Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DC) are crucial for the induction of immune responses and thus an inviting target for modulation by pathogens. We have previously shown that Plasmodium falciparum-infected erythrocytes inhibit the maturation of DCs. Intact P. falciparum-infected erythrocytes can bind directly to CD36 and indirectly to CD51. It is striking that these receptors, at least in part, also mediate the phagocytosis of apoptotic cells. Here we show that antibodies against CD36 or CD51, as well as exposure to early apoptotic cells, profoundly modulate DC maturation and function in response to inflammatory signals. Although modulated DCs still secrete tumor necrosis factor-alpha, they fail to activate T cells and now secrete IL-10. We therefore propose that intact P. falciparum-infected erythrocytes and apoptotic cells engage similar pathways regulating DC function. These findings may have important consequences for the treatment of malaria and may suggest strategies for modulating pathological immune responses in autoimmune diseases.
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PMID:A role for CD36 in the regulation of dendritic cell function. 1144 63

The sequestration of Plasmodium falciparum-infected erythrocytes (pRBC) away from the peripheral circulation is a property of all field isolates. Here we have examined the pRBC of 111 fresh clinical isolates from children with malaria for a number of adhesive features in order to study their possible coexpression and association with severity of disease. A large number of adhesion assays were performed studying rosetting, giant rosetting, and binding to CD36, intercellular adhesion molecule 1, platelet endothelial cell adhesion molecule 1, thrombospondin, heparin, blood group A, and immunoglobulins. Suspension assays were performed at the actual parasitemia of the isolate, while all the static adhesion assays were carried out at an equal adjusted parasitemia. The ability to bind to multiple receptors, as well as the ability to form rosettes and giant rosettes, was found to be more frequent among isolates from children with severe versus mild malaria (P = 0.0015). Rosettes and giant rosettes were more frequent for children with severe malaria, and the cell aggregates were larger and tighter, than for those with mild disease (P = 0.0023). Binding of immunoglobulins (97% of isolates) and of heparin (81% of isolates) to infected erythrocytes was common, and binding to heparin and blood group A was associated with severity of disease (P = 0.011 and P = 0.031, respectively). These results support the idea that isolates that bind to multiple receptors are involved in the causation of severe malaria and that several receptor-ligand interactions work synergistically in bringing about severe disease.
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PMID:Fresh isolates from children with severe Plasmodium falciparum malaria bind to multiple receptors. 1150 Apr 63

Studying 12 selected individuals from a malaria-endemic area in West Africa, 24 variants of the CD36 gene were found, 21 of them novel ones. These included three single-nucleotide substitutions causing non-conservative amino acid exchanges E123K, T174A, and I271T as well as a three base pair (bp) insertion resulting in the addition of an asparagine residue (N232-233ins). The E123K variant was located within the putative ligand-binding domain for oxidized low density lipoprotein, while the other substitutions resided outside any of the binding sites for reaction partners mapped on CD36 so far. Twelve single-nucleotide polymorphisms (SNPs) were identified in untranslated parts of the exons and in introns. Five additional SNPs were located in the promoter region whereby -144G-->T, -53G-->T, and -2A-->G alter putative binding sites for the transcription factors purine factor (PuF), phorbol ester-responsive element AP-2, and CCAAT/enhancer-binding protein. A G-->T exchange at position -50 appears to introduce a new recognition site for PuF. Calculations of nucleotide diversity revealed extraordinarily high numbers for all parts of the gene, which may, however, to some extent be due to the selection of individuals studied.
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PMID:Variability of the CD36 gene in West Africa. 1166 37

The adherence of Plasmodium falciparum-infected RBC (IRBC) to postcapillary venular endothelium is an important determinant of the pathogenesis of severe malaria complications. Cytoadherence of IRBC to endothelial cells involves specific receptor/ligand interactions. The glycoprotein CD36 expressed on endothelial cells is the major receptor involved in this interaction. Treatment of CD36-expressing cells with reducing agents, such as DTT and N-acetylcysteine, was followed by CD36 conformational change monitorable by the appearance of the Mo91 mAb epitope. Only a fraction of the surface expressed CD36 molecules became Mo91 positive, suggesting the presence of two subpopulations of molecules with different sensitivities to reduction. The Mo91 epitope has been localized on a peptide (residues 260-279) of the C-terminal, cysteine-rich region of CD36. Treatment with reducing agents inhibited the CD36-dependent cytoadherence of IRBC to CD36-expressing cells and dissolved pre-existent CD36-mediated IRBC/CD36-expressing cell aggregates. CD36 reduction did not impair the functionality of CD36, since the reactivity of other anti-CD36 mAbs as well as the binding of oxidized low density lipoprotein, a CD36 ligand, were maintained. The modifications induced by reduction were reversible. After 14 h CD36 was reoxidized, the cells did not express the Mo91 epitope, and cytoadherence to IRBC was restored. The results indicate that IRBCs bind only to a redox-modulated fraction of CD36 molecules expressed on the cell surface. The present data indicate the therapeutic potential of reducing agents, such as the nontoxic drug N-acetylcysteine, to prevent or treat malaria complications due to IRBC cytoadhesion.
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PMID:Cytoadherence of Plasmodium falciparum-infected erythrocytes is mediated by a redox-dependent conformational fraction of CD36. 1171 19

