Malaria Bulletin 06-15-00

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Full-text Reports/ArticlesWHO/TDR – Final Report Series No.19 Malaria  (16 June 2000) New SCID mouse model for the maintenance of malaria parasites in human red blood cellsMEASURE – Evaluating Malaria Interventions in Africa: A Review and Assessment of Recent Research, Feb 2000.Mem. Inst. Oswaldo Cruz 
vol.95 n.3 Rio de Janeiro May/Jun. 2000Isolation and identification of actin-binding proteins in Plasmodium falciparum by affinity chromatography
Forero, Claudia; Wasserman, Moisés
abstract   text in english   Plasmodium yoelii: identification of a gene encoding a putative ADP-ribosylation factor-1 GTPase-activating Protein, PyAG1 Hienne, Rémi; et al.
abstract      text in english Aotus infulatus monkey is susceptible to Plasmodium falciparum infection and may constitute an alternative experimental model for malaria  Carvalho, Leonardo JM;  et al.
abstract   text in english PUBMED, June 2-June 15 20001: Am J Epidemiol 2000 May 15;151(10):1029-35Predictors of correct treatment of children with fever seen at outpatient health facilities in the Central African Republic.

Rowe AK, Hamel MJ, Flanders WD, Doutizanga R, Ndoyo J, Deming MS

Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. Email: [email protected]

To identify factors associated with improved performance of health care workers who treat ill children in developing countries, the authors analyzed a sample of consultations of children with malaria (defined as any fever) from a national health facility survey conducted in the Central African Republic from December 1995 to January 1996. Twenty-eight health care workers and 204 children were studied. A univariate analysis revealed the following significant predictors of correct treatment, as defined by the Central African malaria control program: high fever (odds ratio (OR) = 3.25, 95% confidence interval (CI): 1.47, 7.17); correct health care worker diagnosis (OR = 2.59, 95% CI: 1.39, 4.85); and the caregiver’s reporting the child’s fever to the health care worker (OR = 2.18, 95% CI: 1.32, 3.62). There was an unexpected inverse association between the presence of a fever treatment chart and correct treatment (OR = 0.19, 95% CI: 0.04, 0.91). Correct treatment was marginally associated with a longer consultation time (p value for trend = 0.058). Neither in-service training in the treatment of fever nor supervision was significantly associated with correct treatment. For child health programs to improve, targeted studies are needed to understand which factors, alone or in combination, improve health care worker performance.2: Curr Opin Struct Biol 2000 Jun;10(3):343-348Genome data: what do we learn?

Nierman WC, Eisen JA, Fleischmann RD, Fraser CM

The Institute for Genomic Research, Rockville, MD 20850, USA. Email: [email protected]

Genome sequence information has continued to accumulate at a spectacular pace during the past year. Details of the sequence and gene content of human chromosome 22 were published. The sequencing and annotation of the first two Arabidopsis thaliana chromosomes was completed. The sequence of chromosome 3 from Plasmodium falciparum, the second sequenced malaria chromosome, was reported, as was that of chromosome 1 from Leishmania major. The complete genomic sequences of five microbes were reported. Approaches to using data from completely sequenced microbial genomes in phylogenetic studies are being explored, as is the application of microarrays to whole genome expression analysis.

3: Parasite Immunol 2000 Jun;22(6):307-318Apoptosis modulation in mononuclear cells recovered from individuals exposed to Plasmodium falciparum infection.

Balde AT, Aribot G, Tall A, Spiegel A, Roussilhon C

Laboratoire d’Immunologie; Laboratoire d’Epidemiologie, Institut Pasteur, BP 220, Dakar, Senegal; Laboratoire de Parasitologie Bio-Medicale, Institut Pasteur, 28 rue du Dr Roux, 75015 Paris, France.

