EHP Library Malaria Bulletin – March 9 – 20, 2001

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Social Sciences and Malaria

Soc Sci Med 2001 Mar;52(6):885-909Private practitioners and their role in the resurgence of malaria in Mumbai (Bombay) and Navi Mumbai (New Bombay), India: serving the affected or aiding an epidemic?

Kamat VR
Department of Anthropology, Emory University, Atlanta, GA 30322, USA.

The increased emphasis on privatization of the health care sector in many developing countries by international financial institutions and national governments expects an expanding role for private health care practitioners in the management of major communicable diseases such as tuberculosis, malaria, acute respiratory infections (ARIs) and sexually transmitted diseases (STDs). Largely unexamined in the Indian context, however, is the socio-cultural context, the micro-level political environment in which private practitioners carry out their activities, and the quality of care they provide to their patients. Examining these aspects is significant given the impressive growth of the country’s private health sector during the past decade. This paper reports the results of an ethnographic study carried out in Mumbai (Bombay) and Nav Mumbai (New Bombay), India on private general practitioners (GPs) and their role in the management of malaria at a time when these two neighboring cities were in the midst of the worst malaria epidemic in over 60 years. Described are the characteristics of a sample of 48 private practitioners from the two cities, and their clinics. This is followed by a discussion of the data gathered through untructured interviews with practitioners and patients, and complemented by observational data on doctor-patient encounters gathered at 16 clinics over a 9-month period. The findings of the study suggest that many practitioners in Mumbai and Navi Mumbai were poorly qualified and did not play a supportive role in the two cities’ public health departments to bring the epidemic under control. The majority of the practitioners adopted diagnostic and treatment practices that were not consistent with the guidelines laid down by WHO and India’s National Malaria Eradication Programme. Very few practitioners, especially those practicing in low-income areas, relied on a peripheral blood-smear test to make a diagnosis. Practitioners whose clientele was mostly the poor commonly resorted to giving one-day treatment to febrile patients that included injectable antimalarials and broad spectrum antibiotics. Such practitioners justified their mode of diagnosis and treatment by asserting that they were only responding to the demands placed on them by their patients who could not afford a blood-smear test or a full prescription. The paper argues that practitioners who acquiesced to patient demands were at once exacerbating the health problems of their patients and jeopardizing the prospects for the epidemic to be brought under control. Driven primarily by the need to retain the patronage of patients and maintain one’s popularity in a highly competitive health arena, many providers practiced medicine that was unethical and dangerous. The paper concludes by discussing the ramifications of this study for malaria control in Mumbai and Navi Mumbai, and highlights a few salient health policy issues concerning the growth of the private health sector in India and its regulation.


Vaccine 2001 Mar 21;19(17-19):2315-2318
Genomic tools for gene and protein discovery in malaria: toward new vaccines.

Carucci DJ
Malaria Program, Naval Medical Research Center, 20910, Silver Spring, MD, USA

Advances in malaria vaccine and drug development have been hindered in part by the complex multistage life cycle of the parasite, much of which is inaccessible to study, and by a large genome encoding over 5000 genes. Two human models of immunity to malaria, however, suggest that the development of an effective vaccine is within reach. We have outlined a strategy to identify the expression of hundreds to thousands of potential vaccine targets employing recently developed technologies for gene and protein expression. Combined with the exciting developments of malaria DNA vaccine technologies, these approaches form the basis for malaria subunit vaccines that may mimic the protective efficacy of our human model systems and provide the foundation for novel approaches to vaccine development for a range of pathogens.

Vaccine 2001 Mar 21;19(17-19):2309-2314
Transmission blocking malaria vaccines.

Carter R
University of Edinburgh, Division of Biological Sciences, West Mains Road, EH9 3JT, Edinburgh, UK

Transmission blocking vaccines (TBVs) against malaria are intended to induce immunity against the stages of the parasites which infect mosquitoes so that TBV-immunised individuals cannot transmit malaria. As malarial infections are transmitted mainly within a few hundreds of meters from an infectious human source, TBVs used within in a community would protect the immediate neighbourhood of the vaccinated individuals. TBVs against the two major species of human malaria, Plasmodium falciparum and P. vivax, are under development. Candidate TBV constructs for both Plasmodium species have been successfully tested in animal systems and testing is in progress with clinical grade material in humans.

Evol Dev 2000 Nov-Dec;2(6):326-39
Characterization of the Hox gene cluster in the malaria vector mosquito, Anopheles gambiae.

Devenport MP, Blass C, Eggleston P
Department of Genetics, Case Western Reserve University, School of Medicine, Cleveland, OH 44106-4955, USA.

The Hox genes play a central role in regulating development and are involved in the specification of cell fates along the anteroposterior axis. In insects and vertebrates, these genes are clustered and organized in an arrangement that is largely conserved across evolutionary lineages. By exploiting the sequence conservation of the homeobox, orthologues of the Hox genes Sex combs reduced (Scr), fushi tarazu (ftz), Antennapedia (Antp), Ultrabithorax (Ubx), and abdominal-A (abd-A) have been isolated from the malaria vector mosquito, Anopheles gambiae. These genes were first identified in Drosophila, where they achieve a high level of functional complexity, in part, by the use of alternative promoters, polyadenylation sites, and splicing to generate different protein isoforms. Preliminary analyses of the Anopheles Hox genes suggest that they do not achieve their functional complexity in the same manner. Using a combination of in situ hybridization to polytene chromosomes and chromosome walking, the Anopheles Hox genes have been localized to a single cluster in the region 19D-E on chromosome 2R, a situation distinct from that of Drosophila where the Hox complex is split into two clusters. This study, therefore, provides a framework for future comparative analyses of the structure, organization, and expression of developmental regulatory genes between the lower and higher Diptera. Moreover, the genes that have been isolated enhance the genetic and physical maps of chromosome 2R in this medically important mosquito species.

Mol Biochem Parasitol 2001 Mar;113(1):151-6
Complementation of Plasmodium berghei TRAP knockout parasites using human dihydrofolate reductase gene as a selectable marker.

