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)

Infection with Plasmodium berghei ANKA (PbA) leads, in susceptible strains of mice, to the development of cerebral malaria (CM), a lethal syndrome that reproduces some features of human CM. To study a possible relationship between genetic susceptibility to CM and the cytokine expression pattern, we quantitatively evaluated gene expression on RNA extracted from various organs of malaria-infected mice, using strains that are susceptible and resistant to CM. Northern blot analysis and semi-quantitative PCR showed that CM is associated with an increased TNF-alpha mRNA accumulation in the brain of mice developing the neurologic complications of CM. An increased IFN-gamma mRNA accumulation and a decreased expression of IL-4 and TGF-beta genes were also observed in mice susceptible to CM. In vitro restimulation studies using crude malarial Ag showed that lymphoid cell proliferation was higher in CM-susceptible than in CM-resistant infected mice. Moreover, susceptible mice produced large amounts of IFN-gamma, in a dose-dependent manner, in response to PbA Ag, whereas cells from resistant mice failed to produce significant amounts of this cytokine. Conversely, IL-2 and IL-4 production was significantly higher in infected CM-resistant mouse cells. No difference was seen in the production of IL-3 and IL-5 between resistant and susceptible PbA-infected mice. Upon stimulation with various malarial Ag, comparable amounts of TNF-alpha were produced by macrophages of either strain of mice. Taken together, these findings indicate that susceptibility to CM resides at the level of T cells rather than macrophages. Furthermore, the cytokine production profile is consistent with a predominant Th1-like response in mice developing cerebral complications of malaria.
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PMID:Profiles of cytokine production in relation with susceptibility to cerebral malaria. 840 39

In this study, we have identified a dominant glycolipid toxin of Plasmodium falciparum. It is a glycosylphosphatidylinositol (GPI). The parasite GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin 1 production by macrophages and regulates glucose metabolism in adipocytes. Deacylation with specific phospholipases abolishes cytokine induction, as do inhibitors of protein kinase C. When administered to mice in vivo the parasite GPI induces cytokine release, a transient pyrexia, and hypoglycemia. When administered with sensitizing agents it can elicit a profound and lethal cachexia. Thus, the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process, exerting pleiotropic effects on a variety of host cells by substituting for the endogenous GPI-based second messenger/signal transduction pathways. Antibody to the GPI inhibits these toxic activities, suggesting a rational basis for the development of an antiglycolipid vaccine against malaria.
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PMID:Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. 841 96

Cerebral malaria (CM) is the most common cause of death in severe malaria; more than two million children die of CM annually. Although the mechanisms of this neurologic complication remain poorly understood, studies in an experimental model of CM suggest that a natural body protein seems to be a major cause of this deadliest complication of malaria, a finding that could point towards new methods of treatment. We have explored the pathogenesis of CM with particular attention to the possible relationship between susceptibility or resistance to CM and cytokine expression and secretion patterns. We found that CM is associated with an increased expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma and a reduced expression of interleukin-4 (IL-4) and transforming growth factor (TGF)-beta. The data obtained are consistent with a predominantly Th1 response in mice developing the cerebral complications of malaria. The overexpression of TNF in brain was also correlated with the augmented expression of adhesion molecules involved in the sequestration of leukocytes in brain vessels, a distinctive feature of CM. These observations were seen in relation to the immune status of man, in which, akin to the mouse model, a predominant Th1 response and upregulation of adhesion molecules in brain endothelium appear to be associated with susceptibility to the neurological complications of CM.
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PMID:Role of cytokines and adhesion molecules in malaria immunopathology. 845 80

