: http://www.who.int/tdr/publications/publications/sebrep1.htm

Trop Med Int Health 2003 Feb;8(2):133-139

Early treatment of childhood fevers with pre-packaged antimalarial drugs in the home reduces severe malaria morbidity in Burkina Faso.

Sirima SB, Konate A, Tiono AB, Convelbo N, Cousens S, Pagnoni F.

Centre National de Recherche et de Formation sur le Paludisme, Ministere de la Sante, Ouagadougou, Burkina Faso, West Africa Department of Infectious and Tropical Diseases, London School for Tropical Medicine and Hygiene, London, UK Direzione Generale della Cooperazione allo Sviluppo, Roma, Italy.

In rural, malaria-endemic Burkina Faso, we evaluated the impact of the use of pre-packaged antimalarial drugs (PPAM), by mothers in the home, on the progression of disease in children from uncomplicated fever to severe malaria. In each village of one province, a core group of opinion leaders (mainly older mothers) was trained in the management of uncomplicated malaria, including the administration of PPAM. Full courses of antimalarial (chloroquine) and antipyretic (aspirin) drugs were packaged in age-specific bags and made widely available through community health workers who were supplied through the existing drug distribution system. Drugs were sold under a cost-recovery scheme. Local schoolteachers conducted surveys in a random sample of 32 villages at the end of the high transmission seasons in 1998 and 1999. Disease history and the treatment received were investigated for all children under the age of 6 years having suffered from a fever episode in the previous 4 weeks. ‘Uncomplicated malaria’ was defined as every episode of fever and ‘severe malaria’ as every episode of fever followed by convulsions or loss of consciousness. During the study period, 56%[95% confidence interval (CI) 50-62%] of 3202 fever episodes in children under 6 years of age were treated promptly by mothers with the pre-packaged drugs made available by the study. A total of 59% of children receiving PPAM were reported to have received the drugs over the prescribed 3-day period, while 52% received the correct age-specific dose. PPAM use was similar among literate (61%) and non-literate mothers (55%) (P = 0.08). The overall reported risk of developing severe malaria was 8%. This risk was lower in children treated with PPAM (5%) than in children not treated with PPAM (11%) (risk ratio = 0.47; 95% CI 0.37, 0.60; P < 0.0001). This estimate of the impact of PPAM was largely unchanged when account was taken of potential confounding by age, sex, maternal literacy status, year or village. Our findings support the view that, after appropriate training and with adequately packaged drugs made available, mothers can recognize and treat promptly and correctly malarial episodes in their children and, by doing so, reduce the incidence of severe disease.

PubMed

Trop Med Int Health 2003 Feb;8(2):118-24

Reduced prevalence of Plasmodium falciparum infection and of concomitant anaemia in pregnant women with heterozygous G6PD deficiency.

Mockenhaupt FP, Mandelkow J, Till H, Ehrhardt S, Eggelte TA, Bienzle U.

Institut fur Tropenmedizin Berlin, Charite, Humboldt-Universitat zu Berlin, Germany Presbyterian Mission Hospital, Agogo, Ghana Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, The Netherlands.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency confers protection against malaria in children, yet its role in malaria in pregnancy is unknown. In a cross-sectional study among 529 pregnant Ghanaian women, Plasmodium falciparum infection, anaemia and G6PD genotypes were assessed. Of these, 30.4% were heterozygous and 2.6% were homozygous for G6PD deficiency. The prevalence of P. falciparum infection decreased from 66% in G6PD-normal women to 58% in heterozygotes, and to 50% in individuals with homozygous G6PD deficiency (, P = 0.04). Multivariate analysis revealed that in multigravid women but not in primigravidae, heterozygous G6PD deficiency was associated with a reduced risk of P. falciparum infection (Odds ratio (OR), 0.6; 95% confidence interval (95% CI), [0.4-0.9]). This protection against infection was limited to the third trimenon of pregnancy. In addition, heterozygous G6PD deficiency was associated with a reduced risk of anaemia among infected multigravidae (OR, 0.5 [0.3-1.0]). Pregnancy is a period of high vulnerability to malaria. The results of this study provide evidence for protection against malaria in pregnancy caused by heterozygous G6PD deficiency. This advantage, even if confined to multigravid women, may contribute to the selection of G6PD variants in malaria-endemic regions. Curr Opin Hematol 2003 Mar;10(2):108-14

Malaria and anemia.

