EHP Library Malaria Bulletin, Jan 5-18, 2001

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Conference report on traditional medicine in HIV/AIDS and malaria – MIM and Bioresources

A focused research agenda to influence policy and practice in home management for malaria, meeting report: 8-11 May 2000, Kilifi, Kenya – WHO/TDR

Home care of malaria infected children of less than 5 years of age in a rural area of the Republic of Guinea – WHO Bulletin 79(1) Jan 2001.

A natural weapon for prevention of malaria in the Peruvian Amazon – IDRC Reports, January 19, 2001

Pesticides and public health: integrated methods of mosquito management, R.I. Rose

Bull World Health Organ 2000;78(11):1352-7

Malaria in the United Republic of Tanzania: cultural considerations and health-seeking behaviour.

Oberlander L, Elverdan B

Department of General Practice, Institute of Public Health, University of Southern Denmark, Odense, Winslowparken 19, DK-5000 Odense C, Denmark.

Malaria is one of the biggest health problems in sub-Saharan Africa. Large amounts of resources have been invested to control and treat it. Few studies have recognized that local explanations for the symptoms of malaria may lead to the attribution of different causes for the disease and thus to the seeking of different treatments. This article illustrates the local nosology of Bondei society in the north-eastern part of the United Republic of Tanzania and shows how sociocultural context affects health-seeking behaviour. It shows how in this context therapy is best viewed as a process in which beliefs and actions are continuously debated and evaluated throughout the course of treatment.

Tropical Medicine and International Health, 2000, 5/11 (755-764)

Using evidence to change antimalarial drug policy in Kenya 
Shretta R.; Omumbo J.; Rapuoda B.; Snow R.W.
EMAIL: [email protected]

Chloroquine resistance was first detected in Kenya in 1978 and escalated during the 1980s, Chloroquine remained the treatment of choice for uncomplicated malaria infections until revised guidelines were launched in 1998 despite a plethora of scientific evidence on failure. This review analyses the range and quality of the evidence base that was used to change the drug policy in Kenya from chloroquine to SP and examines the process of consensus building and decision making. Our review illustrates the difficulties in translating sensitivity data with gross geographical, temporal and methodological variations into national treatment policy. The process was complicated by limited options, unknown adverse effects of replacement therapies, cost, as well as limited guidance on factors pertinent to changing the drug policy for malaria. Although > 50% of the studies showed parasitological failures by 1995, there was a general lack of consensus on the principles for assessing drug failures, the inclusion criteria for the study subjects and the relative benefits of parasitological and clinical assessments. A change in international recommendations for assessment of drug efficacy in 1996 from parasitological to clinical response further perplexed the decisions. There is an urgent need for international standards and evidence-based guidelines to provide a framework to assist the process by which decision-makers in malaria-endemic countries can make rational choices for antimalarial drug policy change.

Editorial: Mothers, malaria and resistance
Hall A.J. Tropical Medicine and International Health,  2000, 5/11 (753-754)

PUBMED AbstractsParasitology 2000 Dec;121 Pt 6:575-80

Transmission success of the malaria parasite Plasmodium mexicanum into its vector: role of gametocyte density and sex ratio.

Schall JJ

Department of Biology, University of Vermont, Burlington 05405, USA. [email protected]

The life-cycle of Plasmodium depends on transmission of the parasite from the vertebrate host into its vector when the insect takes a bloodmeal. Transmission success may depend in part on the parasite’s gametocyte density and sex ratio in the blood. P. mexicanum, a parasite of fence lizards in California, USA, exploits the sandfly Lutzomyia vexator as its vector. In experimental transmissions using naturally infected lizards as donors of blood, transmission success (measured as percentage of vectors infected and number of parasite oocysts on the insect’s midgut) was positively related to gametocyte density, although density above 20/1000 erythrocytes did not improve transmission. Sex ratio (proportion of microgametocytes in the infection) was positively correlated with gametocyte density. Transmission improved with higher proportion of microgametocytes, but partial correlations revealed that this was a result only of higher gametocyte densities. These results agree with the theory of virulence and sex ratios because single clone infections should produce a more female-biased sex ratio and grow to the minimum parasitaemia that would maximize clonal transmission, whereas multiple clone infections will be closer to a 1:1 sex ratio and yield a higher parasitaemia when each clone competes for transmission to the vector.Curr Opin Immunol 2001 Feb 1;13(1):79-88

Innate immune defense against malaria infection in the mosquito.