Sultan AA, Thathy V, de Koning-Ward TF, Nussenzweig V
Department of Pathology, Michael Heidelberger Division of Immunology, New York University School of Medicine, 10016, New York, NY, USA

Previously we have used the Plasmodium dihydrofolate reductase thymidylate synthase (DHFR-TS) selectable marker to generate Plasmodium berghei TRAP null mutant parasites. These TRAP null mutants do not glide and they showed a great reduction in their ability to infect mosquito salivary glands and the hepatocytes of the vertebrate host. Thus far, complementation of these knockout parasites was not possible due to the lack of additional selectable markers. Recently, a new selectable marker, based on the human dihydrofolate reductase (hDHFR) gene, has been developed which confers resistance to the antifolate drug WR99210. This drug has been found to be highly active against pyrimethamine-sensitive and -resistant strains of P. berghei. In this study, we have used the hDHFR gene as a second selectable marker for the complementation of P. berghei TRAP null mutant parasites. Restoration of the TRAP null mutant parasites to the wild-type phenotype was achieved in this study via autonomously replicating episomes bearing a wild-type copy of the TRAP gene. This is the first report of complementation of a mutant phenotype in malaria parasites.

Mol Biochem Parasitol 2001 Mar;113(1):139-50
Mutagenesis of dihydrofolate reductase from Plasmodium falciparum: analysis in Saccharomyces cerevisiae of triple mutant alleles resistant to pyrimethamine or WR99210.

Ferlan JT, Mookherjee S, Okezie IN, Fulgence L, Sibley CH
Department of Genetics, University of Washington, P.O. Box 357360, 98195-7360, Seattle, WA, USA

Inhibitors of dihydrofolate reductase (DHFR) have been a mainstay of chemotherapy of falciparum malaria for >50 years. Unfortunately, point mutations in DHFR are the major cause of resistance to drugs of this class and mutations have rapidly diminished the clinical effectiveness of these drugs. We designed a simple yeast-based system to produce and analyze point mutations in the Plasmodium falciparum DHFR domain of the DHFR-thymidylate synthase gene that confers resistance to pyrimethamine (PM), the major antifolate currently used in malaria treatment, or to WR99210, an experimental antifolate. We used PCR mutagenesis, screened >1000 DHFR alleles that encoded functional enzymes and studied approximately 100 that were more resistant than a naturally occurring resistant allele (N51I and S108N). The IC(50) values for both drugs were determined for a subset of 44 alleles that carried only a single new mutation. Mutations that increased resistance to PM 10-100 fold (to >10(-4) M) were identified in three regions of the DHFR domain – around amino acids 50, 188 and 213. In contrast, mutations that caused WR-resistance were far less common and only conferred approximately 10-fold resistance (to approximately 10(-7) M). Even more interesting, only the mutations at 188 increased resistance to WR and mutations in the 213 and other regions either had no effect or actually increased sensitivity to WR. This collateral hypersensitivity raises the possibility that opposing selection for resistance/sensitivity to PM and WR might be used to slow selection of populations of P. falciparum resistant to antifolate treatment.

Mol Biochem Parasitol 2001 Mar;113(1):89-96
Bacteria expressing single-chain immunotoxin inhibit malaria parasite development in mosquitoes.

Yoshida S, Ioka D, Matsuoka H, Endo H, Ishii A
Department of Medical Zoology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachimachi, 329-0498, Tochigi, Japan

Single-chain immunotoxins are ideal tools to selectively kill infectious agents. In applying this technology to block transmission of malaria parasites in the mosquito vector, we have constructed a single-chain immunotoxin composed of a single-chain antibody fragment (scFv) directed to Pbs2l on the surface of Plasmodium berghei ookinetes linked to a lytic peptide, Shiva-1. The single-chain immunotoxin was expressed in Escherichia coli, and the protein was purified by a Ni-NTA column. The single-chain immunotoxin was initially shown to exhibit greater killing properties for P. berghei ookinetes in vitro compared with the scFv or synthetic Shiva-1 peptide alone. In an attempt to block malaria transmission by genetically engineered bacteria, recombinant E. coli harboring the single-chain immunotoxin gene were introduced into the mosquito midgut by membrane feeding. The number of infected mosquitoes and their oocyst densities were significantly reduced when the mosquitoes were subsequently allowed to feed on P. berghei-infected mice. These results indicate not only that a single-chain immunotoxin with enhanced parasiticidal activity could form a basis for the development of more effective malaria therapeutic agents, but also that introduction of genetically engineered bacteria into anopheline mosquitoes may offer a practical approach to the regulation of malaria transmission.

Mol Biochem Parasitol 2001 Mar;113(1):23-34
Serial analysis of gene expression (SAGE) in Plasmodium falciparum: application of the technique to A-T rich genomes.

Munasinghe A, Patankar S, Cook BP, Madden SL, Martin RK, Kyle DE, Shoaibi A, Cummings LM, Wirth DF
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard University, Building 1, Room 704, 665 Huntington Ave, 02115, Boston MA, USA

The advent of high-throughput methods for the analysis of global gene expression, together with the Malaria Genome Project open up new opportunities for furthering our understanding of the fundamental biology and virulence of the malaria parasite. Serial analysis of gene expression (SAGE) is particularly well suited for malarial systems, as the genomes of Plasmodium species remain to be fully annotated. By simultaneously and quantitatively analyzing mRNA transcript profiles from a given cell population, SAGE allows for the discovery of new genes. In this study, one reports the successful application of SAGE in Plasmodium falciparum, 3D7 strain parasites, from which a preliminary library of 6880 tags corresponding to 4146 different genes was generated. It was demonstrated that P. falciparum is amenable to this technique, despite the remarkably high A-T content of its genome. SAGE tags as short as 10 nucleotides were sufficient to uniquely identify parasite transcripts from both nuclear and mitochondrial genomes. Moreover, the skewed A-T content of parasite sequence did not preclude the use of enzymes that are crucial for generating representative SAGE libraries. Finally, a few modifications to DNA extraction and cloning steps of the SAGE protocol proved useful for circumventing specific problems presented by A-T rich genomes.

Mol Biochem Parasitol 2001 Mar;113(1):9-21
Sialic acid-dependent binding of baculovirus-expressed recombinant antigens from Plasmodium falciparum EBA-175 to Glycophorin A.