In endemic areas, asymptomatic infection by the malaria parasite Plasmodium falciparum was found associated with elevated percentages of human host’s mononuclear cell spontaneous in-vitro apoptosis. In Dielmo, a village where malaria is holoendemic, apoptosis was age-and parasite-dependent. In-vitro exposure of peripheral blood mononuclear cells (PBMC) to the parasite extract induced a marked increase in the mononuclear cell membrane expression of functional CD95 antigen: a 3-h exposure of the mononuclear cells to anti-CD95 antibodies led to a detectable increase in the mean percentage of apoptotic nuclei found in the cultures carried out in the presence of P. falciparum extracts compared to control cultures. IL-2, IL-4, IL-6 and IL-10 promoted the viability of PBMC in cultures while IL-1alpha or IFN-gamma had no obvious impact and TNFalpha gave conflicting results. IL-2 was the most efficient cytokine at rescuing PBMC from cell death and this effect was associated with a strong increase in T cell activation. In contrast, IL-4 and IL-10 had no such effect on T cell activation, hence they acted as survival factors and not through their mitogenic activity. Taken together, these different observations suggested that the levels of in-vitro apoptosis observed were not only associated with parasite infection, but also potentially modulated by the human host through different pathways.4: J Eukaryot Microbiol 2000 May-Jun;47(3):319-22Sequence analysis of the Rhop-3 gene of Plasmodium yoelii.

Anthony RN, Yang J, Krall JA, Sam-Yellowe TY

Cleveland State University, Department of Biological, Geological and Environmental Sciences, Ohio 44115, USA.

The 110 kDa/Rhop-3 rhoptry protein of Plasmodium falciparum is non-covalently associated with two other proteins, the 140 kDa Rhop-1 and the 130 kDa Rhop-2. cDNAs encoding Rhop-3 from Plasmodium yoelii were isolated using rhoptry-specific antisera from Plasmodium falciparum, P. yoelii, and Plasmodium chabaudi. The cDNAs encoded peptides with partial homology to the C-terminal region (residues 541-861) of P. falciparum Rhop-3. Core regions of homology to the P. falciparum gene will be useful in determining the biological role of Rhop-3 and its potential as a vaccine candidate for malaria.5: Ann Biol Clin (Paris) 2000 May-Jun;58(3):310-6[Malaria diagnosis in non endemic countries : value, limitations and complementarity of existing].

Brenier-Pinchart MP, Pinel C, Grillot R, Ambroise-Thomas P

Departement de parasitologie-mycologie medicale et moleculaire, Centre hospitalier universitaire, BP 217, 38043 Grenoble cedex 9.

The biological diagnosis of malaria is urgent to avoid rapid and fatal outcome. Every year in France, 5,000 imported malaria cases are observed. Thin stained blood smear microscopical examination remains the reference method of diagnosis; however its performance is linked to the professionnal competence of the biologists. Thus easier methods have been developed (QBC test). Some of them, limited to the diagnosis of malaria due to Plasmodium falciparum do not require highly skilled personal to perform or interpret (antigen detection on dipsticks, tests Parasight or cardboard, ICT Malaria Pf), but limitations and errors occure. These different tests must be complementary methods of traditional diagnosis. In association with microscopical examinations, they provide rapid and efficient diagnosis of malaria in non-endemic areas. Relying on our experience, the best association is: QBC + thin blood smear and depending of results antigen detection (ParaSight F, ICT Malaria Pf).6: Indian J Biochem Biophys 1999 Oct;36(5):299-304Inhibition of a protein tyrosine kinase activity in Plasmodium falciparum by chloroquine.

Sharma A, Mishra NC

Department of Protein Biochemistry, Malaria Research Centre, Delhi, India.