Recombinant rat interferon-gamma (rrIFN-gamma) was tested for its antimalarial activity in three different models of Plasmodium chabaudi-blood stage malaria. Doses ranging from 1 x 10(4) to 1 x 10(5) U of rrIFN-gamma were used in each model. In BALB/c mice (lethal infection), prophylactic treatment with daily intraperitoneal (i.p.) injections reduced parasitemia and delayed mortality. In contrast, subcutaneous administration of rrIFN-gamma was inefficient, as was curative schedule of i.p. administration. Euthymic Fischer rats, which develop an acute and resolutive infection, were partly protected by i.p. prophylactic administration of rrIFN-gamma. Parasitemia was reduced without being lengthened, resulting in a marked decrease in parasite burden. Subcutaneous administration was less efficient whereas curative schedule was not. Athymic (nude) Fischer rats which present a longlasting and stable infection were treated with prophylactic and curative schedules of i.p. administration of rrIFN-gamma. In each case, rrIFN-gamma-treated nude rats, as control nude rats, were unable to resolve their chronic infection. The conditions required to obtain a beneficial effect are thus restrictive for a therapeutic use in humans. Moreover, these results show that, despite the fact that IFN-gamma is considered as a major component of the immune response, this cytokine alone is not sufficient to induce the totality of the effector mechanisms necessary to cure malarial infections.
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PMID:IFN-gamma treatment of rodents infected with erythrocytic stages of Plasmodium chabaudi: differential effects according to the immunological status. 850 41

The purpose of this study was to investigate the ability of the antimalarial drug, Ro 42-1611 to block parasite mediated cytokine induction in vitro as well as cytoadherence of infected erythrocytes to melanoma cells in vitro. The biological activity of Ro 42-1611 was confirmed as it blocked Plasmodium falciparum growth in cultures. Ro 42-1611, had no major effect on TNF, IL-alpha or IL-6 cytokine release from mononuclear cells stimulated with malaria antigens or lipopolysaccharide and it did not affect cell viability. Ro 42-1611 only slightly suppressed cytoadherence of infected erythrocytes to melanoma cells. The therapeutic effect of To 42-1611 appears to be confined to its parasite killing activity.
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PMID:The antimalarial drug, Ro 42-1611 (arteflene), does not affect cytoadherence and cytokine-inducing properties of Plasmodium falciparum malaria parasites. 852 91

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

We investigated whether gamma interferon (IFN-gamma; a Th1 cytokine), tumor necrosis factor alpha (TNF-alpha), and interleukin-4 (IL-4; a Th2 cytokine) modulate nitric oxide (NO) production in vivo during blood stage infection with Plasmodium chabaudi AS. Treatment of resistant C57BL/6 mice, which resolve infection with P. chabaudi AS and produce increased levels of IFN-gamma, TNF-alpha, and NO early during infection, with anti-IFN- gamma plus anti-TNF-alpha monoclonal antibodies (MAbs) resulted in a reduction of both splenic inducible NO synthase mRNA and serum NO3- levels by 50 and 100%, respectively. Treatment with the anti-TNF-alpha MAb alone reduced only serum NO3- levels by 35%, and treatment with the anti-IFN-gamma MAb alone had no effect on NO production by these mice during infection. Susceptible A/J mice, which succumb to infection with P. chabaudi AS and produce increased levels of IL-4 but low levels of IFN-gamma, TNF-alpha, and NO early during infection, were treated with an anti-IL-4 MAb. The latter treatment had no effect on NO production by this mouse strain during infection. In addition, our results also demonstrate that treatment of resistant C57BL/6 mice with anti-IFN-gamma plus anti-TNF-alpha MAbs affects, in addition to NO production, other traits of resistance to P. chabaudi AS malaria such as the peak level of parasitemia and the development of splenomegaly. Furthermore, the change in spleen weight was shown to be an IFN-gamma-independent effect of TNF-alpha. Treatment of susceptible A/J mice during infection with an anti IL-4 MAb had no effect on these markers of resistance. Thus, these results demonstrate that TNF-alpha and IFN-gamma are critical in the regulation of NO production and other traits of resistance during P. chabaudi AS malaria in C57BL/6 mice. These data also indicate that treatment with an anti-IL-4 antibody alone is not able to induce NO production or confer resistance to A/J mice against P. chabaudi AS malaria.
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PMID:In vivo regulation of nitric oxide production by tumor necrosis factor alpha and gamma interferon, but not by interleukin-4, during blood stage malaria in mice. 855 72