Ekvall H.

Anemia due to infection is a major health problem in endemic areas for young children and pregnant women. The anemia is caused by excess removal of nonparasitized erythrocytes in addition to immune destruction of parasitized red cells, and impaired compensation for this loss by bone marrow dysfunction. The pathogenesis is complex, and a predominant mechanism has not been identified. Certain parasite and host characteristics may modify the anemia. Concomitant infections and nutritional deficiencies also contribute to anemia and may interact with the malarial infection. Few preventive strategies exist, and the management of severe malarial anemia with blood transfusion carries a risk of HIV transmission. The current increase in malaria-specific childhood mortality in sub-Saharan Africa attributed to drug-resistant infection is likely partly related to an increase in severe anemia. This review summarizes recent findings on the pathogenesis and epidemiology of malarial anemia. Nat Struct Biol 2003 Feb 10; [epub ahead of print]

Structure of a gametocyte protein essential for sexual development in Plasmodium falciparum.

Sharma A, Sharma I, Kogkasuriyachai D, Kumar N. Malaria group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.

Malaria transmission is dependent on the development of sexual forms of Plasmodium falciparum, called gametocytes, in the vertebrate host. Pfg27 is an abundantly expressed sexual stage-specific protein that is essential for gametocytogenesis in P. falciparum. We describe the crystal structure of Pfg27, which reveals a novel fold composed of two pseudo dyad-related repeats of the helix-turn-helix motif. Structurally equivalent helices of each repeat either form a dimer interface or interact with RNA in vitro. One side of the dimer presents an unprecedented juxtaposition of four polyproline (PXXP) motifs. Preliminary binding data indicate that these sites are capable of binding Src homology-3 (SH3) modules. Molecular modeling suggests that the dimer can accommodate two SH3 modules simultaneously, potentially enabling molecular crosstalk between SH3-containing proteins. The structural and initial biochemical evidence suggests that Pfg27 may serve as a platform for RNA and SH3 binding. J Ethnopharmacol 2003 Mar;85(1):145-50

Lansium domesticum: skin and leaf extracts of this fruit tree interrupt the lifecycle of Plasmodium falciparum, and are active towards a chloroquine-resistant strain of the parasite (T9) in vitro.

Yapp DT, Yap SY.

The Institute of Health and Community Medicine, Universiti Malaysia Sarawak, 94300 Kota Samarahan, Sarawak, Malaysia Malaria remains a global problem in the light of chloroquine-resistant strains of Plasmodium falciparum.

New compounds are needed for the development of novel antimalarial drugs. Seed, leaf, and fruit skin extracts of Lansium domesticum, a common fruit tree in South-East Asia, are used by indigenous tribes in Sabah, Malaysia for treating malaria. The skin and aqueous leaf extracts of the tree were found to reduce parasite populations of the drug sensitive strain (3D7) and the chloroquine-resistant strain (T9) of P. falciparum equally well. The skin extracts were also found to interrupt the lifecycle of the parasite. The data reported here indicate that extracts of L. domesticum are a potential source for compounds with activity towards chloroquine-resistant strains of P. falciparum. Science 2003 Feb 21;299(5610):1225-7

Impact of genetic manipulation on the fitness of Anopheles stephensi mosquitoes.

Catteruccia F, Godfray HC, Crisanti A.

Department of Biological Sciences, SAF Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.

Genetic modification of mosquitoes offers exciting possibilities for controlling malaria, but success will depend on how transformation affects the fitness of modified insects. The expression of an exogenous gene, the mutations caused by its insertion, and inbreeding while transformed lines are established can all lead to reductions in fitness. Factors influencing fitness were investigated in cage experiments with four lines of transgenic Anopheles stephensi, a vector species of human malaria. The results indicate direct costs of the introduced transgene in at least three out of the four lines, as well as an apparent cost of the inbreeding involved in making transgenic homozygotes. Infect Immun 2003 Mar;71(3):1584-1586

Expression of Variant Surface Antigens by Plasmodium falciparum Parasites in the Peripheral Blood of Clinically Immune Pregnant Women Indicates Ongoing Placental Infection.

Ofori MF, Staalsoe T, Bam V, Lundquist M, David KP, Browne EN, Akanmori BD, Hviid L.