Dimopoulos G, Muller H, Levashina EA, Kafatos FC

European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany

Anopheles gambiae, the most important vector of malaria, employs its innate immune system in the fight against Plasmodium. This can affect the propagative capacity of Plasmodium in the vector and, in some cases, leads to total refractoriness to the parasite. The components operating in the mosquito’s innate immune system and their potential relevance to antimalarial responses are being systematically dissected.

Blood 2001 Jan 15;97(2):551-556

Polyethylene glycol-coated red blood cells fail to bind glycophorin A-specific antibodies and are impervious to invasion by the Plasmodium falciparum malaria parasite.

Blackall DP, Armstrong JK, Meiselman HJ, Fisher TC

Department of Pathology, University of Tennessee, Memphis, and the Department of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles.

This study was designed to assess the binding of glycophorin A-specific antibodies to polyethylene glycol (PEG)-modified red blood cells (RBCs) and evaluate their resistance to invasion by Plasmodium falciparum malaria parasites. RBCs were conjugated with a range of concentrations (0.05 to 7.5 mM) of activated PEG derivatives of either 3.35 or 18.5 kd molecular mass. The binding of glycophorin A-specific antibodies was assessed by hemagglutination and flow cytometry. PEG-modified RBCs were assessed for their ability to form rosettes around Chinese hamster ovary (CHO) cells transiently expressing the glycophorin A binding domain of EBA-175, a P falciparum ligand crucial to RBC invasion. PEG-RBCs were also tested for their ability to be invaded by the malaria parasite. RBCs coated with 3.35 and 18.5 kd PEG demonstrated a dose-dependent inhibition of glycophorin A-specific antibody binding, CHO cell rosetting, and P falciparum invasion. These results indicate that glycophorin A epitopes responsible for antibody and parasite binding are concealed by PEG coating, rendering these cells resistant to P falciparum invasion. These studies confirm the effectiveness of PEG modification for masking RBC-surface glycoproteins. This may provide a means to prevent alloimmunization in the setting of RBC transfusion and suggests a novel method to enhance the effectiveness of exchange transfusion for the treatment of cerebral malaria. (Blood. 2001;97:551-556)

 Biol Chem 2001 Jan 10; [epub ahead of print]
( free full text at )

Plasmodium falciparum glycosylphosphatidylinositol-induced TNF-{alpha} secretion by macrophages is mediated without membrane insertion or endocytosis.

Vijaykumar M, Naik RS, Gowda DC

Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007.

The glycosylphosphatidylinositols (GPIs) of Plasmodium falciparum are believed to contribute to malaria pathogenesis by inducing the secretion of proinflammatory cytokines by macrophages. Previous studies have shown that P. falciparum GPIs elicit toxic immune responses by PTK- and PKC-mediated cell signaling pathways, which are activated by the carbohydrate and acyl moieties of the intact GPIs, respectively. In this study, we show that induction of TNF-alpha by P. falciparum GPIs in macrophages is mediated by the recognition of the distal fourth mannose residue. This event is critical but not sufficient for the productive cell signaling; interaction by the acylglycerol moiety of GPIs is also required. These novel interactions are coupled to previously demonstrated PTK and PKC pathways since the specific inhibitors of these kinases effectively blocked the GPI-induced TNF-alpha production. Surprisingly, sn-2 lyso-GPIs were also able to elicit TNF-alpha secretion. Contrary to the prevailing notion, GPIs are neither inserted to the plasma membranes nor endocytosized. Thus, this study defines the GPI structural requirements and reveals a novel mechanism for the outside-in activation of cell signaling by P. falciparum GPIs in inducing proinflammatory responsesBoll Soc Ital Biol Sper 1999 Mar-Apr;75(3-4):17-20

Immunological investigation of malaria and new perspectives in paleopathological studies.

Cerutti N, Marin A, Massa ER, Savoia D

Department of Animal and Human Biology, University of Turin.

