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)

Fas is a protein that plays a major role in the apoptotic mechanism of several cell types, including white blood cells (WBC). Mutations of the Fas gene in humans are known to lead to autoimmune lymphoproliferative syndrome (ALPS). Glucocorticoids or cytostatic drugs are sometimes used to treat the lymphoproliferation in these patients. When treated with the anti-malaria drug Fansidar, a patient with ALPS showed a marked shrinkage of the lymph node masses, decrease in peripheral blood lymphocytes (PBL) and an increase in neutrophil numbers. In addition, an increased Fas expression was seen on all types of leucocytes.
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PMID:The use of the anti-malaria drug Fansidar (pyrimethamine and sulphadoxine) in the treatment of a patient with autoimmune lymphoproliferative syndrome and Fas deficiency. 969 76

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 intraerythrocytic stage of the simian malaria parasite Plasmodium coatneyi (CDC strain) was intravenously inoculated into two species of macaques with different susceptibilities to infection with this parasite, including four Japanese macaques (Macaca fuscata) and three cynomolgus macaques (M. fascicularis). The Japanese macaques infected with P. coatneyi developed severe clinical manifestations similar to those of severe human malaria and eventually became moribund, while the infected cynomolgus macaques, natural hosts of the parasite, exhibited no severe manifestation of disease except anemia and finally recovered from the infection. In the infected Japanese macaques, peripheral CD4(+) and CD8(+) T-cell populations were markedly decreased and fragmentation of chromosomal DNA in peripheral blood mononuclear cells was detected during the terminal period of infection, suggesting that apoptotic cell death was responsible at least in part for the T lymphocytopenia. Furthermore, soluble Fas ligand levels in sera of the infected Japanese macaques increased gradually to a markedly high level of 28. 83 +/- 10.56 pg/ml (n = 4) when the animals became moribund. On the other hand, none of the infected cynomolgus monkeys exhibited either T lymphocytopenia or elevated soluble Fas ligand level. These findings suggest that differences in immune response between the two species of macaque tested accounted for the contrasting outcomes after infection with the same isolate of malarial parasite, and in particular that a profound T lymphocytopenia due to Fas-derived apoptosis played a role in the fatal course of malaria in the infected Japanese macaques.
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PMID:Malaria infection induces rapid elevation of the soluble Fas ligand level in serum and subsequent T lymphocytopenia: possible factors responsible for the differences in susceptibility of two species of Macaca monkeys to Plasmodium coatneyi infection. 1120 40

Infection with blood-stage Plasmodium chabaudi chabaudi AS results in splenomegaly, peripheral leukocytosis, and a major activation of the immune system. The frequencies and absolute numbers of T-cell, B-cell, and macrophage populations in spleen and peripheral blood from P. chabaudi-infected BALB/c mice were compared and found to be significantly altered during acute infection. The kinetics of the redistribution of the different cell types in spleen and peripheral blood were different, with T and B cells appearing in the blood when their frequencies and absolute numbers in the spleen were low. The frequency and absolute number of apoptotic cells in the spleen were increased during acute P. chabaudi infection and involved both T cells, B cells, and macrophages. Both Fas and Fas-ligand expression were increased in the spleen. Taken together, our data provide new information on the complex cellular interactions that take place in the immune system during blood-stage malaria infection in a mouse model.
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PMID:Cellular changes and apoptosis in the spleens and peripheral blood of mice infected with blood-stage Plasmodium chabaudi chabaudi AS. 1120 40

Levels of soluble Fas ligand (sFasL) in serum were elevated in patients with Plasmodium falciparum malaria and showed a significant decline during disease course. sFasL levels that were elevated before antimalarial treatment began correlated significantly with depressed total lymphocyte and T-cell counts. These data suggest that Fas-induced apoptosis might play a role in malaria-associated lymphopenia.
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PMID:Increased levels of soluble Fas ligand in serum in Plasmodium falciparum malaria. 1120 40

It is thought that both helper and effector functions of CD4(+) T cells contribute to protective immunity to blood stage malaria infection. However, malaria infection does not induce long-term immunity and its mechanisms are not defined. In this study, we show that protective parasite-specific CD4(+) T cells were depleted after infection with both lethal and nonlethal species of rodent PLASMODIUM: It is further shown that the depletion is confined to parasite-specific T cells because (a) ovalbumin (OVA)-specific CD4(+) T cells are not depleted after either malaria infection or direct OVA antigen challenge, and (b) the depletion of parasite-specific T cells during infection does not kill bystander OVA-specific T cells. A significant consequence of the depletion of malaria parasite-specific CD4(+) T cells is impaired immunity, demonstrated in mice that were less able to control parasitemia after depletion of transferred parasite-specific T cells. Using tumor necrosis factor (TNF)-RI knockout- and Fas-deficient mice, we demonstrate that the depletion of parasite-specific CD4(+) T cells is not via TNF or Fas pathways. However, in vivo administration of anti-interferon (IFN)-gamma antibody blocks depletion, suggesting that IFN-gamma is involved in the process. Taken together, these data suggest that long-term immunity to malaria infection may be affected by an IFN-gamma-mediated depletion of parasite-specific CD4(+) T cells during infection. This study provides further insight into the nature of immunity to malaria and may have a significant impact on approaches taken to develop a malaria vaccine.
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PMID:The mechanism and significance of deletion of parasite-specific CD4(+) T cells in malaria infection. 1192 32