The aim of the present study was to establish the importance of phosphorylation events for parasite growth and maturation. Investigations into the cytosolic Plasmodium falciparum protein tyrosine kinase (PTK) activity revealed that there is a stage specific increase in the activity, in the order ring < trophozoite < schizont in both chloroquine sensitive (CQ-S) and chloroquine resistant (CQ-R) strains (p < 0.05). Our data also show that in vivo conversion of the schizont stage to ring stage via release of merozoites is associated with a decrease in PTK activity. Piceatannol, a specific inhibitor of PTK inhibited the activity in both the CQ-S and CQ-R strains of the parasites. The presence of low levels of chloroquine (CQ) inhibited the cytosolic PTK activity in a dose dependent manner (IC50 = 45 mumoles or 23 micrograms/ml) in CQ-S strains. The effect of varying concentration of CQ on the kinetics of peptide phosphorylation reveal that CQ was a competitive inhibitor of PTK with respect to peptide substrate and non-competitive with respect to ATP indicating that CQ inhibits PTK activity by binding with protein substrate binding site. These data thus suggests that maturation of malaria parasite may be due to this cellular PTK and its inhibition by CQ could provide a hypothesis to explain its antimalarial activity and efficacy.7: Mol Microbiol 2000 May;36(4):955-61Increased sensitivity to the antimalarials mefloquine and artemisinin is conferred by mutations in the pfmdr1 gene of plasmodium falciparum.

Duraisingh MT, Roper C, Walliker D, Warhurst DC

London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.I. C. A. P. B., Ashworth Laboratories, University of Edinburgh, King’s Buildings, West Mains Road, Edinburgh, UK.

The declining efficacy of chloroquine and pyrimethamine/sulphadoxine in the treatment of human malaria has led to the use of newer antimalarials such as mefloquine and artemisinin. Sequence polymorphisms in the pfmdr1 gene, the gene encoding the plasmodial homologue of mammalian multidrug resistance transporters, have previously been linked to resistance to chloroquine in some, but not all, studies. In this study, we have used a genetic cross between the strains HB3 and 3D7 to study inheritance of sensitivity to the structurally unrelated drugs mefloquine and artemisinin, and to several other antimalarials. We find a complete allelic association between the HB3-like pfmdr1 allele and increased sensitivity to these drugs in the progeny. Different pfmdr1 sequence polymorphisms in other unrelated lines were also associated with increased sensitivity to these drugs. Our results indicate that the pfmdr1 gene is an important determinant of susceptibility to antimalarials, which has major implications for the future development of resistance.8: Proc Natl Acad Sci U S A 2000 Jun 6;97(12):6619-6624Anopheles gambiae pilot gene discovery project: Identification of mosquito innate immunity genes from expressed sequence tags generated from immune-competent cell lines.

Dimopoulos G, Casavant TL, Chang S, Scheetz T, Roberts C, Donohue M, Schultz J, Benes V, Bork P, Ansorge W, Soares MB, Kafatos FC

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany; and University of Iowa, 451 Eckstein Medical Research Building, Iowa City, IA 52242.

Together with AIDS and tuberculosis, malaria is at the top of the list of devastating infectious diseases. However, molecular genetic studies of its major vector, Anopheles gambiae, are still quite limited. We have conducted a pilot gene discovery project to accelerate progress in the molecular analysis of vector biology, with emphasis on the mosquito’s antimalarial immune defense. A total of 5,925 expressed sequence tags were determined from normalized cDNA libraries derived from immune-responsive hemocyte-like cell lines. The 3,242 expressed sequence tag-containing cDNA clones were grouped into 2,380 clone clusters, potentially representing unique genes. Of these, 1,118 showed similarities to known genes from other organisms, but only 27 were identical to previously known mosquito genes. We identified 38 candidate genes, based on sequence similarity, that may be implicated in immune reactions including antimalarial defense; 19 of these were shown experimentally to be inducible by bacterial challenge, lending support to their proposed involvement in mosquito immunity.9: Parasitology 2000 May;120 (Pt 5):447-56Chronic Plasmodium falciparum infections in an area of low intensity malaria transmission in the Sudan.

Hamad AA, El Hassan IM, El Khalifa AA, Ahmed GI, Abdelrahim SA, Theander TG, Arnot DE

National Malaria Administration, National Health Laboratory, Ministry of Health, Khartoum, Sudan.