Placenta-sequestered Plasmodium falciparum parasites that cause pregnancy-associated malaria (PAM) in otherwise clinically immune women express distinct variant surface antigens (VSA(PAM)) not expressed by parasites in nonpregnant individuals. We report here that parasites from the peripheral blood of clinically immune pregnant women also express VSA(PAM), making them a convenient source of VSA(PAM) expressors for PAM vaccine research. Infect Immun 2003 Mar;71(3):1416-1426

Geographical Structure of Diversity and Differences between Symptomatic and Asymptomatic Infections for Plasmodium falciparum Vaccine Candidate AMA1.

Cortes A, Mellombo M, Mueller I, Benet A, Reeder JC, Anders RF. Papua New Guinea Institute of Medical Research, Madang, MP511.

Papua New Guinea Institute of Medical Research, Goroka, EHP441, Papua New Guinea. The Cooperative Research Centre for Vaccine Technology, Department of Biochemistry, La Trobe University, Melbourne, Victoria 3086, Australia.

Plasmodium falciparum apical membrane antigen 1 (AMA1) is a prime malaria vaccine candidate. Antigenic diversity within parasite populations is one of the main factors potentially limiting the efficacy of any asexual-stage vaccine, including one based on AMA1. The DNA coding for the most variable region of this antigen, domain I, was sequenced in 168 samples from the Wosera region of Papua New Guinea, including samples from symptomatic and asymptomatic infections. Neutrality tests applied to these sequences provided strong evidence of selective pressure operating on the sequence of ama1 domain I, consistent with AMA1 being a target of protective immunity. Similarly, a peculiar pattern of geographical diversity and the particular substitutions found were suggestive of strong constraints acting on the evolution of AMA1 at the population level, probably as a result of immune pressure. In addition, a strong imbalance between symptomatic and asymptomatic infections was detected in the frequency of particular residues at certain polymorphic positions, pointing to AMA1 as being one of the determinants of the morbidity associated with a particular strain. The information yielded by this study has implications for the design and assessment of AMA1-based vaccines and provides additional data supporting the importance of AMA1 as a malaria vaccine candidate. Infect Immun 2003 Mar;71(3):1242-6 Congenital Exposure to Plasmodium falciparum Antigens: Prevalence and Antigenic Specificity of In Utero-Produced Antimalarial Immunoglobulin M Antibodies. Xi G, Leke RG, Thuita LW, Zhou A, Leke RJ, Mbu R, Taylor DW. Department of Biology, Georgetown University, Washington, DC 20054. Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon. AZ DataClinic, Inc., Rockville, Maryland 20850. Congenital Plasmodium falciparum malaria in newborns is uncommon in sub-Saharan Africa. A significant number of infants, however, become infected or exposed to malarial antigens either in utero or at delivery and have the potential to produce antimalarial antibodies and memory cells before their first natural infection. In Yaounde, Cameroon, parasite-specific immunoglobulin M (IgM) was detected in 14% of cord blood samples. The IgM antibodies reacted with a wide range of asexual-stage antigens, with each newborn having its own unique pattern of IgM reactivity. PCR-based detection and genotyping of cord blood parasites found that the prevalence, total number of parasite genotypes, and complexity of infection were higher in newborns who had produced antimalarial IgM than those who had not. Maternal placental malaria and anemia were associated with the production of P. falciparum-specific IgM by the fetus. The effect of early immune priming on acquisition of immunity by infants is unknown and merits further investigation, since a significant proportion of Cameroonian newborns developed a humoral response to malaria before birth. Exp Parasitol 2002 Aug;101(4):175-182

Plasmodium berghei: analysis of the gamma-glutamylcysteine synthetase gene in drug-resistant lines.

Perez-Rosado J, Gervais GW, Ferrer-Rodri;guez I, Peters W, Serrano AE.

Department of Microbiology and Medical Zoology, School of Medicine, University of Puerto Rico, P.O. Box 365067, 00936-5067, San Juan, Puerto Rico.

