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)

To discover how nitric oxide (NO) synthesis is controlled in different tissues as cells within these tissues combat intracellular pathogens, we examined three distinctively different experimental murine models designed for studying parasite-host interactions: macrophage killing of Leishmania major; nonspecific protection against tularemia (Francisella tularensis) by Mycobacterium bovis (BCG); and specific vaccine-induced protection against hepatic malaria with Plasmodium berghei. Each model parasite and host system provides information on the source and role of NO during infection and the factors that induce or inhibit its production. The in vitro assay for macrophage antimicrobial activity against L. major identified cytokines involved in regulating NO-mediated killing of this intracellular protozoan. L. major induced the production of two competing cytokines in infected macrophages: (1) the parasite activated the gene for tumor necrosis factor (TNF), and production of TNF protein was enhanced by the presence of interferon-gamma (IFN-gamma). TNF then acted as a autocrine signal to amplify IFN-gamma-induced production of NO; and (2) the parasite upregulated production of transforming growth factor-beta (TGF-beta), which blocked IFN-gamma-induced production of NO. Whether parasite-induced TNF (parasite destruction) or TGF-beta (parasite survival) prevailed depended upon the presence and quantity of IFN-gamma at the time of infection. The relationship between NO production in vivo and host resistance to infection was demonstrated with M. bovis (BCG).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide: cytokine-regulation of nitric oxide in host resistance to intracellular pathogens. 753 21

When murine peritoneal macrophages were loaded in vitro with Plasmodium vinckei hemozoin and stimulated for 24 hours with interferon-gamma and/or Escherichia coli lipopolysaccharide, the production of interleukin 6 (IL-6) was drastically reduced, whereas the secretion of tumor necrosis factor (TNF) was increased. In addition, non-radioactive in situ hybridizations in spleen sections of P. vinckei infected mice showed more TNF than IL-6 gene expression in the red pulp around hemozoin accumulation. These results provide evidence that IL-6 and TNF are differentially modulated by hemozoin and that subsequently, the secretion of IL-6 seems to be independent of the TNF production during murine malaria.
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PMID:Hemozoin differentially modulates the production of interleukin 6 and tumor necrosis factor in murine malaria. 757 88

Radix bupleuri, the root of Bupleuri spp., Chinese medicinal herbs used for the treatment of influenza, malaria and menstrual disorders, were extracted with hot water and separated into five different fractions (RB, RBI, RBII, RBIII and RBIV) by stepwise alcohol precipitation. One of these fractions, RBI, was then fractionated into RBIa and RBIb by gel filtration using G-100 Sephadex. These two fractions were further purified into RBIai, RBIaii and RBIbi, RBIbii fractions respectively by ion-exchange chromatography using DEAE-Sephadex. Each of these fractions is a heteropolymer consisting mainly of carbohydrate and varying proportions of protein and uronic acid. RBIaii was found to show strong anti-tumor activities in sarcoma-bearing mice. Mechanistic studies showed that RBIaii exhibited a potent activating effect on the cytotoxic activity of macrophages, NK and LAK cells against tumor cells. In addition, RBIaii could increase the number of tumor infiltrating lymphocytes (TILs) in the tumor site of WEHI-164-bearing mice. Furthermore, RBIaii could induce the release of interferon-gamma by lymphocytes in vitro.
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PMID:Activation of the anti-tumor effector cells by Radix bupleuri. 759 16

The relevance of the antibody-dependent cellular inhibition (ADCI) of Plasmodium falciparum to clinical protection has been previously established by in vitro studies of material obtained during passive transfer of protection by immunoglobulin G in humans. We here report further in vitro investigations aimed at elucidating the mechanisms underlying this ADCI effect. Results obtained so far suggest that (a) merozoite uptake by monocytes (MN) as well as by polymorphonuclear cells has little influence on the course of parasitemia; (b) the ADCI effect is mediated by a soluble factor released by MN; (c) this or these factors are able to block the division of surrounding intraerythrocytic parasites at the one nucleus stage; (d) the critical triggering antigen(s) targeted by effective Abs would appear to be associated with the surface of merozoites, as opposed to that of infected red blood cells; (e) the MN receptor for Abs effective in ADCI is apparently Fc gamma RII, and not RI; (f) MN function is up- and down-regulated by interferon-gamma and interleukin 4, respectively; and (g) of several potential mediators released by MN, only tumor necrosis factor (TNF) proved of relevance. The involvement of TNF in defense may explain the recently described increased frequency of the TNF-2 high-expression promoter in individuals living in endemic regions despite its compromising role in severe malaria.
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PMID:Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. 762 3