Ockenhouse CF, Barbosa A, Blackall DP, Murphy CI, Kashala O, Dutta S, Lanar DE, Daugherty JR
Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, MD, USA

The Plasmodium falciparum Erythrocyte Binding Antigen-175, EBA-175, is a soluble merozoite stage parasite protein which binds to glycophorin A surface receptors on human erythrocytes. We have expressed two conserved cysteine-rich regions, region II and region VI, of this protein as soluble His-tagged polypeptides in insect cell culture, and have tested their function in erythrocyte and glycophorin A binding assays. Recombinant region II polypeptides comprised of the F2 sub-domain or the entire region II (F1 and F2 sub-domains together) bound to erythrocytes and to purified glycophorin A in a manner similar to the binding of native P. falciparum EBA-175 to human red cells. Removal of sialic acid residues from the red cell surface totally abolished recombinant region II binding, while trypsin treatment of the erythrocyte surface reduced but did not eliminate recombinant region II binding. Synthetic peptides from three discontinuous regions of the F2 sub-domain of region II inhibited human erythrocyte cell binding and glycophorin A receptor recognition. Immune sera raised against EBA-175 recombinant proteins recognized native P. falciparum-derived EBA-175, and sera from malaria-immune adults recognized recombinant antigens attesting to both the antigenicity and immunogenicity of proteins. These results suggest that the functionally-active recombinant region II domain of EBA-175 may be an attractive candidate for inclusion in multi-component asexual blood stage vaccines.

Thorax 2001 Apr;56(4):290-5
Prenatal risk factors of wheezing at the age of four years in Tanzania.

Sunyer J, Mendendez C, Ventura PJ, Aponte JJ, Schellenberg D, Kahigwa E, Acosta C, Anto JM, Alonso PL
Unitat de Recerca Respiratoria I Ambiental, Institut Municipal d’Investigacio Medica (IMIM), Doctor Aiguader 80, E-08003 Barcelona, Spain.

BACKGROUND: A study was undertaken to assess the interactions between prenatal exposures, early life infections, atopic predisposition, and allergen exposures in the development of wheezing up to the age of 4 years in a tropical region of Africa. METHODS: The study subjects comprised children born at the district hospital in Ifakara, Tanzania during a 1 year period who were participating in a trial of iron supplementation and malaria chemoprophylaxis during the first year of life and followed for up to 4 years. From this group of subjects, 658 (79%) participated in the interview at 18 months and 528 (64%) in a second interview at 4 years. Wheezing was measured with the ISAAC questionnaire. A hospital based inpatient and outpatient surveillance system was set up to document all attendance by study children for any cause, including episodes of clinical malaria and lower respiratory tract infections. Total IgE levels and malaria parasites were measured in maternal and cord blood. Total IgE was also measured at 18 months of age. Indoor environmental levels of Der p I and Fel d I were determined using an enzyme linked immunosorbent assay at the same time as the interview at the age of 18 months. RESULTS: The prevalence of wheezing at 4 years is common in Ifakara (14%, range 13-15%). The presence of malaria parasites in cord blood (odds ratio, OR = 6.84, 95% CI 1.84 to 24.0) and maternal asthma (OR = 8.47, 95% CI 2.72 to 26.2) were positively associated with wheezing at the age of 4 years, and cord blood total IgE was negatively associated (OR = 0.24, 95% CI 0.07 to 0.85) (all p<0.05). Parasitaemia at birth was not related to total IgE levels in cord blood (p=0.6). Clinical episodes of malaria during infancy were not associated with wheezing, and nor were levels of indoor aeroallergens. CONCLUSION: These findings suggest that events occurring during pregnancy may play a role in the future appearance of wheezing, although the results must be interpreted with caution because of the small numbers studied.

Infect Immun 2001 Apr;69(4):2558-68
Rhoptry-Associated Protein 1-Binding Monoclonal Antibody Raised against a Heterologous Peptide Sequence Inhibits Plasmodium falciparum Growth In Vitro.

Moreno R, Poltl-Frank F, Stuber D, Matile H, Mutz M, Weiss NA, Pluschke G
Swiss Tropical Institute, CH-4002 Basel, Switzerland.

Monoclonal antibodies (MAbs) specific for Plasmodium falciparum rhoptry-associated protein 1 (RAP-1) were generated and tested for inhibition of parasite growth in vitro. The majority of indirect immunofluorescence assay (IFA)-positive MAbs raised against recombinant RAP-1 positions 23 to 711 (rRAP-1(23-711)) recognized epitopes located in the immunodominant N-terminal third of RAP-1. MAbs specific for the building block 35.1 of the synthetic peptide malaria vaccine SPf66 also yielded an IFA staining pattern characteristic for rhoptry-associated proteins and reacted specifically with rRAP-1 and parasite-derived RAP-1 molecules p67 and p82. Cross-reactivity with RAP-1 was blocked by the 35.1 peptide. Epitope mapping with truncated rRAP-1 molecules and overlapping peptides identified the linear RAP-1 sequence Y(218)KYSL(222) as a target of the anti-35.1 MAbs. This sequence lacks primary sequence similarity with the 35.1 peptide (YGGPANKKNAG). Cross-reactivity of the anti-35.1 MAbs thus appears to be associated with conformational rather than sequence homology. While the anti-35.1 MAb SP8.18 exhibited parasite growth-inhibitory activity, none of the tested anti-rRAP-1(23-711) MAbs inhibited parasite growth, independently of their fine specificity for the RAP-1 sequences at positions 33 to 42, 213 to 222, 243 to 247, 280 to 287, or 405 to 446. The growth-inhibitory activity of MAb SP8.18 was, however, accelerated by noninhibitory anti-RAP-1 MAbs. Results demonstrate that in addition to fine specificity, other binding parameters are also crucial for the inhibitory potential of an antibody.

Infect Immun 2001 Apr;69(4):2535-41
Antibody Recognition of Rodent Malaria Parasite Antigens Exposed at the Infected Erythrocyte Surface: Specificity of Immunity Generated in Hyperimmune Mice.

Mota MM, Brown KN, Do Rosario VE, Holder AA, Jarra W
Division of Parasitology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.