During Plasmodium falciparum infection leading to cerebral malaria, cytokine production and cytoadherence of parasitized erythrocytes (PRBCs) to postcapillary venules are involved. We demonstrate that PRBC adhesion induces apoptosis in human endothelial cells (HLECs). PRBC adhesion modulated HLEC gene expression in tumor necrosis factor-alpha superfamily genes (Fas, Fas L, and DR-6) and apoptosis-related genes (Bad, Bax, caspase-3,SARP 2, DFF45/ICAD, IFN-gamma receptor 2, Bcl-w, Bik, and iNOS). Apoptosis was confirmed by (1) morphological modifications by electron microscopy, (2) annexin V binding, (3) DNA degradation, by measuring intracytoplasmic nucleosomes, and (4) caspase activity. The apoptotic stimulus was physical contact between HLECs and PRBCs and not parasite-secreted molecules. In addition, it was found that cytoplasmic (caspase 8) and mitochondrial (caspase 9) pathways were involved in this process. These data not only describe the direct apoptotic effect of PRBC adhesion on endothelial cells but also provide new useful tools that allow an evaluation of potential pharmaceuticals.
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PMID:Plasmodium falciparum--infected erythrocyte adhesion induces caspase activation and apoptosis in human endothelial cells. 1269 8

The ability of human NK cells to inhibit the growth in vitro of the asexual blood stages of Plasmodium falciparum was tested. Purified NK cells from donors with no prior exposure to malaria significantly inhibited parasite growth after 48 hours of co-culture in the presence of human immune serum. This inhibition was completely abrogated by pre-treatment of the NK cells with an anti-CD95 (anti-Fas) monoclonal antibody and human Fas-Fc soluble protein. The level of growth inhibition was also substantially reduced by pre-treatment with an anti-CD56 antibody. These two antibodies caused reductions, to varying levels, of the amounts of NK cell-derived granzyme B (GrB) and pro-inflammatory cytokines, but only the anti-CD95 antibody affected the production of soluble Fas ligand (sFasL). Direct destruction of parasite-infected red cells by NK cells, in the absence of serum, was also observed in a standard 51Cr cytotoxicity test, during which N-carboxybenzoxy-L-lysine thiobenzil ester (BLT esterase) activity, which catalyzes serine protease granule release, was detected. The results obtained are indicative of a novel mechanism of NK cell-mediated cytotoxic activity against Plasmodium falciparum-infected red cells, which is mediated in part by both Fas and by GrB.
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PMID:Natural killer (NK) cell-mediated cytolysis of Plasmodium falciparum-infected human red blood cells in vitro. 1465 86

During Plasmodium falciparum infection leading to cerebral malaria, mechanisms such as cytokine generation and cytoadherence of parasitized red blood cells (PRBC) to post-capillary venules are clearly involved. We demonstrated that PRBC adhesion to human lung endothelial cells (HLEC) upregulated TNF-alpha superfamily genes and genes related to apoptosis and inflammation. Apoptosis was confirmed by standard techniques (annexin-V binding, genomic DNA fragmentation, and caspases activation). This apoptotic process involved the cytoplasmic pathway from a death receptor (DR-6, Fas, TNF-R1) through caspase 8, and the mitochondrial pathway though Bad and caspase 9 activation. Oxidative stress has been implicated in apoptosis induction in various pathological models. Superoxide anion (O(2)*(-)) is a key molecule in the oxidative stress pathway which can form peroxynitrites (ONOO(-)) in association with nitric oxide (NO*). Even though the role of NO* in malaria physiopathology is still a matter of controversy, we demonstrated that PRBC-induced apoptosis in endothelial cells is mediated through an oxidative stress pathway. The inhibition of NO* synthesis protected the endothelial cells suggesting a deleterious role for NO*. In addition, the superoxide dismutase mimetic, MnTBAP, also protected the HLEC against PRBC-induced apoptosis, revealing the role of O(2)*(-) and ONOO(-).
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PMID:Redox-dependent apoptosis in human endothelial cells after adhesion of Plasmodium falciparum-infected erythrocytes. 1503 96

Bupleuri Radix (Chai-hu in Chinese and Saiko in Japanese) is one of the most important traditional Chinese crude drugs for treating hepatitis malaria and intermittent fever. B. kaoi is one of the Bupleurum spp. families locally found in Taiwan. The effects of saponin-enriched fraction (SEF) from Bupleurum Kaoi in human non-small cell lung cancer A549 cells were investigated in this study. An enhancement in Fas and its two forms of ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), was responsible for the apoptotic effect induced by SEF. Taken together, our study suggests that the activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of SEF in A549 cells.
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PMID:The antiproliferative activity of saponin-enriched fraction from Bupleurum Kaoi is through Fas-dependent apoptotic pathway in human non-small cell lung cancer A549 cells. 1525 50


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