Cytoadherence to HB3 and FC27 strains of Plasmodium falciparum-parasitized red blood cells (PRBC) was studied under shear conditions to elucidate the pathways of adherence to microvascular endothelial cells (MEC). HB3 PRBC bound exclusively to MEC CD36 and intercellular adhesion molecule-1 (ICAM-1) receptors. FC27 PRBC bound to CD36 and another unidentified pathway but not to ICAM-1. Down-regulation of CD36 and ICAM-1 expression by phorbol 12,13-dibutyrate abolished HB3 PRBC adherence. Selective up-regulation of CD36 with interferon-gamma (IFN-gamma) increased PRBC adherence. Conversely, selective up-regulation of ICAM-1 with tumor necrosis factor did not elevate cytoadherence. These data have defined the relative contributions of both CD36 and ICAM-1 to PRBC binding to MEC and have provided evidence for the presence of a novel adhesion mechanism. Furthermore, in addition to antibody blocking of cell adhesion molecules, anti-IFN-gamma antibody therapy or pharmacologic manipulation of endothelial cell receptor expression may reduce PRBC sequestration and ameliorate the events associated with human cerebral malaria.
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PMID:Cytoadherence of Plasmodium falciparum-infected erythrocytes to microvascular endothelium is regulatable by cytokines and phorbol ester. 768 61

It has never been explained why it takes so long for humans to develop immunity to malaria, although factors such as antigenic variation, antigenic polymorphism, and poor immunological responses to critical antigens are thought to be important. Models of malaria, particularly in rodents, have not been helpful. The course of malaria infection differs considerably between humans and rodents. Mice rapidly develop immunity whereas for most humans it takes several years of exposure for this to occur. Mice typically exhibit high parasitaemias whereas humans typically do not. A significant difference in the immune response of humans and mice to malaria parasites might, in part, explain these differences. Most humans have a preexisting population of activated malaria parasite-specific T cells (cross-reactive T cells) which we have referred to as 'natural' T cells, but such cells have not been observed in mice. These cells, many of which secrete interferon-gamma, might control parasitaemia early in the infection, but a by-product of their further activation by malaria parasites might be disease symptoms. Development of immunity has been thought of as an active process--acquisition of specific antibody and effector T cell responses. However, it might in part reflect induction of tolerance of this preexisting population of disease-inducing T cells as a result of chronic parasitaemia. The initial presence of these Th1-like cells may also impede the development of a Th2-like response necessary for the production of protective antibodies. Persistent cross-reactive stimulation may significantly impede this process.
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PMID:Development of immunity to malaria may not be an entirely active process. 776 Nov 8

The development of antidisease immunity in children infected with Plasmodium falciparum is thought to be related to their immunologic responses to certain soluble parasite-derived exoantigens. We have assessed both cellular and humoral responses to these antigens in a cross-sectional study of a cohort of Gabonese schoolchildren who live in an area where malaria is holoendemic and perenially transmitted, in an attempt to identify immunologic markers of this early developing protective immunity. Concurrent parasitemia was found to have a significant influence on lymphoproliferative and antibody responses to the exoantigens. Individuals with higher levels of parasitemia had significantly lower proliferative and IgG isotype responses. Higher concentrations of specific IgG1 and IgG3, in particular, were associated with lower or no parasitemia, suggesting a possible protective role for these isotypes, whereas the level of IgM antibodies showed a trend towards higher concentrations in those with parasitemia, perhaps indicative of an exoantigen-induced T cell-independent response. Cytokine responses were unaffected by either the presence or the intensity of parasitemia and were dissociated from both proliferative and antibody response to the exoantigens. However, the mitogen-stimulated production of tumor-necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL)-6 was positively correlated with the corresponding lymphoproliferative responses. At the individual level, mitogen-stimulated TNF-alpha, interferon-gamma, IL-2, and IL-6 responses were positively correlated, as were mitogen- and exoantigen-induced TNF-alpha. The results are discussed in the light of current knowledge of immune responses to the exoantigens and the development of protective immunity to P. falciparum.
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PMID:Immunologic responses to soluble exoantigens of Plasmodium falciparum in Gabonese children exposed to continuous intense infection. 781 Aug 4