In regions where malaria is endemic, inhabitants remain susceptible to repeated reinfection as they develop and maintain clinical immunity. This immunity includes responses to surface-exposed antigens on Plasmodium sp.-infected erythrocytes. Some of these parasite-encoded antigens may be diverse and phenotypically variable, and the ability to respond to this diversity and variability is an important component of acquired immunity. Characterizing the relative specificities of antibody responses during the acquisition of immunity and in hyperimmune individuals is thus an important adjunct to vaccine research. This is logistically difficult to do in the field but is relatively easily carried out in animal models. Infections in inbred mice with rodent malaria parasite Plasmodium chabaudi chabaudi AS represent a good model for Plasmodium falciparum in humans. This model has been used in the present study in a comparative analysis of cross-reactive and specific immune responses in rodent malaria. CBA/Ca mice were rendered hyperimmune to P. chabaudi chabaudi (AS or CB lines) or Plasmodium berghei (KSP-11 line) by repeated infection with homologous parasites. Serum from P. chabaudi chabaudi AS hyperimmune mice reacted with antigens released from disrupted P. chabaudi chabaudi AS-infected erythrocytes, but P. chabaudi chabaudi CB and P. berghei KSP-11 hyperimmune serum also contained cross-reactive antibodies to these antigens. However, antibody activity directed against antigens exposed at the surfaces of intact P. chabaudi chabaudi-infected erythrocytes was mainly parasite species specific and, to a lesser extent, parasite line specific. Importantly, this response included opsonizing antibodies, which bound to infected erythrocytes, leading to their phagocytosis and destruction by macrophages. The results are discussed in the context of the role that antibodies to both variable and invariant antigens may play in protective immunity in the face of continuous susceptibility to reinfection.

Infect Immun 2001 Apr;69(4):2364-71
Cellular Basis of Early Cytokine Response to Plasmodium falciparum.

Hensmann M, Kwiatkowski D
Department of Paediatrics, Oxford University, Oxford OX3 9DU, United Kingdom.

Uncertainty remains about the cellular origins of the earliest phase of the proinflammatory cytokine response to malaria. Here we show by fluorescence-activated cell sorter analysis that gammadelta T cells and CD14(+) cells from nonimmune donors produce tumor necrosis factor and that gammadelta T cells also produce gamma interferon within 18 h of contact with mycoplasma-free Plasmodium falciparum-infected erythrocytes in vitro. This early cytokine response is more effectively induced by intact than by lysed parasitized erythrocytes. However, the IFN-gamma response to lysed parasites is considerably enhanced several days after peripheral blood mononuclear cells are primed with low numbers of intact parasitized erythrocytes, and in this case it derives from both alphabeta and gammadelta T cells. These data show that naive gammadelta T cells can respond very rapidly to malaria infection but that malaria fever may involve a multistage process in which the priming of both gammadelta and alphabeta T-cell populations boosts the cytokine response to lysed parasite products released at schizont rupture.

Infect Immun 2001 Apr;69(4):2245-51
Different Regions of the Malaria Merozoite Surface Protein 1 of Plasmodium chabaudi Elicit Distinct T-Cell and Antibody Isotype Responses.

Quin SJ, Langhorne J
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, United Kingdom.

In this study we have investigated the antibody and CD4 T-cell responses to the well-characterized malaria vaccine candidate MSP-1 during the course of a primary Plasmodium chabaudi chabaudi (AS) infection. Specific antibody responses can be detected within the first week of infection, and CD4 T cells can be detected after 3 weeks of infection. The magnitude of the CD4 T-cell response elicited during a primary infection depended upon the region of MSP-1. In general, the highest precursor frequencies were obtained when a recombinant MSP-1 fragment corresponding to amino acids 900 to 1507 was used as the antigen in vitro. By contrast, proliferative and cytokine responses against amino acids 1508 to 1766 containing the C-terminal 21-kDa region of the molecule were low. The characteristic interleukin 4 (IL-4) switch that occurs in the CD4 T-cell population after an acute blood stage P. c. chabaudi infection was only consistently observed in the response to the amino acid 900 to 1507 MSP1 fragment. A lower frequency of IL-4-producing cells was seen in response to other regions. Although the magnitudes of the immunoglobulin G antibody responses to the different regions of MSP-1 were similar, the isotype composition of each response was distinct, and there was no obvious relationship with the type of T helper cells generated. Interestingly, a relatively high antibody response to the C-terminal region of MSP-1 was observed, suggesting that T-cell epitopes outside of this region may provide the necessary cognate help for specific antibody production.

Rev Panam Salud Publica 2001 Jan;9(1):23-9
[No title available].  [Article in Spanish]

Blair S, Lacharme LL, Fonseca JC, Tobon A
Grupo de Malaria, Facultad de Medicina, Universidad de Antioquia. [email protected]

In 1998 we determined in vivo and in vitro the frequency and the degree of resistance of Plasmodium falciparum to the three antimalarials (chloroquine, amodiaquine, and sulfadoxine/pyrimethamine) most utilized in the municipality of Turbo (in the area of Uraba, Antioquia, Colombia), in a sample representative of the population with malaria. We carried out clinical and parasitological analyses over a 14-day period using the standard test recommended by the World Health Organization. In vivo, P. falciparum showed resistance to chloroquine, amodiaquine, and sulfadoxine/pyrimethamine, with a frequency of 97%, 7%, and 13%, respectively. In vitro, the corresponding figures were 21%, 23%, and 9%, respectively. For chloroquine the level of agreement between the in vivo and in vitro results was 23%.

Trop Med Int Health 2001 Feb;6(2):102-107
Evidence for a reduced effect of chloroquine against Plasmodium falciparum in alpha-thalassaemic children.

Mockenhaupt FP, May J, Bergqvist Y, Meyer CG, Falusi AG, Bienzle U
Institute of Tropical Medicine and Medical Faculty Charite, Humboldt-University Berlin, Germany; Department of Clinical Chemistry, Dalarna University College, Borlange, Sweden; Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany; Postgraduate Institute for Medical Research and Training, University of Ibadan, Nigeria.

Alpha-thalassaemia is common in malaria-endemic regions and is considered to confer protection from clinical disease due to infection with Plasmodium falciparum. In vitro, sensitivity to chloroquine (CQ) of P. falciparum infecting alpha-thalassaemic erythrocytes is reduced. We examined, in a cross-sectional study of 405 Nigerian children, associations between alpha-globin genotypes, blood concentrations of CQ, and P. falciparum parasitaemia. Of the children, 44% were alpha+-thalassaemic (36.8% heterozygous, 7.6% homozygous). CQ in blood and P. falciparum-infection were observed in 52 and 80%, respectively. CQ was more frequently found in homozygous alpha+-thalassaemic (71%) than in non-thalassaemic children (50%; odds ratio, 2.42; 95% confidence interval, 1.01-5.8). Among children with CQ in blood and despite similar drug concentrations, alpha+-thalassaemic individuals had fewer infections below the threshold of microscopy which were detectable by PCR only, and they had a higher prevalence of elevated parasitaemia than non-thalassaemic children. No such differences were discernible among drug-free children. CQ displays a lowered efficacy in the suppression of P. falciparum parasitaemia in alpha+-thalassaemic children; hence protection against malaria due to alpha+-thalassaemia may be obscured in areas of intense CQ usage. Moreover, alpha+-thalassaemia may contribute to the expansion of CQ resistance.

