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)

Cytokine regulation was compared in three groups of Gabonese patients with Plasmodium falciparum malaria before and after therapy; adults with uncomplicated malaria, children with uncomplicated malaria, and children with severe malaria. Plasma levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-8, TNF receptors (TNF R), and the TNF/TNF R ratios were significantly higher in severe malaria compared with uncomplicated malaria. High plasma levels of all immunoregulatory molecules were associated with slow cure after therapy. In all patients, phytohemagglutinin-induced cytokine production was depressed on admission compared with convalescence. A significant difference was the higher TNF production capacity in patients with severe malaria on day 2 and day 5 compared with that in patients with uncomplicated malaria. In contrast to IL-6 and IL-8, a high TNF production capacity during the acute phase of malaria predicted a rapid clinical and parasitologic cure in the patients. These findings illustrate the dual role of TNF in the protection and pathology of malaria.
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PMID:Prediction of accelerated cure in Plasmodium falciparum malaria by the elevated capacity of tumor necrosis factor production. 748 13

V gamma 9+ T cells from malaria non-exposed donors make proliferative responses to Plasmodium falciparum on in vitro stimulation. V gamma 9+ cells are strongly activated by components of the schizont stage of the parasite and by antigens released into the culture upon schizogony, while CD4+V gamma 9- cells are stimulated by the earlier stages of the parasite. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we determined mRNA expression for 14 cytokines in highly purified V gamma 9+ cells enriched by positive selection after in vitro stimulation with P. falciparum schizont antigens. Interferon-gamma (IFN-gamma) and Tumor Necrosis Factor-alpha (TNF-alpha) were detected in all samples tested. The majority of samples also expressed TNF-beta, transforming growth factor-beta (TGF-beta) and Interleukin-8 (IL-8). Only occasional samples expressed IL-2, IL-5 and IL-10. Using the ELISPOT assay we found that a large fraction of the reactive V gamma 9+ cells produced IFN-gamma and that gamma delta T cells are the major producers of IFN-gamma in cultures stimulated with schizont antigens. The majority of V gamma 9+ cells in these cultures also express the membrane-bound form of TNF-alpha. Expression of these cytokines speaks for a cytolytic and/or inflammatory role of gamma delta cells in the response to malaria in non-exposed individuals.
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PMID:Cytokine profiles for human V gamma 9+ T cells stimulated by Plasmodium falciparum. 750 22

Plasmodium vivax and the related monkey malaria, P. knowlesi, require interaction with the Duffy blood group antigen, a receptor for a family of chemokines that includes interleukin 8, to invade human erythrocytes. One P. vivax and three P. knowlesi proteins that serve as erythrocyte binding ligands in such interactions share sequence homology. Expression of different regions of the P. vivax protein in COS7 cells identified a cysteine-rich domain that bound Duffy blood group-positive but not Duffy blood group-negative human erythrocytes. The homologous domain of the P. knowlesi proteins also bound erythrocytes, but had different specificities. The P. vivax and P. knowlesi binding domains lie in one of two regions of homology with the P. falciparum sialic acid binding protein, another erythrocyte binding ligand, indicating conservation of the domain for erythrocyte binding in evolutionarily distant malaria species. The binding domains of these malaria ligands represent potential vaccine candidates and targets for receptor-blockade therapy.
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PMID:Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. 804 29

The scientific interest in the physical interaction of Plasmodium falciparum-infected erythrocytes with host cells stems from the suggestion that excessive binding in the microvasculature leads to severe malaria. The authors studied, therefore, two parasites for their ability to adhere to normal human cells and to induce cytokine production, one parasite lacking a binding capacity (DD2) and one which adhered to CD36+ transfected CHO cells (MCAMP). The MCAMP parasites readily bound to platelets and erythrocytes and to monocytes, polymorphonuclear granulocytes and EBV-transformed B cells as seen by light and electron microscopy. Platelets were frequently attached in large numbers to the infected erythrocyte surface and groups of infected erythrocytes were sometimes held together by several platelets. Nine out of 17 cytokines tested were found to be secreted into the culture supernatants after 35 h of co-cultures containing monocytes or unfractionated peripheral blood mononuclear cells (PBMC) and parasites (IL-1RA, IL-6, IL-8, IL-10, TGF beta, TNF alpha, G-CSF, IL-1-beta, and GM-CSF). Three additional cytokines were also present in low levels (< 200 pg/ml, IL-2, IL-4, IFN gamma) in the culture supernatants after incubation of the cells for 4 days. TNF alpha, IL-RA, and IL-8 were secreted from polymorphonuclear granulocytes, LGLs and T cells. Platelets and, to a lesser degree, monocytes and T cells secreted large amounts of TGF beta (10-30 ng/ml). Cytokines may participate in the pathogenesis but also the suppression of immune responses seen during acute malarial infections.
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PMID:Adhesion of Plasmodium falciparum-infected erythrocytes to human cells and secretion of cytokines (IL-1-beta, IL-1RA, IL-6, IL-8, IL-10, TGF beta, TNF alpha, G-CSF, GM-CSF. 855 86