Previous studies have indicated the inositol monophosphate (IMP) is a component of the malaria parasite toxin that induces cytokines such as tumour necrosis factor (TNF). To further characterize the toxin we have labeled Plasmodium falciparum in vitro cultures with [14C]inositol or [35S]-methionine and immunoprecipitated the labeled antigens with an antiserum against IMP which blocks malaria parasite-induced TNF production. We detected four proteins associated with IMP when the immunoprecipitates were separated by SDS-PAGE and analyzed by autoradiography. To evaluate the capacity of different P. falciparum antigens to induce cytokine production we separated a mixture of exoantigens by SDS-PAGE gels. Antigen fractions of 43-71 kDa and of a low molecular mass of <20 kDa contained the dominant inducers of TNF alpha interleukin 1 alpha, and interleukin 6 production from human mononuclear cells. The low-molecular-mass antigen fraction contained hemoglobin, while no parasite-specific proteins were detectable when tested by immunoblotting. Hemoglobin may act as a carrier for cytokine-inducing malaria parasite toxins.
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PMID:Plasmodium falciparum: characterization of toxin-associated proteins and identification of a hemoglobin containing parasite cytokine stimulator. 861 41

The Epstein-Barr Virus (EBV) is consistently found in tumor cells of Burkitt's lymphoma (BL) endemic in central Africa and malaria is considered a pathogenic cofactor. In contrast, fewer than 20% of BL cases occurring in Western countries are EBV-associated. We have investigated 54 BL cases from Bahia, a tropical region of Northeast Brazil, for expression of EBV gene products by in situ hybridization and immunohistology and performed typing of the EBV by polymerase chain reaction. Ten pediatric BL cases from Germany served as controls. New cases of malaria were not observed in the period and area of our study. Small nuclear EBV encoded transcripts, EBER, were found in tumor cells of 47 of 54 Brazilian cases (87%) but in only 2 of 10 German cases (20%). Type I latency of the EBV infection with absence of EBV-encoded proteins LMP1 and EBNA2 was found in 45 of 47 of the EBER-positive Brazilian cases. In two cases, occasional LMP1-containing tumor cells were found in the neighborhood of small Schistosoma mansoni granulomas and scars. BHLF1 transcripts associated with lytic EBV infection could be detected in few cells in 3 of the 40 EBER-positive Brazilian cases investigated. EBV type A was found in the majority of Brazilian BL cases (20 of 30 A-type, 7 of 30 B-type, and 3 of 30 not amplifiable). Our results indicate that the association of Bahian BL with EBV, but not the regional prevalence of malaria, is similar to endemic African BL. In two cases, type II latency was found in association with schistosomiasis, suggesting a role of this parasitosis in the induction of an EBV expression pattern that is unusual for BL. Because chronic schistosomiasis is associated with elevated Th2 cytokine expression resulting in reduced cell-mediated cytotoxicity, it seems possible that altered local immunity is responsible for this peculiar phenotype.
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PMID:Expression of Epstein-Barr virus-gene products in Burkitt's lymphoma in Northeast Brazil. 973 Oct 79

A proportion of children with Plasmodium falciparum infection have a high parasitaemia without accompanying fever, indicative of different clinical thresholds of parasitaemia. Higher levels of IL-10, IL-1Ra and sIL-4R but not sIL-2R were found in children with P. falciparum malaria, compared with levels in children with asymptomatic P. falciparum infections and in healthy children. Concentrations of IL-10 and IL-1Ra were correlated with levels of parasitaemia, but the association of cytokine levels with disease was independent of the association with parasitaemia. Children may tolerate a high parasitaemia by neutralizing the parasite-derived toxins. When studying potential anti-toxic molecules we found that children with symptomatic infections had lower concentrations of a phospholipid-binding molecule, beta 2-glycoprotein I (beta 2-GPI), compared with children with asymptomatic infections or healthy children. In conclusion, cytokines were found in much higher concentrations in children with symptomatic P. falciparum malaria than in children with asymptomatic infections, whilst the former had lower concentrations of beta 2-GPI.
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PMID:Soluble products of inflammatory reactions are not induced in children with asymptomatic Plasmodium falciparum infections. 869 38


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