Trop Med Int Health 2001 Feb;6(2):99-101
Paracheck-Pf(R): a new, inexpensive and reliable rapid test for P. falciparum malaria.

Proux S, Hkirijareon L, Ngamngonkiri C, McConnell S, Nosten F
Shoklo Malaria Research Unit, Mae Sod, Thailand; Programme for Appropriate Technology in Health, Ottawa, Canada; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine, John Radcliffe Hospital, Oxford, UK.

We compared the performance of Paracheck-Pf(R), a new and cheap rapid malaria test, with ICT-Pf/Pv(R) and microscopy in two malaria surveys in Thai villages on the Thai-Burmese border. The specificity, sensitivity, predictive positive and negative values of the Paracheck-Pf(R) and ICT-Pf(R) tests were calculated taking microscopy results as the gold standard. The 294 ICT-Pf/Pv tests resulted in two invalid (no control line) and 11 doubtful results. Both the ICT-Pf/Pv(R) and Paracheck-Pf(R) tests reliably detected P. falciparum infections. However, Paracheck-Pf(R) failed to detect three P. falciparum cases and likewise, ICT-Pf/Pv(R) failed to detect the same three cases and an additional four cases. These seven cases were detected by microscopy and had a parasitaemia under 150 parasites/?l. At a cost of c. US $1.00, the Paracheck-Pf(R) test, based on the detection of the P. falciparum specific HRP-2 protein, is a reliable, easy to use and affordable tool for the diagnosis of P. falciparum malaria.

Trop Med Int Health 2001 Feb;6(2):92-8
Parasitaemia and gametocytaemia after treatment with chloroquine, pyrimethamine/sulfadoxine, and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria.

Seidlein LV, Jawara M, Coleman R, Doherty T, Walraven G, Targett G
Medical Research Council Laboratories, Fajara, The Gambia; Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK.

As part of a study to assess the infectivity of gametocytes after treatment with four antimalarial regimens, the efficacy of each treatment was also determined. From September to December 1998, 598 children with uncomplicated malaria were treated; 135 received chloroquine (CQ) alone, 276 received pyrimethamine/sulfadoxine (FansidarCopyright, PSD) alone, 113 received PSD with a single dose of artesunate (PSD + 1ART) and 74 received PSD combined with three doses of artesunate (PSD + 3ART). On day 28 19/63 (30.2%; 95% C.I. 19.2% to 43.1%) of children treated with CQ alone, 5/134 (3.7%; 95% C.I. 1.2% to 8.5%) treated with PSD alone, 1/71 (1.4%, 95% C.I. 0.0% to 7.9%) treated with PSD + 1ART and 0/45 (0.0%; 95% C.I. 0.0% to 7.9%) treated with PSD + 3ART were parasitaemic. The proportion of children with gametocytes on day 7 after treatment with CQ alone was 16/89 (18.0%; 95% C.I. 10.6% to 27.6%), 98/174 (56.3%; 95% C.I. 48.6% to 63.8%) after treatment with PSD alone, 8/70 (11.4%; 95% C.I. 5.1% to 21.3%) after treatment with PSD + 1ART and 4/46 (8.7%; 95% C.I., 2.4% to 20.8%) after treatment with PSD + 3ART. CQ thus has a lower efficacy than PSD or either of the PSD and artesunate combinations. Use of PSD alone as an alternative first line treatment results in a very high post-treatment gametocyte prevalence that is likely to enhance transmission. There would be greater and more sustainable benefits from using PSD and artesunate combinations.

Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3050-5
A yeast-like mRNA capping apparatus in Plasmodiumfalciparum.

Ho CK, Shuman S
Molecular Biology Program, Sloan-Kettering Institute, New York, NY 10021.

Analysis of the mRNA capping apparatus of the malaria parasite Plasmodium falciparum illuminates an evolutionary connection to fungi rather than metazoans. We show that P. falciparum encodes separate RNA guanylyltransferase (Pgt1) and RNA triphosphatase (Prt1) enzymes and that the triphosphatase component is a member of the fungal/viral family of metal-dependent phosphohydrolases, which are structurally and mechanistically unrelated to the cysteine-phosphatase-type RNA triphosphatases found in metazoans and plants. These results highlight the potential for discovery of mechanism-based antimalarial drugs designed to specifically block the capping of Plasmodium mRNAs. A simple heuristic scheme of eukaryotic phylogeny is suggested based on the structure and physical linkage of the triphosphatase and guanylyltransferase enzymes that catalyze cap formation.

Parasite Immunol 2001 Feb;23(2):103-8
Immune responses to multiple antigen peptides containing T and B epitopes from Plasmodium falciparum circumsporozoite protein of Brazilian individuals naturally exposed to malaria.

Avila SL, Goldberg AC, Arruk VG, Marin ML, Guilherme L, Kalil J, Ferreira AW
Institute of Tropical Medicine of Sao Paulo, School of Medicine, University of Sao Paulo, Brazil and Heart Institute, InCor, School of Medicine, University of Sao Paulo, Brazil.

We have evaluated the immune responses of individuals living in a malaria endemic area of Brazil to the (T1B)4, a multiple antigen peptide (MAP) from Plasmodium falciparum circumsporozoite (CS) protein and the related monoepitope MAPs, B4 and (T1)4, and the linear peptides, T1B and B. The highest antibody frequencies were against MAPs containing the B cell epitope sequence (T1B)4 (42.2%) and B4 (28.8%), while the highest lymphoproliferative response frequencies were against the MAPs containing the T cell epitope sequence (T1)4 (47%) and (T1B)4 (36.4%). We analysed individual responses considering lymphoproliferative response to (T1)4 MAP and IgG antibody titre to (T1B)4 as patterns of ideal cellular and humoral responses, respectively. The frequency of responders, cellular and/or humoral was 66.6%, significantly higher than non responders (P = 0.003). We also determined the HLA class II haplotype of each individual but no association between these and immune response patterns to the MAPs was observed. The results showed that individuals primed against P. falciparum in their natural habitat, present a very diverse array of responses against the same peptide antigens, varying from no response in one-third of the individuals to cognate B and T cell responses. Our study underlines the importance of previous studies of vaccine candidates to guarantee that the immunization will be capable of reverting inefficient or absent responses to malaria epitopes.