We applied a paleoimmunological investigation, using an immunoenzymatic assay revealing trophozoite derived Plasmodium falciparum histidine rich protein-2 antigen (PfHRP-2). The investigation was carried out on skin, muscle and bone samples. We examined predynastic egyptian mummies (3200 B.C.) from Gebelen, belonging to the Marro’s Collection of the Anthropological and Ethnographic Museum of Turin, to assay the presence of malaria. The results obtained suggest an incidence of malaria of about 40% in the mummies of Gebelen group. Data are compatible with other observations effected on populations living in similar ecological conditions of malarial areas.Diagn Microbiol Infect Dis 2000 Dec;38(4):233-236

The potential utility of the Semi-Nested Multiplex PCR technique for the diagnosis and investigation of congenital malaria.

Rubio JM, Roche J, Berzosa PJ, Moyano E, Benito A

Unidad de Investigacion en Medicina Tropical y Salud Internacional, Servicio de Parasitologia, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain

We report three cases of congenital malaria involving two malarial immune mothers living in Spain. Diagnostic PCR and Genotyping PCR for merozoite surface proteins 1 and 2 were essential to show that mothers and new-borns had different Plasmodium population parasites at the moment of the delivery, and that the infection was acquired earlier in gestation by transplacental transmission. In the first case the Plasmodium species founded in both, mother and child were different. Malaria in the twins showed a mixed infection (P. falciparum plus P. malariae) while the mother presented a P. falciparum infection. These facts were confirmed studying the polymorphisms for MSP1 and MSP2. Blood samples of the newborns were analyzed an half hour after delivery excluding the possibility of re-infection by mosquito bite and indicating a vertical transmission during pregnancy.

Cytokine 2001 Jan;13(2):65-74


Crampton AL, Luckhart S

Department of Biochemistry, Virginia Tech, Engel Hall, Blacksburg, VA, 24061, USA

We have isolated the first mosquito member of the TGF-beta superfamily, As60A. As60A is a single copy gene, approximately 5 kb in length and encodes eight exons. Here we report the isolation and characterization of two of four transcripts produced from this gene. The transcripts As60A(1)and As60A(2)encode related 5’UTR/exon 1 sequences. As60A is most similar to the 60A genes from Drosophila and is thus a member of the Dpp/BMP subfamily of the TGF-beta superfamily. The splice junction of intron 2 is conserved among As60A, BMP2, BMP4, Tc-Dpp, Bm-tgh-1, TGF-beta1 and Dpp. Intron 2 also contains three putative binding sites for a Dorsal/Gambif1 transcription factor. The large number of introns and the conservation of intron 2 indicate that As60A is relatively ancient compared to the other arthropod TGF-beta genes. We also propose that As60A plays a role in the mosquito immune response to Plasmodium infection. Copyright 2001 Academic Press.

J Neural Transm 2000;107(11):1273-87

Increased plasma levels of histidine and histamine in falciparum malaria: relevance to severity of infection.

Enwonwu CO, Afolabi BM, Salako LO, Idigbe EO, Bashirelah N

Department of OCBS, School of Dentistry, University of Maryland, Baltimore 21201-1586, USA.

Severe falciparum malaria, with its associated hyperpyrexia, distorts plasma levels of large neutral amino acids (NAA) and consequently, brain uptake of individual NAA. Since brain levels of NAA determine cerebral synthesis of monoamines (serotonin, histamine, catecholamines), we measured plasma concentrations of NAA, and also plasma histamine (Hm) in children with falciparum malaria and in uninfected controls. Malaria elicited a marked (P < 0.025) increase in plasma histidine (His) with a 5-fold significant (P < 0.001) elevation in histamine, as well as a 2.5-fold increase (P < 0.005) in plasma phenylalanine (Phe), with no changes in the other NAA. Using kinetic parameters of NAA transport at human blood-brain barrier (BBB), we showed that malaria significantly altered calculated brain uptake of His (+30%), Phe (+96%), Trp (-30%) and Ile (-27%), with no change in the other NAA, compared with controls. Our data suggested enhanced cerebral synthesis of Hm with impaired production of serotonin and the catecholamines in the patients, and therefore, the need to evaluate the encephalopathy in severe malaria within the context of abnormalities in metabolism of Hm and other monoamines resulting from imbalance in plasma levels of the large neutral amino acids. Of clinical relevance also is the impaired inactivation of increased brain Hm by antimalarials such as the widely used aminoisoquinolines leading to elevated brain levels of imidazole-4-acetic acid (IAA), a potent inducer of a sleep-like state often accompanied by seizures, analgesia, decreased blood pressure and other effects.