Chronic Plasmodium falciparum malaria infections in a Sudanese village, in an area of seasonal and unstable malaria transmission, were monitored and genetically characterized to study the influence of persistent infection on the immunology and epidemiology of low endemicity malaria. During the October-December malaria season of 1996, 51 individuals out of a population of 420 had confirmed and treated P. falciparum malaria in the village of Daraweesh in eastern Sudan. In a cross-sectional survey carried out in December 1996, an additional 6 individuals were found to harbour a microscopically negative but polymerase chain reaction (PCR)-positive P. falciparum infection. On 1 January 1997, a cohort of 43 individuals aged from 9 to 53, recruited from this group of recently malaria-infected individuals agreed to donate fortnightly blood samples for the next 9 months, the first 6 of which constitute the long Sudanese dry season when transmission falls to undetectable levels. Each blood sample was tested for the presence of persistent malaria infection by microscopy and PCR. Parasite-positive samples were genotyped using PCR assays that detect allelic polymorphism at the MSP-1, MSP-2 and GLURP marker gene loci. Of 43 individuals 16 were found to maintain chronic P. falciparum infections which were continuously genetically characterized.10: Anat Embryol (Berl) 2000 May;201(5):383-97Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei.

Petras JM, Young GD, Bauman RA, Kyle DE, Gettayacamin M, Webster HK, Corcoran KD, Peggins JO, Vane MA, Brewer TG

Division of Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.

Malaria poses a threat across several continents: Eurasia (Asia and parts of Eastern Europe), Africa, Central and South America. Bradley (1991) estimates human exposure at 2,073,000,000 with infection rates at 270,000,000, illnesses at 110,000,000, and deaths at 1,000,000. Significant mortality rates are attributed to infection by the parasite Plasmodium falciparum, with an estimated 90% among African children. A worldwide effort is ongoing to chemically and pharmacologically characterize a class of artemisinin compounds that might be promising antimalarial drugs. The U.S. Army is studying the efficacy and toxicity of several artemisinin semi-synthetic compounds: arteether, artemether, artelinic acid, and artesunate. The World Health Organization and the U.S. Army selected arteether for drug development and possible use in the emergency therapy of acute, severe malaria. Male Rhesus monkeys (Macaca mulatta) were administered different daily doses of arteether, or the vehicle alone (sesame oil), for a period of either 14 days, or 7 days. Neuropathological lesions were found in 14-day arteether treated monkeys in the precerebellar nuclei of the medulla oblongata, namely: (1) the lateral reticular nuclei (subnuclei magnocellularis, parvicellularis, and subtrigeminalis), (2) the paramedian reticular nuclei (subnuclei accessorius, dorsalis, and ventralis), and the perihypoglossal nuclei (n. intercalatus of Staderini, n. of Roller, n. prepositus hypoglossi). The data demonstrate that the simina meduallry precerebellar nuclei have a high degree of vulnerability when arteether is given for 14 days at dose levels between 8mg/kg per day and 24 mg/kg per day. The neurological consequences of this treatment regimen could profoundly impair posture, gait, and autonomic regulation, while eye movement disorders might also be anticipated.		PUBMED, June 2-June 15 2000
(continued)11: Mol Biochem Parasitol 2000 May 1;108(2):237-247Plasmodium falciparum erythrocyte membrane protein 1 is anchored to the actin-spectrin junction and knob-associated histidine-rich protein in the erythrocyte skeleton.