Parasite Immunol 2001 Feb;23(2):51-59
Do maternally acquired antibodies protect infants from malaria infection?

Riley EM, Wagner GE, Akanmori BD, Koram KA
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK, Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, UK and Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.

Neonates and infants are relatively protected from clinical malaria, but the mechanism of this protection is not well understood. Maternally derived antibodies are commonly believed to provide protection against many infectious diseases, including malaria, for periods of up to 6-9 months but several recent epidemiological studies have produced conflicting results regarding a protective role of passively acquired antimalarial antibodies. In this article, we review the epidemiological evidence for resistance of young infants to malaria, summarize the data on antimalarial antibody levels and specificity and their association with protection from malaria infection or clinical disease, and explore alternative explanations for resistance to malaria in infants.

Health Policy Plan 2001 Mar;16(1):1-12
The challenge of chloroquine-resistant malaria in sub-Saharan Africa.

Nuwaha F
Department of Community Health, Mbarara University, Mbarara, Uganda.

For the last decade chloroquine-resistant Plasmodium falciparum (CRPF) has spread explosively in sub-Saharan Africa. In some areas of the continent, CRPF is so intense that chloroquine can hardly be said to have any efficacy. There is emerging evidence that CRPF is linked with increased incidence of mortality, severe disease and emergence of epidemics. Whereas the normal response to this trend of events would be replacing chloroquine with another effective drug, such a decision is hampered by the limited number of antimalarials currently available. There is a fear that changing too early would lead to depletion of available drugs. Yet a delay may be costly and catastrophic. Since the development of new antimalarials is deemed commercially unviable by high-income countries, there is need for a pan-African project aimed at the development of new antimalarials. Such a project could be jointly funded from African governments and the donor community under the coordination of either the World Health Organization or the Organization of African Unity. To delay the emergence and spread of resistance by P. falciparum to new and old drugs, there is need for: improving rational drugs use; limiting mass use of drugs as in chemoprophylaxis and in medicated salt; and increasing the use of impregnated bed nets.

J Infect Dis 2001 Apr 1;183(7):1165-9
Variants of Plasmodium falciparum Erythrocyte Membrane Protein 1 Expressed by Different Placental Parasites are Closely Related and Adhere to Chondroitin Sulfate A.

Khattab A, Kun J, Deloron P, Kremsner PG, Klinkert MQ
Department of Parasitology, Institute for Tropical Medicine, University of Tubingen, Tubingen, Germany.

Plasmodium falciparum-infected erythrocytes adhere to syncytiotrophoblast cells lining the placenta via glycosaminoglycans, such as chondroitin sulfate A (CSA) and hyaluronic acid. Adherence of infected erythrocytes to host receptors is mediated by P. falciparum erythrocyte membrane protein-1 (PfEMP-1). A single PfEMP-1 domain (duffy binding-like [DBL]-3, of the gamma sequence class) from laboratory-adapted strains is thought to be responsible for binding to CSA. In this study, DBL-gamma domains expressed by placental P. falciparum isolates were shown to have an affinity to CSA. All parasite populations accumulating in infected placentas express only 1 variant of PfEMP-1, each of which contains a DBL-gamma domain with CSA binding capacities. Furthermore, sequence analysis data provide evidence for antigenic conservation among the DBL-gamma sequences expressed by different placental parasites. This study offers a close reflection of the process of parasite adhesion in the placenta and is crucial to the understanding of the pathogenesis of malaria during pregnancy.

J Infect Dis 2001 Apr 1;183(7):1161-4
Procalcitonin as a Parameter of Disease Severity and Risk of Mortality in Patients with Plasmodium falciparum Malaria.

Chiwakata CB, Manegold C, Bonicke L, Waase I, Julch C, Dietrich M
Department of Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

The serum levels of procalcitonin (PCT) in Plasmodium falciparum malaria were evaluated for clinical significance in 66 nonimmune and semi-immune patients. Of the 66 patients, 36 had uncomplicated malaria, 24 had severe and complicated malaria, and 6 had fatal malaria (5 from previous studies). Pretreatment PCT concentrations were closely correlated with parasitemia. Concentrations were lowest in semi-immune patients with uncomplicated malaria, compared with those in nonimmune patients (geometric mean concentrations [GMCs], 1.07 and 2.37 ng/mL, respectively), and were highest in severe and complicated cases (GMC, 10.67 ng/mL; P<.001 among all subgroups). Six of 7 patients with PCT concentrations >25 ng/mL died. PCT concentrations decreased on day 2 of treatment in survivors but not in patients with fatal outcome. Thus, repeated PCT measurements may provide useful prognostic information, especially in medical centers that are not experienced in parasite density determination.

J Infect Dis 2001 Apr 1;183(7):1100-7
Placental malaria is associated with cell-mediated inflammatory responses with selective absence of natural killer cells.

Ordi J, Menendez C, Ismail MR, Ventura PJ, Palacin A, Kahigwa E, Ferrer B, Cardesa A, Alonso PL
Department of Pathology, Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)/Hospital Clinic, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain. 
[email protected]

Immunosuppression, particularly of cell-mediated responses, has classically been thought to play a major role in the increased susceptibility to malaria observed in pregnant women. An immunohistochemical characterization of the inflammatory infiltrate in a group of 41 placentas from women living in a Plasmodium falciparum-hyperendemic area in Tanzania revealed a marked increase in the number of monocytes and macrophages and cytotoxic T cells in the intervillous space of placentas with active malaria infection, compared with noninfected placentas, placentas from women with past infection, and a control group of placentas from Spain. This increase was associated with the severity of the infection. High numbers of monocytes and macrophages were associated with low birth weight. We also detected a complete absence of NK cells in the intervillous space in all placentas. This apparently physiological absence of NK cells may contribute to hindering the clearance of the parasite. These results indicate that placental malaria does not appear to be associated with cell-mediated immunosuppression. The role of the absence of NK cells in increased susceptibility to malaria needs to be further elucidated.