Immunity to Plasmodium falciparum in African children has been correlated with antibodies to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) variant gene family expressed on the surface of infected red cells. We immunized Aotus monkeys with a subregion of the Malayan Camp variant antigen (MCvar1) that mediates adhesion to the host receptor CD36 on the endothelial surface and present data that PfEMP1 is an important target for vaccine development. The immunization induced a high level of protection against the homologous strain. Protection correlated with the titer of agglutinating antibodies and occurred despite the expression of variant copies of the gene during recurrent waves of parasitemia. A second challenge with a different P. falciparum strain, to which there was no agglutinating activity, showed no protection but boosted the immune response to this region during the infection. The level of protection and the evidence of boosting during infection encourage further exploration of this concept for malaria vaccine development.
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PMID:Immunization of Aotus monkeys with a functional domain of the Plasmodium falciparum variant antigen induces protection against a lethal parasite line. 1190 37

Supplementation with vitamin A potentiates host resistance to malaria, however, the underlying mechanism is unknown. We tested the effects of 9-cis-retinoic acid, a metabolite of vitamin A, on CD36 expression, non-opsonic phagocytic clearance of parasitised erythrocytes, and TNFalpha production in human monocytes and macrophages. We found reduced secretion of TNFalpha, upregulated CD36 expression, and increased phagocytosis of Plasmodium falciparum-parasitised erythrocytes. Increased parasite clearance and reduced proinflammatory cytokine responses to infection might partly explain the beneficial effects of supplementation with vitamin A in malaria.
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PMID:Mechanism of protection induced by vitamin A in falciparum malaria. 1197 40

The Plasmodium falciparum multigene var family codes for approximately 50 variant adhesive proteins expressed in a mutually exclusive manner at the surface of infected red blood cells (iRBCs). Switching expression of var genes can lead to fundamental changes in the adhesive and antigenic properties of iRBCs. For example, a specific phenotypic switch in adhesion from CD36 to chondroitin sulphate A (CSA) is associated with malaria pathogenesis in pregnant women. The factors and DNA elements that control the expression of a particular member of the var gene family during gestational malaria remains enigmatic. Here, we report that the subtelomeric FCR3 varCSA is expressed under the control of a unique DNA element of 1.8 kb, whereas the other members of the var multigene family are flanked by common regulatory elements. The 5' varCSA-type element is conserved as a single copy in laboratory strains and clinical isolates from Brazil and West Africa and contains two distinct repetitive elements of 150 bp and 60 bp respectively. The 5' varCSA-type sequence tags a var gene in the 3D7 genome that is homologous to the FCR3 varCSA gene. A recombinant DBL gamma domain of this var gene showed specific binding to CSA. This subtelomeric varCSA gene is transcribed in the opposite sense when compared with the usual orientation of telomere-adjacent var genes. This unique arrangement might explain why the varCSA gene is relatively conserved in genetically distinct parasites despite being located in a highly recombinogenic chromosome compartment. The 5' untranslated region (UTR) of the varCSA-type sequence is also transcribed in placental isolates that bind to CSA, illustrating an important role for the unique 5' varCSA-type sequence in the regulation of var genes involved in malaria pathogenesis in pregnant women. However, this promoter is not always found to be transcribing var genes selected for expression of products that bind to CSA in vitro. Our work identifies a sequence tag for the identification of varCSA genes in placental isolates for the first time.
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PMID:A distinct 5' flanking var gene region regulates Plasmodium falciparum variant erythrocyte surface antigen expression in placental malaria. 1210 May 56