Oh SS, Voigt S, Fisher D, Yi SJ, LeRoy PJ, Derick LH, Liu S, Chishti AH

Department of Medicine, Section of Hematology-Oncology Research, St. Elizabeth’s Medical Center, Tufts University School of Medicine, 736 Cambridge Street, 02135, Boston, MA, USA

A distinctive pathological feature of Plasmodium falciparum malaria is the endothelial attachment of erythrocytes infected with mature asexual-stage parasites in microvessels of the major organs. Electron-dense protrusions described as knobs are displayed on the surface of parasitized erythrocytes and act as attachment points in cytoadherence. Parasite-encoded knob-associated histidine-rich protein (KAHRP) is a major component of knobs found on the cytoplasmic side of the host cell membrane. P. falciparum erythrocyte membrane protein 1 (PfEMP1) is a family of parasite-encoded cytoadherence receptors localized to knobs on the surface of parasitized erythrocytes. Despite its high antigenic diversity, PfEMP1 has a remarkably conserved cytoplasmic domain. We demonstrate in this study that the cytoplasmic domain of PfEMP1 (VAR(CD)) binds to host spectrin and actin and to full-length KAHRP in vitro. Apparent dissociation constants determined for VAR(CD)/F-actin and VAR(CD)/KAHRP interactions are 44.9+/-6.4 and 10.7+/-2.2 nM, respectively. Further, we provide evidence that KAHRP polypeptides self-associate in solution to form structures similar to knobs and show binding of self-associated KAHRP clusters to spectrin-actin-protein 4.1 complexes. Findings in this study suggest that PfEMP1 is localized to the knob in P. falciparum-infected erythrocytes by binding to the host spectrin-actin junction and to self-associated KAHRP through its conserved cytoplasmic domain.12: Acta Trop 2000 May 31;75(3):349-59Plasmodium falciparum: red blood cell binding studies of peptides derived from histidine-rich KAHRP-I, HRP-II and HRP-III proteins.

Lopez R, Urquiza M, Curtidor H, Eduardo Caminos J, Mora H, Puentes A, Elkin Patarroyo M

Instituto de Inmunologia, Hospital San Juan de Dios, Universidad Nacional de Colombia, Avda 1 No 10-01 Santafe de, AA:44709, Bogota, Colombia.

Histidine-rich proteins have been associated with Plasmodium falciparum infected red blood cells (RBC) cytoadherence, and RBC rosetting; these phenomena may cause clogging of the post-capillary venules, this being one of the main causes of severe cerebral malaria. They may also participate in parasite mature stages’ evasion of the immune system and their subsequent destruction in the spleen. Non-overlapping synthetic peptides, corresponding to entire amino acid sequences reported for the KAHRP-I, HRP-II and HRP-III proteins, were used in RBC binding assays. Peptides with high and low binding activity were recognized. The KAHRP-I protein shows 3 peptides with high binding affinity to RBCs, two of them variable (peptide 6783, sequence 321QNYVHPWSGYSAPYGVPHGA(340) and peptide 6789, sequence 441KKREKSIMEKNHAAKKLTKK(460)) and the other conserved (peptide 6786, sequence 381KSKKHKDHDGEKKKSKKHKD(400)) having affinity constant of around 190 nM and 1000 binding sites per cell. Interestingly, this peptide shares aminoacid sequences with one reported as being recognized by malaria exposed human antibodies. The HRP-I protein also presents one conserved peptide (peptide 6800, sequence 24NNSAFNNNLCSKNAKGLNLN(43)) with high affinity, located in the amino terminal region of the native protein, having 210 nM affinity constant and 6000 receptor sites. The HRP-III protein only contains peptides with low binding activity. Treatment of red blood cells with neuraminidase reduces the binding of the conserved high binding 6786 and 6800 peptides. Anti-glycophorins A, B and C antibodies inhibit the binding of the conserved high binding 6786 and 6800 peptides. Furthermore, the specific determination of glycoproteins by chemioluminescenoe, in SDS/PAGE western blot, suggests that these glycophorins could be the receptor for these high binding peptides. High binding peptides’ critical amino acids, involved in RBC binding were determined by means of competition binding assays.13: J Infect Dis 2000 Jun;181(6):2111-2115Differential Cellular Accumulation of Transforming Growth Factor-beta1, -beta2, and -beta3 in Brains of Patients Who Died with Cerebral Malaria.