The rapid emergence of multidrug-resistant Plasmodium falciparum is a worldwide concern. Despite the magnitude of the problem, the mechanisms involved in this phenomenon are not well understood. One current proposal suggests that toxic heme molecules are degraded by glutathione (GSH), and that anti-malarial drugs, such as chloroquine (CQ), inhibit this degradation, thus implicating GSH in drug resistance. Furthermore, in some strains of Plasmodium berghei and P. falciparum, chloroquine resistance is accompanied by an increase in glutathione levels and increased activity in GSH-related enzymes. We are investigating the relationship between the gamma-glutamylcysteine synthetase (ggcs) gene, the rate-limiting enzyme in de novo synthesis of GSH, and drug resistance in P. berghei at the molecular level. In this report, we have demonstrated an increase in pbggcs mRNA levels associated with CQ and mefloquine (MFQ) resistance. In addition, the pbggcs gene locus structure was shown to be similar and localized to chromosome 8 in four parasite lines of P. berghei with different drug resistance profiles. This work suggests a link between increased GSH levels and drug resistance in Plasmodium. Clin Infect Dis 2003 Mar 1;36(5):652-62

Review of human immunodeficiency virus type 1-related opportunistic infections in sub-saharan Africa.

Holmes CB, Losina E, Walensky RP, Yazdanpanah Y, Freedberg KA.

Divisions of Infectious Disease and General Medicine and Partners AIDS Research Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Email: [email protected]

Understanding the natural history of human immunodeficiency virus type 1 (HIV-1) and opportunistic infections in sub-Saharan Africa is necessary to optimize strategies for the prophylaxis and treatment of opportunistic infections and to understand the likely impact of antiretroviral therapy. We undertook a systematic review of the literature on HIV-1 infection in sub-Saharan Africa to assess data from recent cohorts and selected cross-sectional studies to delineate rates of opportunistic infections, associated CD4 cell counts, and associated mortality. We searched the MEDLINE database and the Cochrane Database of Systematic Reviews and Cochrane Clinical Trials Register for English-language literature published from 1990 through April 2002. Tuberculosis, bacterial infections, and malaria were identified as the leading causes of HIV-related morbidity across sub-Saharan Africa. Of the few studies that reported CD4 cell counts, the range of cell counts at the time of diagnosis of opportunistic infections was wide. Policies regarding the type and timing of opportunistic infection prophylaxis may be region specific and urgently require further study. Clin Infect Dis 2003 Mar 1;36(5):541-9

A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Trial of Tafenoquine for Weekly Prophylaxis against Plasmodium falciparum.

Hale BR, Owusu-Agyei S, Fryauff DJ, Koram KA, Adjuik M, Oduro AR, Prescott WR, Baird JK, Nkrumah F, Ritchie TL, Franke ED, Binka FN, Horton J, Hoffman SL.

US Navy Medical Research Unit No. 3, Cairo, Egypt.

Tafenoquine is a promising new 8-aminoquinoline drug that may be useful for malaria prophylaxis in nonpregnant persons with normal glucose-6-phosphate dehydrogenase (G6PD) function. A randomized, double-blind, placebo-controlled chemoprophylaxis trial was conducted with adult residents of northern Ghana to determine the minimum effective weekly dose of tafenoquine for the prevention of infection by Plasmodium falciparum. The primary end point was a positive malaria blood smear result during the 13 weeks of study drug coverage. Relative to the placebo, all 4 tafenoquine dosages demonstrated significant protection against P. falciparum infection: for 25 mg/week, protective efficacy was 32% (95% confidence interval [CI], 20%-43%); for 50 mg/week, 84% (95% CI, 75%-91%); for 100 mg/week, 87% (95% CI, 78%-93%); and for 200 mg/week, 86% (95% CI, 76%-92%). The mefloquine dosage of 250 mg/week also demonstrated significant protection against P. falciparum infection (protective efficacy, 86%; 95% CI, 72%-93%). There was little difference between study groups in the adverse events reported, and there was no evidence of a relationship between tafenoquine dosage and reports of physical complaints or the occurrence of abnormal laboratory parameters. Tafenoquine dosages of 50, 100, and 200 mg/week were safe, well tolerated, and effective against P. falciparum infection in this study population. Proc Natl Acad Sci U S A 2003 Feb 19; [epub ahead of print]

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria.

Makobongo MO, Riding G, Xu H, Hirunpetcharat C, Keough D, De Jersey J, Willadsen P, Good MF.

Cooperative Research Centre for Vaccine Technology, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane 4029, Australia; Commonwealth Scientific and Industrial Research Organisation Livestock Industries, Gehrmann Labs, Institute for Molecular Bioscience, and paragraph sign Department of Molecular and Microbial Sciences, University of Queensland, Brisbane 4072, Australia; and Department of Microbiology, Faculty of Public Health, Mahidol University, 420/1 Rajvithi Road, Bangkok 10400, Thailand.