The microvascular endothelial cell (MVEC) is a major target of inflammatory cytokines overproduced in conditions such as sepsis and infectious diseases. We addressed the direct and indirect effects of tumor necrosis factor (TNF) on endothelial cells that can be relevant for the pathogenesis of septic shock, with particular attention to the acute respiratory distress syndrome (ARDS) and to cerebral malaria (CM). To identify functional and phenotypical changes occurring in MVEC during sepsis, we isolated these cells from the lungs of patients who died of ARDS. The constitutive expression of ICAM-1 and, to a lesser extent, VCAM-1, CD14, and TNFR2 were significantly increased on MVEC isolated from ARDS patients compared with control MVEC, whereas ELAM-1 and TNFR1 were not increased. We found that lung MVEC from ARDS patients present a procoagulant profile and a higher production capacity of interleukin-6 (IL-6) and IL-8 when compared with those from controls. As in pulmonary MVEC derived from ARDS patients, the only TNFR type found up-regulated in brain microvessels during CM was TNFR2. This increase in TNFR2 expression only occurred in CM-susceptible mice at the onset of the neurological syndrome. We therefore investigated the role of TNFR2 in the development of this brain pathology by comparing the incidence of CM in wild-type and TNF receptor knock-out mice. Unexpectedly, the genetic deficiency in TNFR2, but not in TNFR1, conferred protection against CM and its associated mortality. No ICAM-1 up-regulation was detected in the brain of Tnfr2 knockout mice, indicating a close correlation between protection against CM-associated brain damage, absence of TNFR2, and absence of ICAM-1 up-regulation in the brain. Our results in ARDS and CM indicate a specific up-regulation of TNFR2, but not of TNFR1, on lung and brain MVEC, respectively. This increased expression leads to a reduced sensitivity toward TNFR1-mediated phenomena, such as the sensitized TNF cytolytic activity on lung MVEC. In contrast, the sensitivity toward TNFR2-mediated effects, such as ICAM-1 induction by membrane-bound TNF, is increased on brain and lung MVEC expressing increased levels of TNFR2. Therefore, the ICAM-1-inducing effect, rather than the direct cytotoxicity of inflammatory cytokines, such as TNF, appears to be crucial in ARDS and CM-induced endothelial damage, and TNFR2 seems to play an important role in this activity in vivo.
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PMID:TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria. 912 3

The Duffy Antigen Receptor for Chemokines (DARC) belongs to a family of erythrocyte chemokine receptors that bind C-X-C and C-C chemokines such as interleukin 8 (IL-8), monocyte chemoattractant protein 1 (MCP-1) and regulated-on-activation, normal T cell-expressed and -secreted (RANTES), but not macrophage inflammatory protein 1 alpha (MIP-1 alpha) or MIP-1 beta. DARC has also been identified to a receptor for malaria parasites Plasmodium vivax and Plasmodium knowlesi. In the present study, we show that HIV-1 binds to RBCs from Caucasian individuals via DARC making RBCs able to transmit HIV to peripheral blood mononuclear cells (PBMCs). Furthermore, binding of HIV-1 particles to RBCs is inhibited by treating these cells with recombinant RANTES, but not with recombinant MIP-1 alpha prior to their incubation with HIV-1. This finding suggests that RBCs may function as a reservoir for HIV-1 or as a receptor for the entry of HIV-1 into CD4-cell subsets as well as neurons or endothelial cells.
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PMID:Binding of HIV-1 to RBCs involves the Duffy antigen receptors for chemokines (DARC). 992 12