Deininger MH, Kremsner PG, Meyermann R, Schluesener HJ

Institute of Brain Research, University of Tubingen, Medical School, D-72076 Tubingen, Germany.

Email: [email protected]

In cerebral malaria (CM), pathologic cytokine expression patterns are thought to contribute to disruption of the blood-brain barrier, inflammation, and astrocytic scar formation. Expression of transforming growth factor (TGF)-beta1, -beta2, and -beta3 was analyzed in the brains of 7 patients who died with CM and in 8 control patients. In the brains of patients with CM, there were significantly (P=.0003) more TGF-beta1-immunoreactive astrocytes adjacent to brain vessels with deposition of malarial pigment, significantly (P=.0081) more TGF-beta2-expressing macrophages/microglial cells in glioses of ring hemorrhages and Durck’s granulomas, and significantly (P=.0022) more TGF-beta3-expressing smooth-muscle cells and endothelial cells of brain vessels with sequestration. It is concluded that focal accumulation of TGF-beta1, -beta2, and -beta3 provides evidence for their involvement in the reorganization process of the brain parenchyma, immunologic dysfunction, and endothelial cell activation in patients with CM.14: J Infect Dis 2000 Jun;181(6):2023-2028Molecular Evidence of Greater Selective Pressure for Drug Resistance Exerted by the Long-Acting Antifolate Pyrimethamine/Sulfadoxine Compared with the Shorter-Acting Chlorproguanil/Dapsone on Kenyan Plasmodium falciparum.

Nzila AM, Nduati E, Mberu EK, Hopkins Sibley C, Monks SA, Winstanley PA, Watkins WM

Wellcome Trust Research Laboratory, Nairobi, Kenya.Email: [email protected]

Pyrimethamine (PM) plus sulfadoxine (SD) is the last remaining affordable drug for treating uncomplicated malaria in Africa. The selective pressure exerted by the slowly eliminated combination PM/SD was compared with that exerted by the more rapidly eliminated combination chlorproguanil/dapsone (CPG/Dap) on Kenyan Plasmodium falciparum. Point mutations were analyzed in dihydrofolate reductase and dihydropteroate synthase and in the genetic diversity of 3 genes in isolates collected before and after CPG/Dap and PM/SD treatments. PM/SD was associated strongly with the disappearance of fully drug-sensitive parasites and with a significant increase in the prevalence of resistant parasites in subsequent parasitemias. However, this was not a characteristic of treatment with CPG/Dap. Moreover, most of the patients who returned with recrudescent infections were in the PM/SD-treated group. The data predict a longer useful therapeutic life for CPG/Dap than for PM/SD, and, thus, CPG/Dap is a preferable alternative for treatment of chloroquine-resistant falciparum malaria in sub-Saharan Africa.15: Parasitol Res 2000 May;86(5):345-51Epitope-specific impairment of production of antibody against merozoite surface glycoprotein 1 of Plasmodium falciparum in symptomatic patients with malaria.

Fu J, Hato M, Ohmae H, Matsuoka H, Kawabata M, Tanabe K, Miyamoto Y, Leafasia JL, Chinzei Y, Ohta N

Department of Medical Zoology, Mie University School of Medicine, Tsu, Japan.

We analyzed the relationships between levels of antibody specific for merozoite surface glycoprotein-1 (MSP1) of Plasmodium falciparum and clinical manifestations in humans. We prepared recombinant MSP1 proteins representing block 3 (M3), block 6 (M6), blocks 1-6 (M1/6), and block 17. When we divided the slide-positive individuals in Guadalcanal into symptomatic and asymptomatic groups, the former group showed lower IgG levels against M6 and block 17, but not against M3, than did the asymptomatic group (P < 0.01). The possibility of nonspecific suppression was unlikely, given that the levels of antibody against poliomyelitis virus observed in the two groups were almost the same. Among the IgG subclasses tested, production of cytophilic IgG3 seemed to be dominant. When we analyzed epitopes recognized by antibodies against block 17, a peptide (SSSNFLGIS) was preferentially recognized by sera from asymptomatic individuals. These results suggest that clinical symptoms occurring during falciparum malaria seem to be associated with the development of levels of antibody against particular epitopes on MSP1, which is under the control of an immunoregulatory mechanism.
16: Nat Med 2000 Jun;6(6):689-92A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses.