Although there is good evidence that immunity to the blood stages of malaria parasites can be mediated by different effector components of the adaptive immune system, target antigens for a principal component, effector CD4(+) T cells, have never been defined. We generated CD4(+) T cell lines to fractions of native antigens from the blood stages of the rodent parasite, Plasmodium yoelii, and identified fraction-specific T cells that had a Th1 phenotype (producing IL-2, IFN-gamma, and tumor necrosis factor-alpha, but not IL-4, after antigenic stimulation). These T cells could inhibit parasite growth in recipient severe combined immunodeficient mice. N-terminal sequencing of the fraction showed identity with hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT). Recombinant HGXPRT from the human malaria parasite, Plasmodium falciparum, activated the T cells in vitro, and immunization of normal mice with recombinant HGXPRT reduced parasite growth rates in all mice after challenge. J Immunol 2003 Mar 1;170(5):2759-2764

Host Response to Malaria During Pregnancy: Placental Monocyte Recruitment Is Associated with Elevated beta Chemokine Expression.

Abrams ET, Brown H, Chensue SW, Turner GD, Tadesse E, Lema VM, Molyneux ME, Rochford R, Meshnick SR, Rogerson SJ.

Departments of Anthropology, Pathology, and Epidemiology, University of Michigan, Ann Arbor, MI 48104. Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, United Kingdom. Department of Obstetrics and Gynaecology and Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi. School of Tropical Medicine, University of Liverpool, Liverpool, United Kingdom. Department of Epidemiology, University of North Carolina, Chapel Hill, NC 27514. Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Australia.

Malaria during pregnancy is associated with poor birth outcomes, particularly low birth weight. Recently, monocyte infiltration into the placental intervillous space has been identified as a key risk factor for low birth weight. However, the malaria-induced chemokines involved in recruiting and activating placental monocytes have not been identified. In this study, we determined which chemokines are elevated during placental malaria infection and the association between chemokine expression and placental monocyte infiltration. Placental malaria infection was associated with elevations in mRNA expression of three beta chemokines, macrophage-inflammatory protein 1 (MIP-1) alpha (CCL3), monocyte chemoattractant protein 1 (MCP-1; CCL2), and I-309 (CCL1), and one alpha chemokine, IL-8 (CXCL8); all correlated with monocyte density in the placental intervillous space. Placental plasma concentrations of MIP-1alpha and IL-8 were increased in women with placental malaria and were associated with placental monocyte infiltration. By immunohistochemistry, we localized placental chemokine production in malaria-infected placentas: some but not all hemozoin-laden maternal macrophages produced MIP-1beta and MCP-1, and fetal stromal cells produced MCP-1. In sum, local placental production of chemokines is increased in malaria, and may be an important trigger for monocyte accumulation in the placenta. Bull Entomol Res 2003 Feb;93(1):31-7

Enrichment of a single clone from a high diversity library of phage-displayed antibodies by panning with Anopheles gambiae (Diptera: Culicidae) midgut homogenate.

Killeen GF, Foy BD, Frohn RH, Impoinvil D, Williams A, Beier JC.

Department of Tropical Medicine, Tulane School of Public Health and Tropical Medicine, 1430 Tulane Avenue SL29A, New Orleans, LA, 70112, USA.

A high diversity library of recombinant human antibodies was selected on complex antigen mixtures from midguts of female Anopheles gambiae Giles. The library of phage-displayed single chain variable region fragment constructs, derived from beta-lymphocyte mRNA of naive human donors, was repeatedly selected and reamplified on the insoluble fraction of midgut homogenates. Five rounds of panning yielded only one midgut-specific clone, which predominated the resulting antibody panel. In A. gambiae, the epitope was found throughout the tissues of females but was absent from the midgut of males. The cognate antigen proved to be detergent soluble but very sensitive to denaturation and could not be isolated or identified by Western blot of native electrophoresis gels or by immunoprecipitation. Nevertheless, immunohistology revealed that this sex-specific epitope is associated with the lumenal side of the midgut. Severe bottlenecking may limit the utility of phage display selection from naive libraries for generating diverse panels of antibodies against complex mixtures of antigens from insect tissues. These results suggest that the selection of sufficiently diverse antibody panels, from which mosquitocidal or malaria transmission-blocking antibodies can be isolated, may require improved selection methods or specifically enriched pre-immunized libraries. Protein Sci 2003 Mar;12(3):501-509

Probing the structure of falcipain-3, a cysteine protease from Plasmodium falciparum: Comparative protein modeling and docking studies.