Ann Trop Med Parasitol 2000 Oct;94(7):689-97

The chemotherapy of rodent malaria. LIX. Drug combinations to impede the selection of drug resistance, Part 3: Observations on cyproheptadine, an antihistaminic agent, with chloroquine.

Peters W, Robinson BL, Stewart LB, Butcher GA

Tropical Parasitic Diseases Unit, Northwick Park Institute for Medical Research, Harrow HA1 3UJ, U.K. 
Email: [email protected]

Several compounds in current clinical use as antihistaminic agents, among them cyproheptadine (CYP), have been shown, in experimental models, to reverse resistance of the asexual, intra-erythrocytic stages of rodent or human malarial parasites to chloroquine (CQ). Although preliminary clinical trials with CYP failed to confirm such activity in subjects with naturally acquired infection with Plasmodium falciparum, Nigerian investigators have reported that another antihistaminic, chlorpheniramine, significantly restores the blood schizontocidal action of CQ in semi-immune patients with CQ-resistant P. falciparum, when the two compounds are administered together. The rates at which resistance to CYP can be produced, in mice infected either with CQ-resistant P. yoelii ssp. NS or CQ-resistant P. yoelii nigeriensis, when drug-selection pressure is exerted with this compound alone have now been compared with the rate and extent to which resistance develops in infected animals that are treated with various combinations of CYP and CQ. The data indicate that, in both parasites, stable resistance develops slowly to CYP alone and that exposure to a combination of CYP plus CQ significantly impedes the selection of resistance to CYP. Although the antimalarial action of CYP is reported to extend to the pre-erythrocytic hepatic stages, there was no evidence of gametocytocidal activity in the present study. The future implications of these observations are discussed in relation to the clinical potential of CYP + CQ and similar combinations and possible future research.

Ann Trop Med Parasitol 2000 Oct;94(7):675-88

Temporal and spatial distribution of the variants of merozoite surface protein-1 (MSP-1) in Plasmodium falciparum populations in Brazil.

Silva NS, Silveira LA, Machado RL, Povoa MM, Ferreira MU

Laboratorio de Parasitologia Molecular, Departamento de Doencas Infecciosas e Parasitarias, Faculdade de Medicina e Enfermagem de Sao Jose do Rio Preto, Sao Jose do Rio Preto, SP, Brazil.

The polymorphic, merozoite surface protein-1 (MSP-1) of Plasmodium falciparum, an antigen of the parasite’s asexual blood-stages, is a major malaria-vaccine candidate. Nucleotide sequences of each variable domain or block of this antigen may be grouped into one of three possible allelic types (K1, MAD20 and RO33), and 24 major types of the msp-1 gene may be defined, as unique combinations of allelic types in these variable blocks. Isolates collected from the Brazilian Amazon, over a period of 14 years, have now been investigated, by PCR-based typing of the msp-1 gene. Thirteen of the 24 possible gene-types were identified, and 336 P. falciparum clones were fully typed among 239 isolates. Most parasites (87%) belonged to one of the seven most frequent gene-types. Marked temporal variation in the distribution of msp-1 variants was found when comparing parasites sampled in the same sites at intervals of at least 5 years. Spatial variations were also found when comparing parasites from both neighbouring and distant sites within the Amazon Basin. The between-population variance in the frequencies of msp-1 allelic types found in Brazil, as estimated by Wright’s FST statistic, is of similar magnitude to that found in previous world-wide comparisons. The potential implications of these findings for the development of an MSP-1-based, multivalent malaria vaccine are discussed.

Salud Publica Mex 1999 Sep-Oct;41(5):410-9

Is primaquine useful and safe as true exo-erythrocytic merontocidal, hypnozoitocidal and gametocidal antimalarial drug?