Conway DJ, Cavanagh DR, Tanabe K, Roper C, Mikes ZS, Sakihama N, Bojang KA, Oduola AM, Kremsner PG, Arnot DE, Greenwood BM, McBride JS

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT.

New strategies are required to identify the most important targets of protective immunity in complex eukaryotic pathogens. Natural selection maintains allelic variation in some antigens of the malaria parasite Plasmodium falciparum. Analysis of allele frequency distributions could identify the loci under most intense selection. The merozoite surface protein 1 (Msp1) is the most-abundant surface component on the erythrocyte-invading stage of P. falciparum. Immunization with whole Msp1 has protected monkeys completely against homologous and partially against non-homologous parasite strains. The single-copy msp1 gene, of about 5 kilobases, has highly divergent alleles with stable frequencies in endemic populations. To identify the region of msp1 under strongest selection to maintain alleles within populations, we studied multiple intragenic sequence loci in populations in different regions of Africa and Southeast Asia. On both continents, the locus with the lowest inter-population variance in allele frequencies was block 2, indicating selection in this part of the gene. To test the hypothesis of immune selection, we undertook a large prospective longitudinal cohort study. This demonstrated that serum IgG antibodies against each of the two most frequent allelic types of block 2 of the protein were strongly associated with protection from P. falciparum malaria.17: EMBO J 2000 Jun 1;19(11):2435-2443RAP1 controls rhoptry targeting of RAP2 in the malaria parasite Plasmodium falciparum.

Baldi DL, Andrews KT, Waller RF, Roos DS, Howard RF, Crabb BS, Cowman AF

The Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Queensland Institute of Medical Research, Brisbane, Plant Cell Biology Research Center, School of Botany, University of Melbourne, Melbourne, Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia, Department of Biology, University of Pennsylvania, Philadelphia, PA 19104 and Seattle Biomedical Research Institute, Seattle, WA 98109, USA 

Email: [email protected]

Rhoptry associated protein 1 (RAP1) and 2 (RAP2), together with a poorly described third protein RAP3, form the low molecular weight complex within the rhoptries of Plasmodium falciparum. These proteins are thought to play a role in erythrocyte invasion by the extracellular merozoite and are important vaccine candidates. We used gene-targeting technology in P.falciparum blood-stage parasites to disrupt the RAP1 gene, producing parasites that express severely truncated forms of RAP1. Immunoprecipitation experiments suggest that truncated RAP1 species did not complex with RAP2 and RAP3. Consistent with this were the distinct subcellular localizations of RAP1 and 2 in disrupted RAP1 parasites, where RAP2 does not traffic to the rhoptries but is instead located in a compartment that appears related to the lumen of the endoplasmic reticulum. These results suggest that RAP1 is required to localize RAP2 to the rhoptries, supporting the hypothesis that rhoptry biogenesis is dependent in part on the secretory pathway in the parasite. The observation that apparently host-protective merozoite antigens are not essential for efficient erythrocyte invasion has important implications for vaccine design.18: Crit Care Med 2000 May;28(5):1353-62Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis.

Day NP, Phu NH, Mai NT, Bethell DB, Chau TT, Loc PP, Chuong LV, Sinh DX, Solomon T, Haywood G, Hien TT, White NJ

Wellcome Trust Clinical Research Unit, Ho Chi Minh City, Viet Nam.