Sabnis YA, Desai PV, Rosenthal PJ, Avery MA.

Department of Medicinal Chemistry, National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, Mississippi 38677-1848, USA Department of Chemistry, University of Mississippi, University, Mississippi 38677-1848, USA Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California 94143-0811, USA.

Increasing resistance of malaria parasites to conventional antimalarial drugs is an important factor contributing to the persistence of the disease as a major health threat. The ongoing search for novel targets has resulted in identification and expression of several enzymes including cysteine proteases that are implicated in hemoglobin degradation. Falcipain-2 and falcipain-3 are considered to be the two principal cysteine proteases in this degradation, and hence, are potential drug targets. A homology model of falcipain-3 was built and validated by various structure/geometry verification tools as well as docking studies of known substrates. The correlation coefficient of 0.975 between interaction energies and K(m) values of these substrates provided additional support for the model. On comparison with the previously reported falcipain-2 homology model, the currently constructed falcipain-3 structure showed important differences between the S2 pockets that might explain the variations in the K(m) values of various substrates for these enzymes. Further, docking studies also provided insight into possible binding modes and interactions of ligands with falcipain-3. Results of the current study could be employed in de novo drug design leading to development of new antimalarial agents. Curr Genet 2003 Feb;42(5):292-300 Proteobacteria-like ferrochelatase in the malaria parasite. Sato S, Wilson RJ. Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, NW7 1AA, London, UK, Email: [email protected] A gene encoding the heme biosynthetic enzyme ferrochelatase (FC) was found in the genomic DNA databases of Plasmodium spp. The predicted amino acid sequence of malarial FC is highly conserved and fairly well conserved by comparison with other orthologues. The FC genes of P. falciparum and P. yoelii are transcribed and the mRNAs are processed to encode polypeptides of the expected amino acid sequence. The cloned cDNA for the FC of P. falciparum successfully rescued a FC-null mutant of Escherichia coli, indicating that it encodes an active enzyme. Unlike eukaryotic FCs, the malarial enzyme lacks a characteristic extension at the C-terminus. In addition, the sequence of the malarial FC resembles proteobacterial orthologues rather than eukaryotic enzymes. Strikingly, the malarial FC lacks a bipartite presequence at its N-terminus, unlike delta-aminolevulinic acid dehydratase of the same organism. This suggests an unusual intracellular distribution of heme biosynthetic enzymes, involving multiple subcellular compartments. Trends Parasitol 2003 Feb;19(2):94-101 Molecular strategies to study Plasmodium-mosquito interactions. Ghosh A, Srinivasan P, Abraham EG, Fujioka H, Jacobs-Lorena M. Case Western Reserve University, Department of Genetics, 10900 Euclid Avenue, 44106-4955, Cleveland, Ohio, USA It is widely known that malaria kills millions of people every year. Less well recognized is the fact that the situation is steadily deteriorating for a lack of effective means to counter the disease. An essential first step towards the development of new approaches to fight malaria is a thorough understanding of the mechanisms that direct parasite growth and differentiation, including parasite-host interactions. This article reviews recent achievements and introduces some promising new technologies and approaches for studying host-parasite interactions. Trends Parasitol 2003 Feb;19(2):88-93 T cells as mediators of protective immunity against liver stages of Plasmodium. Tsuji M, Zavala F. Department of Medical and Molecular Parasitology, New York University School of Medicine, 341 East 25th Street, 10010, New York, NY, USA T cells from different subsets play a major role in protective immunity against pre-erythrocytic stages of malaria parasites. Exposure of humans and animals to malaria sporozoites induces (alphabeta CD8(+) and CD4(+) T cells specific for antigens expressed in pre-erythrocytic stages of Plasmodium. These T cells inhibit parasite development in the liver, and immunization with subunit vaccines expressing the respective antigenic moieties confers protection against sporozoite challenge. gammadelta and natural killer T cells can also play a role in protective immunity. Recent studies with mice transgenic for the alphabeta T-cell receptor have revealed the existence of complex mechanisms regulating the induction and development of these responses. Trends Parasitol 2003 Feb;19(2):74-8

Pre-erythrocytic antigens of Plasmodium falciparum: from rags to riches?

Charlotte Gruner A, Snounou G, Brahimi K, Letourneur F, Renia L, Druilhe P.