T cells from most adult non-exposed donors, which express a memory phenotype (CD45RO+), can respond by proliferation to P. falciparum asexual stages in vitro. Such cells may have arisen from exposure to environmental organisms. To address the efficacy of such cells in eliminating parasites and investigate the mechanisms involved, we have used an in vitro assay where parasite growth can be precisely monitored in the presence of different cell preparations. Unfractionated peripheral blood mononuclear cells (PBMC) from both malaria-exposed and non-exposed donors inhibited parasite growth by up to 62% in a two day assay. Purified T cells in the presence of adherent cells had a similar effect, but purified T cells alone or adherent cells alone had minimal effect. Antigens released at the time of schizont rupture were maximally effective in stimulating interferon-gamma (IFN gamma) production. Neutralizing antibodies to IFN gamma showed a partial reduction of growth inhibition in some individuals tested suggesting that different mechanisms may be operative. Neutralizing antibody to TNF alpha had a partial effect in combination with anti-IFN gamma. Antibodies to IL-1 and IL-4 had no effect. T cell fractionation experiments showed that while purified CD4+ T cells from some donors produced IFN gamma and inhibited parasite growth, purified CD8+ T cells could inhibit parasite growth to a greater extent without production of detectable IFN gamma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of Plasmodium falciparum growth in vitro by CD4+ and CD8+ T cells from non-exposed donors. 786 64

Serum levels of interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) were determined in 37 patients with acute Plasmodium falciparum malaria in Bangkok, Thailand. Serum levels of IL-10 and IFN-gamma were markedly elevated in patients with malaria prior to treatment (717 +/- 260 pg/ml versus 2.2 +/- 1.3 pg/ml in healthy controls; 123 +/- 71 pg/ml versus 29 +/- 9 pg/ml, respectively; mean +/- SD). Serum levels of IFN-gamma and IL-10 dropped significantly during treatment and were normal 14 and 21 days, respectively, after treatment was started. Prior to therapy a correlation between serum levels of IFN-gamma and IL-10 existed (r = 0.563). These results suggest that stimulatory and inhibitory cytokines for macrophage activation and/or antibody production (i.e., TH1- and TH2-type immunoreaction, respectively) are coexpressed during acute P. falciparum infection and stress the multifactorial network between host and parasite in malaria immunology.
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PMID:Elevated serum levels of IL-10 and IFN-gamma in patients with acute Plasmodium falciparum malaria. 799 21

The induction of T helper cell subsets during the course of non-lethal or lethal blood-stage Plasmodium chabaudi AS infection was investigated using inbred strains of mice which differ in the level of resistance to this intraerythrocytic parasite. Resistant C57Bl/6 mice experience a non-lethal course of infection characterized by moderate levels of both parasitaemia and anaemia and resolution of primary acute infection by 4 weeks, while susceptible A/J mice experience lethal infection with fulminant parasitaemia and severe anaemia. T helper subset function was assessed during infection by determining the kinetics of spleen cell production in vitro of the Th1-derived cytokine, interferon-gamma (IFN-gamma), and of the Th2-derived cytokine, IL-5, using sandwich ELISAs. Spleen cells from resistant C57Bl/6 mice were found to produce high levels of IFN-gamma within 1 week of infection in response to both the mitogen concanavalin A (Con A) and malaria antigen. Furthermore, CD4+ T cells were found to be the source of IFN-gamma while both CD4+ and CD8+ T cells were found to produce IL-5. Decreased IFN-gamma production after day 10 was concomitant with significant production of IL-5 between 2 and 3 weeks post infection. In contrast, spleen cells from susceptible A/J mice produced high levels of IL-5 within the first week of infection. In addition, these animals were found to have high serum levels of IL-5. These results, thus, confirm previous observations that resolution of primary blood-stage P. chabaudi infection occurs by sequential activation of Th1 CD4+ T cells followed by activation of the Th2 subset, and in addition, suggest that induction of a strong Th2 response early in infection may lead to a severe and lethal course of malaria.
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PMID:Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice. 809 4


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