OBJECTIVE: To describe and compare the effects of dopamine and epinephrine in various doses on renal hemodynamics and oxygen transport in patients with severe malaria and severe sepsis. DESIGN: Prospective, controlled, crossover trial. SETTING: The intensive care unit of an infectious diseases hospital in Viet Nam. PATIENTS: Fourteen patients with severe falciparum malaria and five with severe sepsis. INTERVENTIONS: In an open, crossover design, we observed the effects on renal and systemic hemodynamics and oxygen transport of separate stepped infusions of epinephrine and dopamine. We measured renal blood flow (RBF) and cardiac output by the thermodilution method using fluoroscopically guided catheters. Creatinine clearance at each time point was calculated from the renal plasma flow and the renal arteriovenous difference in plasma creatinine. MEASUREMENTS AND MAIN RESULTS: Dopamine at a “renal” dose (2.5 microg/kg/min) was associated with a mean (95% confidence interval) fractional increase in the absolute renal blood flow index (RBFI) of 37% (13% to 61%) and in RBF as a fraction of cardiac output (RBF/CO) of 35% (10% to 59%; p = .007 and p = .014, respectively). The consequent 39% (14% to 64%) increase in renal oxygen supply (p = .002) was accompanied by a 32% (20% to 44%) decrease in the renal oxygen extraction ratio (p = .0003), leading to no net change in renal oxygen consumption. At higher doses (10 microg/kg/min), both RBF and RBF/CO were not significantly different from baseline values and decreased further as the dose was reduced again. There was no obvious explanation for this hysteresis. There was no change in renal oxygen consumption throughout the study. Because lactic acidosis developed, epinephrine was only given to eight of the 19 patients, and the full stepped epinephrine infusion was given to four patients. Epinephrine infusion was associated, both in absolute terms and when compared with dopamine, with a significant increase in renal vascular resistance (p = .0008 and .0005, respectively), a decrease in RBF/CO (p = .002 and .03), and a compensatory increase in the renal oxygen extraction ratio (p = .005 and .0001). RBFI and renal oxygen consumption remained constant throughout the epinephrine infusion profile. Neither epinephrine nor dopamine significantly affected creatinine clearance or urine output. Twelve patients (63%) were in established renal failure (plasma creatinine, >3 mg/dL) at the time of the study, although the presence or absence of renal failure did not significantly influence the effects of the study drugs. However, overall, the presence of renal failure was associated with a lower mean renal oxygen consumption, a lower mean renal oxygen consumption as a fraction of systemic oxygen consumption, and a higher mean renal vascular resistance. CONCLUSION: Although dopamine increased and epinephrine decreased fractional renal blood flow, there was no evidence that either drug produced either a beneficial or a deleterious effect on renal oxygen metabolism or function at any of the doses investigated.19: Placenta 2000 May;21(4):417-421Placental Haemozoin and Malaria in Pregnancy.

Sullivan AD, Nyirenda T, Cullinan T, Taylor T, Lau A, Meshnick SR

Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA

Malaria infections in pregnant women cause poor birth outcomes. Malaria pigment (haemozoin) accumulates in the placenta within macrophages and extracellularly, but its pathological significance is not understood. In order to study the potential role of haemozoin in malaria pathogenesis, we enrolled primigravid women at a Malawian government antenatal clinic and followed them through delivery. One hundred and thirteen women (71 per cent) out of 159 women followed through delivery were parasitaemic at least once. Mean placental haemozoin concentrations were significantly higher in women with delivery parasitaemias (223 ng/mg protein) than in women who never had a detectable parasitaemia (43 ng/mg protein;P< 0.05), but were not significantly higher in women who were parasitaemic only during the antenatal period (67 ng/mg protein). Haemozoin was not associated with preterm delivery (PTD) or intrauterine growth retardation (IUGR) (P -values, 0.307-0.787). Thus, placental haemozoin is associated with malaria infection at the time of delivery and does not seem to be associated with poor birth outcome. Copyright 2000 Harcourt Publishers Ltd.

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