Lopez-Antunano FJ

Instituto Nacional de Salud Publica, Avenida Universidad 655, colonia Santa Maria Ahuacatitlan, 62508 Cuernavaca, Morelos, Mexico. 
Email: [email protected]

The main objective of this paper is to make available in a single document, a sequence of events that have been published on the biology of malaria parasites and their interaction with the human host, looking for arguments for effective and save treatment: what we know and what we would like to know about the effects of primaquine in order to justify its use in clinical and public health practice. The practicioner should be aware that the antimalarial activity, hemolytic and methemoglobinemic side effects, and detoxification of primaquine are all thought to depend on various biotransformation products of the drug. In spite of the universal use during over six decades, their site and mechanism of formation and degradation and their specific biologic effects remain very poorly understood in human beings. The mature gametocytes of P. falciparum are naturally resistant to chloroquine and other blood merontocides, but they are usually eliminated with a single dose of 1.315 mg/kg per os (p.o.) of primaquine phosphate (equivalent to 0.75 mg-base). Rather than empirically, related with relapses frequency, dosage schedules should only be determined through consideration of the kinetics and dynamics of the drug and its effect on sporozoites, pre and exo-erythrocytic merontes, hypnozoites and gametocytes of P. vivax. Where medical care services are not available or not capable to detect glucose-6-phosphate dehydrogenese- (G-6-PD) deficiencies and deleterious effects of the drug, we recommend not to use primaquine. Both, P. vivax primary clinical attack and P. vivax relapses, as and when they occur should be treated with a course of 10 mg/kg chloroquine-base p.o. Prevention of relapses is probably related to strain characteristics of P. vivax hypnozoites populations involved. If well informed and qualified medical care workers decide to use primaquine in the absence of enzime deficiencies and are able to follow-up the clinical, toxicological and parasitic results, a daily dose of 0.25 mg/kg primaquine-base during 14 days could be administered safety for possible prevention of P. vivax relapses.

Mem Inst Oswaldo Cruz 2000;95 Suppl 1:25-32

The London School of Hygiene and Tropical Medicine: a new century of malaria research.

Riley EM

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7HT, UK. 
Email: [email protected]

The global malaria situation has scarcely improved in the last 100 years, despite major advances in our knowledge of the basic biology, epidemiology and clinical basis of the disease. Effective malaria control, leading to a significant decrease in the morbidity and mortality attributable to malaria, will require a multidisciplinary approach. New tools–drugs, vaccine and insecticides–are needed but there is also much to be gained by better use of existing tools: using drugs in combination in order to slow the development of drug resistance; targeting resources to areas of greatest need; using geographic information systems to map the populations at risk and more sophisticated marketing techniques to distribute bed nets and insecticides. Sustainable malaria control may require the deployment of a highly effective vaccine, but there is much that can be done in the meantime to reduce the burden of disease.

Science 2001 Jan 5;291(5501):141-4

Migration of plasmodium sporozoites through cells before infection.

Mota MM, Pradel G, Vanderberg JP, Hafalla JC, Frevert U, Nussenzweig RS, Nussenzweig V, Rodriguez A

Department of Pathology, Department of Medical and Molecular Parasitology, New York University School of Medicine, 341 East 25 Street, New York, NY 10010, USA.

Intracellular bacteria and parasites typically invade host cells through the formation of an internalization vacuole around the invading pathogen. Plasmodium sporozoites, the infective stage of the malaria parasite transmitted by mosquitoes, have an alternative mechanism to enter cells. We observed breaching of the plasma membrane of the host cell followed by rapid repair. This mode of entry did not result in the formation of a vacuole around the sporozoite, and was followed by exit of the parasite from the host cell. Sporozoites traversed the cytosol of several cells before invading a hepatocyte by formation of a parasitophorous vacuole, in which they developed into the next infective stage. Sporozoite migration through several cells in the mammalian host appears to be essential for the completion of the life cycle.

Am J Pathol 2001 Jan;158(1):163-172

Cerebral Malaria in Mice : Interleukin-2 Treatment Induces Accumulation of gammadelta T Cells in the Brain and Alters Resistant Mice to Susceptible-Like Phenotype.