J Infect Dis 2001 Mar 15;183(6):967-72
Malaria enhances expression of cc chemokine receptor 5 on placental macrophages.

Tkachuk AN, Moormann AM, Poore JA, Rochford RA, Chensue SW, Mwapasa V, Meshnick SR
Department of Epidemiology, University of Michigan, Ann Arbor, Michigan USA.

Malaria and human immunodeficiency virus (HIV) coinfections are common in pregnant women in sub-Saharan Africa. The current study shows that placentas of malaria-infected women contain 3 times as much CC chemokine receptor 5 (CCR5) RNA as placentas of women without malaria. By immunohistochemistry, CCR5(+) maternal macrophages were seen in placentas from malaria-infected women but not in placentas from malaria-uninfected women. In addition, CCR5 also was found on fetal Hofbauer cells in placentas from both groups. Thus, malaria infections increase the potential reservoir for HIV in the placenta by increasing the number of HIV target cells.

Ann Trop Med Parasitol 2001 Jan;95(1):7-18
Clinical characteristics and disposition kinetics of the hepatomegaly associated with acute, uncomplicated, Plasmodium falciparum malaria in children.

Sowunmi A, Adedeji AA, Sowunmi CO, Falade CO, Falade AG, Ohaeri B, Happi TC, Oduola AM
Department of Pharmacology and Therapeutics and Postgraduate Institute for Medical Research & Training, University of Ibadan, Nigeria. 
[email protected]

The clinical characteristics and the kinetics of the disposition of the hepatomegaly associated with acute, uncomplicated Plasmodium falciparum malaria were investigated in 162 children in an endemic area of Nigeria. Hepatomegaly was significantly more common in the younger than in the older children. Complete resolution occurred in 48% following antimalarial chemotherapy. In the children in whom hepatomegaly did not resolve, a reduction in liver size of < 17% by the time parasitaemia was cleared (usually on day 3) was associated with non-resolution of hepatomegaly by days 7 or 14 of follow-up. An increase in liver size to at least 125% of the baseline value by day 4 or 5 was associated with a lack of therapeutic response, providing the child involved was aged < 5 years. In the children who had complete clearance of parasitaemia and resolution of hepatomegaly, there was no significant relationship between the parasitaemia-derived conventional indices of therapeutic response [i.e. time to clearance of 50% (PC50) or 90% (PC90) of the parasitaemia, and the parasite-clearance time (PCT)] and the corresponding parameters derived from measurement of liver size [i.e. time for resolution of 50% (HR50) or 90% (HR90) of the hepatomegaly and the hepatomegaly-resolution time (HRT)] in the same patients. However, as the HR50:PC50, HR90:PC90 and HRT:PCT ratios were similar (range = 1.6-2.1), the liver parameters may have therapeutic application. In the children with drug-sensitive P. falciparum infections and in whom hepatomegaly completely resolved, the area produced by plotting liver size against time (i.e. the area under the curve of hepatomegaly v. time, or AUChp) increased in proportion to the liver size below the costal margin (P = 0.02, from analysis of variance), but there was no significant difference in the half-lives of hepatomegaly (t1/2hp) or in the ratios of liver size to AUChp, indicating that the kinetics of the resolution of hepatomegaly were linear in the range examined. Comparison of the kinetic indices of hepatomegaly and parasitaemia showed that, although the half-lives of parasitaemia and hepatomegaly and the corresponding clearance values were similar, there was no correlation between these parameters among those in whom hepatomegaly completely resolved and parasitaemia completely cleared. These results indicate that routine clinical measurement of the liver size in children with hepatomegaly during acute, uncomplicated, P. falciparum malaria may have some use in evaluating and monitoring the therapeutic responses of infections. The resolution of hepatomegaly, a reflection of pathological changes, lags behind clearance of parasitaemia in children with P. falciparum malaria, and supports the use of the liver ‘rate’ as a malariometric index for assessing the intensity of transmission in endemic areas.

Ann Trop Med Parasitol 2001 Jan;95(1):41-6
Resistance of Plasmodium falciparum malaria to chloroquine is widespread in eastern Afghanistan.

Rab MA, Freeman TW, Durrani N, de Poerck D, Rowland MW
HealthNet International, 11-A Circular Lane, University Town, P.O. Box 889, Peshawar, Pakistan. 
[email protected]

After two decades of war and conflict in Afghanistan, the public-health system is in disarray and malaria has re-emerged as a major disease, with Plasmodium falciparum malaria becoming increasingly common. The limited healthcare services that are available are mainly delivered by non-governmental organizations in collaboration with the Ministry of Health. Although chloroquine (CQ) remains the official first-line treatment against P. falciparum malaria, there is little information on the severity or distribution of resistance to this drug in Afghanistan. In-vivo surveys, co-ordinated by the Malaria Reference Centre in Jalalabad, were therefore performed to determine the frequency and grades of CQ resistance in the three eastern provinces of Kunar, Nangarhar and Laghman. Of the 142 cases enrolled in the study, only 47 (33%) were sensitive. Most of the cases (55%) showed RI resistance but RII/RIII resistance was not uncommon (11%). The prevalence of resistance appeared similar in children and adults, in males and females, and in each of the three provinces investigated. Gametocyte carriage post-treatment was elevated in the resistant cases. As in neighbouring Pakistan, the resurgence of P. falciparum in Afghanistan is probably associated with the transmission and spread of chloroquine-resistant strains. The first-line therapy used against P. falciparum malaria must be changed in order to reverse this trend.

Ann Trop Med Parasitol 2001 Jan;95(1):31-9
Immunological alterations associated with Plasmodium vivax malaria in South Korea.

Lee HK, Lim J, Kim M, Lee S, Oh EJ, Lee J, Oh J, Kim Y, Han K, Lee EJ, Kang CS, Kim BK
Department of Clinical Pathology, College of Medicine, Catholic University of Korea, 62 Youido-dong, Youngdeungpo-gu, Seoul, 150-713, South Korea.