Unite de Parasitologie Biomedicale, Institut Pasteur, 25 Rue du Dr Roux, 75724 Cedex 15, Paris, France.

A growing number of Plasmodium genomes have joined the sequencing treadmill, and the genome of Plasmodium falciparum has recently been published. Most malaria vaccinologists will soon be confronted by a bewildering array of new potential antigens from the recently completed genome of this parasite. However, for those aiming to target the pre-erythrocytic stages of the hepatic parasite, the wait might be long. In the absence of readily available materials and specific reagents, the selection of pre-erythrocytic antigens from raw sequence data is likely to prove difficult. Here, current knowledge of pre-erythrocytic antigens is updated in the light of recent results, and the post-genomic prospects of completing the antigenic repertoire of these immunologically important and intriguing stages is discussed. Trends Parasitol 2003 Feb;19(2):70-3 Malaria control and the evolution of drug resistance: an intriguing link. Hastings IM. Liverpool School of Tropical Medicine, Pembroke Place, L3 5QA, Liverpool, UK Does antimalarial drug resistance evolve faster in areas of high or low transmission? Suggestions that resistance evolves faster in areas of low transmission cast a cloud over control measures, such as bednet provision and insecticide spraying, by implying that their impact could be offset by the enhanced evolution of drug resistance. Theoretical analyses are ambivalent on this question, but a recent field study has attempted to measure the relationship empirically, and has generated some intriguing data: antimalarial drug resistance could be inhibited in the early stages of control programmes, only starting to resurge as the disease nears eradication.

Trends Parasitol 2003 Feb;19(2):60-3 Molecular monitoring in malaria vaccine trials.

Felger I, Genton B, Smith T, Tanner M, Beck HP.

Swiss Tropical Institute, Socinstrasse 57, PO Box 4002, Basel, Switzerland.

Molecular techniques offer new approaches for malaria field trials, particularly PCR techniques, which facilitate accurate diagnosis of Plasmodium infections and increase the power of estimates of vaccine effects on malaria prevalence or incidence. Molecular methods also help to assess selective effects of vaccines. Longitudinal genotyping data can be used to initiate novel analyses of parasite dynamics, including estimates of incidence of infection with individual parasite clones and duration of infections. In addition, high-throughput methods can be used to apply these techniques routinely in randomized controlled trials, as well as programme-based evaluations of malaria control. Trop Med Int Health 2003 Feb;8(2):140-3 Short communication: Concomitant malaria and filariasis infections in Georgetown, Guyana. Chadee DD, Rawlins SC, Tiwari TS. Insect Vector Control Division, St Joseph, Trinidad Caribbean Epidemiology Centre, Port of Spain, Trinidad Ministry of Health, Georgetown, Guyana. Lymphatic filariasis and malaria are endemic in Guyana, South America. To determine the prevalence of concomitant infections, we conducted a 1-year survey of febrile patients attending the malaria (day) and filariasis (night) clinics in Georgetown. In all, 1278 thick blood smears were collected: 769 for filariasis, of which 103 were positive for Wuchereria bancrofti, and three for both W. bancrofti and malaria parasites; and 509 for malaria, 21 of which tested positive for malaria and 17 for both malaria and filariasis. The age groups and sex of the infected persons with malaria and W. bancrofti are described. These results suggest that the incidence of concomitant infections in Guyana may be quite low but efforts should be made to reduce the disease burden in Georgetown, Guyana. Trop Med Int Health 2003 Feb;8(2):125-8 Plasma glucose and tumour necrosis factor-alpha in adult patients with severe falciparum malaria. Manish R, Tripathy R, Das BK. Department of Internal Medicine, S.C.B. Medical College, Cuttack, Orissa, India Department of Biochemistry, S.C.B. Medical College, Cuttack, Orissa, India. Plasma glucose was assessed in 81 patients with severe falciparum malaria at the time of presentation along with tumour necrosis factor-alpha (TNF-alpha). The lowest plasma glucose value was 3.38 mmol/l and none of the patients had hypoglycaemia at admission. Plasma glucose values were not significantly lower in those with multiple organ dysfunction (MOD) than in patients with single organ dysfunction (cerebral malaria only) and in those who died compared with patients who survived. Conversely, TNF-alpha showed a good correlation with depth of coma and was significantly higher in patients who had MOD and those who died. There was no correlation between plasma glucose and TNF-alpha values.