Haque A, Echchannaoui H, Seguin R, Schwartzman J, Kasper LH, Haque S

Immunologie et Genetique des Maladies Parasitaires, INSERM U399, Faculte de Medecine, Universite de la Mediterranee, La Timone, Marseille, France. and Pathology, Dartmouth Medical School, Lebanon, New Hampshire.

In this study, we report that infection with Plasmodium yoelii 17XL, a lethal strain of rodent malaria, does not result in death in the DBA/2 strain of mice. In contrast to BALB/c mice, DBA/2 mice developed significantly less parasitemia and never manifested symptoms of cerebral malaria (CM) on infection with this parasite. Moreover, the histological changes evident in the brain of susceptible BALB/c were absent in DBA/2 mice. Interestingly, the resistant DBA/2 mice when treated with recombinant interleukin (IL)-2, were found to develop CM symptoms and the infection became fatal by 6 to 8 days after infection. This condition was associated with an augmented interferon-gamma and nitric oxide production. Unexpectedly, IL-10 levels were also elevated in IL-2-treated DBA/2 mice during late stage of infection (at day 6 of infection) whereas the inverse relationship between IL-10 and interferon-gamma or nitric oxide was maintained in the early stage of infection (at day 3 after infection). The level of tumor necrosis factor-alpha production was moderately increased in the late phase of infection in these mice. Histology of brain from IL-2-treated mice demonstrated the presence of parasitized erythrocytes and infiltration of lymphocytes in cerebral vessels, and also displayed some signs of endothelial degeneration. Confocal microscopical studies demonstrated preferential accumulation of gammadelta T cells in the cerebral vessels of IL-2-treated and -infected mice but not in mice treated with IL-2 alone. The cells recruited in the brain were activated because they demonstrated expression of CD25 (IL-2R) and CD54 (intercellular adhesion molecule 1) molecules. Administration of anti-gammadelta mAb prevented development of CM in IL-2-treated mice until day 18 after infection whereas mice treated with control antibody showed CM symptoms by day 6 after infection. The information concerning creating pathological sequelae and death in an otherwise resistant mouse strain provides an interesting focus for the burden of pathological attributes on death in an infectious disease.

Folia Biol (Praha) 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: [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 Thl and Th2 subsets. However, T cells carrying the gamma6 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.

Folia Biol (Praha) 2000;46(6):210-8

Macrophage preconditioning with synthetic malaria pigment reduces cytokine production via heme iron-dependent oxidative stress.

Taramelli D, Recalcati S, Basilico N, Olliaro P, Cairo G

Istituto di Microbiologia, Universita di Milano, Milan, Italy. Email: [email protected]

Hemozoin (malaria pigment), a polymer of hematin (ferri-protoporphyrin IX) derived from hemoglobin ingested by intraerythrocytic plasmodia, modulates cytokine production by phagocytes. Mouse peritoneal macrophages (PM) fed with synthetic beta-hematin (BH), structurally identical to native hemozoin, no longer produce tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) in response to lipopolysaccharide (LPS). Impairment of NO synthesis is due to inhibition of inducible nitric oxide synthase (iNOS) production. BH-mediated inhibition of PM functions cannot be ascribed to iron release from BH because neither prevention by iron chelators nor down-regulation of iron-regulatory protein activity was detected. Inhibition appears to be related to pigment-induced oxidative stress because (a) thiol compounds partially restored PM functions, (b) heme oxygenase (HO-1) and catalase mRNA levels were up-regulated, and (c) free radicals production increased in BH-treated cells. The antioxidant defenses of the cells determine the response to BH: microglia cells, which show a lower extent of induction of HO-1 and catalase mRNAs and lower accumulation of oxygen radicals, are less sensitive to the inhibitory effect of BH on cytokine production. Results indicate that BH is resistant to degradation by HO-1 and that heme-iron mediated oxidative stress may contribute to malaria-induced immunosuppression. This study may help correlate the different clinical manifestations of malaria, ranging from uncomplicated to severe disease, with dysregulation of phagocyte functions and promote better therapeutic strategies to counteract the effects of hemozoin accumulation.

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