Single doses (250, 500, 1,000, or 2,000 units/kg) of an ovine polyclonal-specific Fab fragment directed against tumor necrosis factor-alpha (TNF-alpha) were given to 17 adult patients with severe falciparum malaria immediately before treatment with artesunate in a pilot study to assess safety and optimal dosage with a view to future studies. Clinical and laboratory variables were compared with 11 controls. In the groups given Fab, there was a tendency for a faster resolution of clinical manifestations and reduction of fever but also a tendency towards longer parasite clearance times. Adverse events were more common in the control group and no early anaphylactic or late serum sickness reactions occurred in the Fab treated patients. On admission all patients had markedly elevated levels of TNF-alpha (85-1,532 ng/L) and interleukin-6 (IL-6) (30-27,500 ng/L). Also, 86% had elevated interferon-gamma (IFN-gamma) levels, 75% had increased IL-2 levels, 36% had increased IL-8 levels, and 21% had increased IL-1beta levels. Antibody treatment reduced IFN-gamma concentrations in a dose-related manner, but had no obvious effects on levels of other cytokines in this small study, although unbound TNF-alpha was undetectable after Fab treatment. Circulating concentrations of soluble E-selectin, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not affected by Fab treatment. The Fab exhibited a two-compartment, dose-proportional kinetics with an average elimination half-life of 12.0 hr, with about 20% being excreted renally. These results encourage a randomized, placebo-controlled trial in patients with cerebral malaria and provide some guidance about dosage.
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PMID:Polyclonal anti-tumor necrosis factor-alpha Fab used as an ancillary treatment for severe malaria. 1043 50

Malaria infections during pregnancy can lead to the delivery of low-birth-weight infants. In this study, cytokine mRNA was measured in placentas from 23 malaria-infected and 21 uninfected primigravid women who had delivered in Mangochi, Malawi, a region with a high rate of transmission of falciparum malaria. Significantly increased expression of interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha and decreased expression of IL-6 and transforming growth factor-beta1 were found in malaria-infected compared with uninfected placentas. TNF-alpha and IL-8 were produced by maternally derived hemozoin-laden placental macrophages. Increased TNF-alpha expression was associated with increased placental hemozoin concentrations. Increased TNF-alpha or IL-8 expression in the placenta was associated with intrauterine growth retardation but not with preterm delivery. The results suggest that malaria infections induce a potentially harmful proinflammatory response in the placenta.
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PMID:Malaria and pregnancy: placental cytokine expression and its relationship to intrauterine growth retardation. 1055 56

The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.
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PMID:Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules. 1060 13

The balance between pro- and antiinflammatory cytokines may be important in malaria presentation and outcome. Malaria tends to be more severe in children than in adults, presumably because partial immunity develops with age. However, the full nature of, and age-related differences in, anti-malarial immunity are unknown. We compared: (1) serum and cell-specific cytokines of patients with acute malaria to those of patients with other acute illnesses and to those of healthy adults and (2) the cytokine responses of parasitemic children and parasitemic adults. Flow cytometry was done on the peripheral blood mononuclear cells of 148 hospitalized children, 161 febrile hospitalized adults, and 20 healthy adults in Malawi, Africa, a malaria-endemic country. Serum cytokines were also assessed for 80 of these patients. Thirty-eight participants were parasitemic with Plasmodium falciparum. Serum interleukin (IL)-10 (an antiinflammatory, immunoregulatory, and type 2 cytokine) levels were higher in malaria patients than in other patients (medians 502 pg/mL vs 16 pg/mL, P = 0.002), and the percentages of various lymphocyte populations making IL-6 (a proinflammatory, type 2 cytokine regulating iron distribution) were lower in malaria patients than in other patients (e.g., for spontaneous production by children's CD8(+) T cells: medians 1.4% vs 33.1%, P = 0.004). For adult patients, the percentages of lymphocytes spontaneously making IL-4 (a type 2 cytokine) were significantly lower in those with malaria than in those without malaria (medians 0.9% vs 2.1%, P = 0.005). The percentages of monocytes spontaneously making IL-8 (a chemotactic, proinflammatory chemokine) were higher in parasitemic children than in parasitemic adults (medians 5.8% vs 1.7%, P = 0.003). A number of cellular proinflammatory, type 1 parameters were significantly higher in all children (with or without malaria) than in all adults; these included the percentages of various lymphocyte populations making IL-6, both IL-6 and interferon-gamma, or IL-8. These data support the importance of IL-10 in malaria parasitemia. Given the lack of an IL-4 (type 2) response, IL-10's primary role may be immunoregulatory rather than type 2 in nature. In this study, the immune response to malaria was more proinflammatory in children than in adults. This difference, if corroborated by other studies, could be related to malaria's greater severity in children.
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PMID:Cytokines and malaria parasitemia. 1146 50


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