The alpha thalassaemias are the commonest known human genetic disorders. Although they have almost certainly risen to their current frequencies through natural selection by malaria, the precise mechanism of malaria protection remains unknown. We have investigated the characteristics of red blood cells (RBCs) from individuals heterozygous for alpha(0)thalassaemia (-/alphaalpha) from a range of perspectives. On the basis of the hypothesis that defects in membrane transport could be relevant to the mechanism of malaria protection, we investigated sodium and potassium transport and the activity of the Plamodium falciparum-induced choline channel but found no significant differences in -/alphaalpha RBCs. Using flow cytometry, we found that thalassaemic P. falciparum-infected RBCs (IRBCs) bound 44% more antibody from immune plasma than control IRBCs. This excess binding was abrogated by predigestion of IRBCs with trypsin but was not directed at the variant surface molecule PfEMP1. Furthermore, we found no evidence for altered cytoadhesion of alpha-thalassaemic IRBCs to the endothelial receptors intercellular adhesion molecule-1 (ICAM-1), CD36 or thrombospondin. We hypothesize that altered red-cell membrane band 3 protein may be a target for enhanced antibody binding to alpha-thalassaemic IRBCs and could be involved in the mechanism of malaria protection.
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PMID:The membrane characteristics of Plasmodium falciparum-infected and -uninfected heterozygous alpha(0)thalassaemic erythrocytes. 1213 62

In falciparum malaria, the malaria parasite induces changes at the infected red blood cell surface that lead to adherence to vascular endothelium and other red blood cells. As a result, the more mature stages of Plasmodium falciparum are sequestered in the microvasculature and cause vital organ dysfunction, whereas the ring stages circulate in the blood stream. Malaria is characterized by fever. We have studied the effect of febrile temperatures on the cytoadherence in vitro of P. falciparum-infected erythrocytes. Freshly obtained ring-stage-infected red blood cells from 10 patients with acute falciparum malaria did not adhere to the principle vascular adherence receptors CD36 or intercellular adhesion molecule-1 (ICAM-1). However, after a brief period of heating to 40 degrees C, all ring-infected red blood cells adhered to CD36, and some isolates adhered to ICAM-1, whereas controls incubated at 37 degrees C did not. Heating to 40 degrees C accelerated cytoadherence and doubled the maximum cytoadherence observed (P < 0.01). Erythrocytes infected by ring-stages of the ICAM-1 binding clone A4var also did not cytoadhere at 37 degrees C, but after heating to febrile temperatures bound to both CD36 and ICAM-1. Adherence of red blood cells infected with trophozoites was also increased considerably by brief heating. The factor responsible for heat induced adherence was shown to be the parasite derived variant surface protein PfEMP-1. RNA analysis showed that levels of var mRNA did not differ between heated and unheated ring-stage parasites. Thus fever-induced adherence appeared to involve increased trafficking of PfEMP-1 to the erythrocyte membrane. Fever induced cytoadherence is likely to have important pathological consequences and may explain both clinical deterioration with fever in severe malaria and the effects of antipyretics on parasite clearance.
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PMID:Febrile temperatures induce cytoadherence of ring-stage Plasmodium falciparum-infected erythrocytes. 1217 47

A feature of infection with Plasmodium falciparum is the ability of parasite-infected erythrocytes to adhere to vascular endothelial cells and accumulate in vital organs, associated with severe clinical disease. Hyaluronic acid was recently identified as a receptor for adhesion and has been implicated in mediating the accumulation of parasites in the placenta. Here, we report in vitro assays to measure specific adhesion of infected erythrocytes to hyaluronic acid that is distinct from binding to chondroitin sulphate A, another glycosaminoglycan implicated as a receptor in placental malaria. In this study, specific adhesion of mature stage infected erythrocytes to hyaluronic acid of high purity immobilised on plastic surfaces was abolished by pre-treating hyaluronic acid with a specific hyaluronate lyase from Streptomyces, whereas the same treatment of chondroitin sulphate A had little effect. Adhesion to hyaluronic acid could not be explained by the presence of chondroitin sulphate A or other glycosaminoglycans in the hyaluronic acid preparations. Chinese hamster ovary cells bound in a similar manner in the assays and confirmed that hyaluronic acid was appropriately immobilised for cell adhesion. In contrast to parasites, these cells did not adhere to chondroitin sulphate A. The adsorption of hyaluronic acid onto plastic surfaces was also confirmed by the use of a specific hyaluronic acid-binding protein. Fixing cells with glutaraldehyde at the completion of adhesion assays reduced the number of parasites remaining adherent to hyaluronic acid, but not to chondroitin sulphate A or CD36. These findings have important implications for understanding and evaluating interactions between P. falciparum and hyaluronic acid that may be involved in disease pathogenesis.
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PMID:Evaluating specific adhesion of Plasmodium falciparum-infected erythrocytes to immobilised hyaluronic acid with comparison to binding of mammalian cells. 1220 24


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