Various haematological and immunological studies on patients infected with Plasmodium vivax were undertaken, at diagnosis (day 0), after treatment with chloroquine but during primaquine treatment (day 10) and after all treatment (day 59), in South Korea (where there has been a recent and abrupt increase in the incidence of such infection). The main aims were to gain an understanding of the haemto-immunological alterations of this malarial infection, both before and after treatment, and to identify at least one useful marker for the diagnosis and post-treatment monitoring of P. vivax malaria. Thirty-eight patients with P. vivax malaria were compared with 20, apparently healthy controls. At diagnosis, the patients had lymphopenia, marked eosinopenia (the eosinophil count being correlated with the platelet count) and thrombopenia. Cells of most of the lymphocyte subsets investigated [i.e. CD3+, CD8+, CD19+, CD56+, CD3-/CD56+ and CD8+/CD56+ but not CD4+, CD3+/CD56+ or CD25+] were significantly less common among the lymphocytes of patients at diagnosis than among those of the controls. After initiating treatment, the numbers of CD19+ lymphocytes gradually increased (to normal values by day 59), whereas those of CD3+/56+ lymphocytes remained abnormally low throughout the follow-up period. The proportions of lymphocytes identified as CD4+ appeared to be unaffected by treatment. Although serum concentrations of IgE (and, to a lesser extent, IgM) were elevated in the patients at diagnosis, they were subnormal on day 10 post-treatment and normal at the day-59 follow-up. Serum concentrations of IgG and IgA in the patients were always found to be similar to those in the controls. At diagnosis the serum concentrations of complements C3 and C4 were significantly elevated in the patients. C3 remained at the same high concentration during follow-up but the concentration of C4, like that of IgE, was found to be subnormal on day 10 and normal 7 weeks later. The level of parasitaemia (%) was only found to be significantly correlated with haemoglobin concentration. The observation of eosinopenia with elevated IgE and C4 could be a useful indicator of P. vivax malaria, and treatment response could be followed by serial monitoring of serum concentrations of IgE and C4.

Ann Trop Med Parasitol 2001 Jan;95(1):19-29
Malaria during pregnancy and infancy, in an area of intense malaria transmission in central India.

Singh N, Mehra RK, Srivastava N
Malaria Research Centre, Field Station (ICMR), Medical College Buildings, Jabalpur 482003, India. 
[email protected]

The clinico-epidemiological pattern of malarial infection in a cohort of pregnant women and infants was analysed during a malaria epidemic (1997-1998). The subjects were all members of tribal communities in an isolated and almost inaccessible area of central India. Overall, 151 (55%) of the 274 pregnant women investigated were found to have malarial infections at some time during the study, with Plasmodium falciparum predominating (88% of infections). All of the women investigated, whether primigravidae (42% found infected), secundigravidae (68%) or multigravidae (54%), were at great risk of developing severe malaria. When trimesters were compared, the highest prevalence of P. falciparum infection was recorded in the second (59% infected), irrespective of parity. Of the women found infected with P. falciparum, 3% had abortions, 4% stillbirths and 2% had babies who died while neonates. The small number of P. vivax infections observed prevented similar analyses for this species of parasite. Malarial infection was also seen in 218 (41%) of the 535 infants investigated. The values of age-specific prevalences revealed that > 30% of the infants examined at 2 months of age were then found to have P. vivax and/or P. falciparum parasitaemias. At 1 year of age, overall malaria prevalence was 50%, with P. vivax representing 25% of the infections and P. falciparum the rest. Subsequent follow-up revealed that three of the infants investigated, each of whom had had P. falciparum infections previously, died before their first birthdays. Re-infections (or treatment failures) were found to be common, both in the infants and the pregnant women. Pregnant women and infants from the study area clearly require systematic intervention to reduce their malaria-attributable morbidity.

Wien Klin Wochenschr 2001 Jan 15;113(1-2):63-4
Declining chloroquine resistance of Plasmodium falciparum in Lambarene, Gabon from 1992 to 1998.

Schwenke A, Brandts C, Philipps J, Winkler S, Wernsdorfer WH, Kremsner PG
Research Unit, Albert Schweitzer Hospital, Lambarene, Gabon.

Plasmodium falciparum malaria continues to threaten human populations in the tropics and travellers in endemic areas. Drug resistance of the parasite is a major problem in treating this devastating disease. In a prospective trial we investigated the in vitro sensitivity of Plasmodium falciparum to chloroquine, quinine and mefloquine in the Albert Schweitzer Hospital in Lambarene, Gabon every second year from 1992 to 1998. We used the standard WHO in vitro sensitivity assay. Parasite sensitivity to quinine and mefloquine remained stable over the years. However, parasite resistance to chloroquine decreased highly significantly with the change in local malaria treatment policy. In 1992, 100% of parasite isolates showed resistance to chloroquine, whereas in 1998 only 45% were found resistant.

Folia Biol (Krakow) 2000;46(6):210-8
Malaria blood-stage infection and its control by the immune system.

Perlmann P, Troye-Blomberg M
Department of Immunology, Stockholm University, Sweden. 
[email protected]

Malaria is caused by the protozoon Plasmodium, transmitted to humans by Anopheles mosquitoes. The most dangerous of the plasmodia infecting humans is Plasmodium falciparum. The disease is caused by those parasite stages which multiply asexually in red blood cells. In non-immune individuals, P. falciparum may cause severe and life-threatening disease. Another risk group is constituted by pregnant women, particularly during their first pregnancies. Immunity to malaria usually requires repeated exposure to the parasite to become long lasting. One reason for this is the capacity of the parasite to vary the antigens which are major targets for protective antibodies. Antibody-dependent protection is primarily mediated by cytophilic IgG antibodies activating cytotoxic and phagocytic effector functions of neutrophils and monocytes. Malaria infection also involves elevated production of IgE antibodies. However, IgE-containing immune complexes are pathogenic rather than protective by crosslinking IgE receptors (CD23) on monocytes, leading to local overproduction of TNF, a major pathogenic factor in this disease. T cells are essential for both acquisition and regulation of malaria immunity. The major T cells controlling blood stage infections are CD4+ of both the Th1 and Th2 subsets. However, T cells carrying the gammadelta receptor also contribute to this control. The balance between the cytokines produced by different cell types is critical for the course of infection, with IFN-gamma having a key role in anti-malaria defence. Blood-stage infections are also under complex genetic control. Among the regulatory genes, those involved in elevated production of TNF are associated with increased risk of severe disease and death due to P. falciparum infection.

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