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)

Granulocyte macrophage-colony stimulation factor (GM-CSF), which is a haematopoietic cytokine generated by activated T lymphocytes and macrophages during infection, was investigated for its effects on human neutrophil-mediated killing of asexual blood forms of Plasmodium falciparum. Pretreatment of neutrophils with human recombinant-GM-CSF markedly increased the parasite killing (measured by a radiometric assay), in the presence of normal serum (containing complement), immune serum (IS), purified IgG (from IS) or heat inactivated IS. GM-CSF pretreatment also enhanced phagocytosis of the parasite by neutrophils and the expression of CR3, Fc gamma RII and Fc gamma RIII receptors. Treatment of neutrophils with a combination of GM-CSF and TNF resulted in a synergistic increase in phagocytosis and killing of the parasite. The findings suggest that GM-CSF is likely to form part of the cytokine network responsible for regulating the antiparasitic activity of the neutrophil in malaria.
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PMID:GM-CSF-induced priming of human neutrophils for enhanced phagocytosis and killing of asexual blood stages of Plasmodium falciparum: synergistic effects of GM-CSF and TNF. 922 65

T cell responses to leucoagglutinin, PPD, and seven Plasmodium falciparum blood stages antigens were investigated in 164 cord blood samples from Cameroonian neonates. In vitro T cell responses were measured by lymphocyte proliferation, and IL-2, IFN-gamma, and IL-4 release in the presence of crude schizont extract, purified Pf155/RESA protein, and synthetic peptides from Pf155/ RESA. Following culture in presence of leucoagglutinin or PPD, proliferation and cytokine production were very low, as compared to adults from the same area. Interestingly, following stimulation of cord blood lymphocytes by malaria antigens, the percentage of responders and the mean level of positive responses were of the same order than those observed in adults for IL-2 production, while proliferative and IL-4 responses were only marginally decreased. Conversely, IFN-gamma production was highly reduced, as compared to adults. Our results demonstrate that prenatal immune priming to malarial antigens is common in this area and that the fetal immune system is able to respond to antigenic stimuli, as cells proliferate and generate cytokines. As cord blood lymphocytes may be induced to differentiate into effector cells producing predominantly Th1 or Th2 cytokines, malaria during pregnancy might direct the functional capacity of fetal T cells to respond to further infection.
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PMID:Malaria cellular immune responses in neonates from Cameroon. 922 85

Although glucose production is increased in severe malaria, the influence of uncomplicated malaria on glucose production is unknown. Therefore, we measured in eight adult Vietnamese patients with uncomplicated falciparum malaria and eight healthy Vietnamese controls glucose production (by infusion of [6,6-2H2]glucose) and the fractional contribution of gluconeogenesis (by oral ingestion of 2H2O); glycogenolysis was calculated as the difference between the two. After 20 h of fasting, plasma glucose was 4.7 +/- 0.2 mmol/l in the patients and 4.3 +/- 0.2 mmol/l in the controls (not significant). Glucose production was approximately 25% higher in the patients (16.9 +/- 1.3 vs. 13.4 +/- 0.3 mumol.kg-1.min-1, P = 0.01). Fractional and absolute gluconeogenesis were increased in the patients (approximately 87 vs. approximately 59%, P < 0.001; and 14.6 +/- 1.3 vs. 7.9 +/- 0.2 mumol.kg-1.min-1, P < 0.001, respectively). The contribution of glycogenolysis to total glucose production was decreased in the patients: 2.3 +/- 0.5 vs. 5.5 +/- 0.4 mumol.kg-1.min-1 (P < 0.002). In conclusion, in adult patients with uncomplicated falciparum malaria, glucose production is increased by approximately 25% due to an increased rate of gluconeogenesis, whereas glycogenolysis is decreased. The mechanism by which these changes occur is uncertain. However, counterregulatory hormone and cytokine concentrations were increased in the patients.
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PMID:Glucose production and gluconeogenesis in adults with uncomplicated falciparum malaria. 922 52

In tropical areas where Plasmodium falciparum malaria is endemic, concurrent HIV infection does not appear to increase malaria prevalence. To investigate the immunologic interactions between these two infections, 66 adults from Bobo Dioulasso, Burkina Faso, were enrolled in a study in May 1994. The group included 29 HIV-negative adults and 37 hospitalized HIV-positive adults with clinical AIDS and under 250 CD4+ cells per mcgl of blood. All subjects belonged to a population exposed to numerous falciparum malaria infections since birth and were thus presumed to have developed specific antimalarial protective immune mechanisms prior to HIV infection. AIDS patients had a reduced hemoglobin content and a lower number of CD3+ and CD4+ lymphocytes than healthy controls. All thick blood smears were negative for malaria parasites, but the mean level of antibodies to P. falciparum was lower and the total immunoglobulin G content of plasma was higher in AIDS patients than controls. In vitro lymphocyte proliferation and cytokine (IFN-psi, IL-2, and IL-4) production were assessed in isolated mononuclear cells (PBMC) in the presence of PHA, PPD, or 3 antimalarial agents: the baculovirus-expressed protein from P. falciparum Merozoite Surface Protein-1, a P. falciparum in vitro culture, and a crude schizont extract. AIDS patients presented with decreased levels of cell proliferation and of IFN-psi and IL-2 production compared to healthy controls in response to all antigens except the schizont extract. IL-4 production levels were similar in both groups. Mitogenic stimulation of whole blood cultures revealed similar trends in cytokine production as in PBMC cultures. These findings confirm that not all effector cells involved in the immune responses directed against malaria are affected by concurrent HIV infection and/or that important CD4+ independent mechanisms of protection against malaria are conserved. It has been proposed that HIV infection causes a selective depletion of T cell subsets that are not implicated in the antimalarial immune response.
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PMID:Selected P. falciparum specific immune responses are maintained in AIDS adults in Burkina Faso. 922 86

The Plasmodium yoelii murine model was used to test several combinations of blood-stage antigens and adjuvants for the ability to induce immunity to blood-stage malaria. Upon fractionation of whole blood-stage antigen into soluble and insoluble components, only the particulate antigens (pAg) induced protective immune responses. Of a number of adjuvants tested, Quil A was the most effective. Immunization with pAg plus Quil A induced solid protection against nonlethal and lethal P. yoelii challenge infection. Analysis of cytokine production revealed mRNA for Th1-type cytokines (interleukin 2 [IL-2] and gamma interferon) as well as Th2-type cytokines (IL-4 and IL-10) in the spleens of both protected and susceptible animals. The data suggested that the protective pAg response was associated with the earlier production of cytokine mRNA with a Th2 phenotype somewhat favored. Immunization of B-cell-deficient JHD mice indicated that the protection against P. yoelii induced by pAg immunization was B cell dependent. Although immunization with pAg plus Quil A increased the levels of antigen-specific antibodies of all four immunoglobulin G (IgG) isotypes, protection correlated most closely with the presence of IgG1 and IgG2b antibodies. Sera from pAg-plus-Quil A-immunized animals recognized only a limited subset of six to eight distinct P. yoelii antigens, primarily associated with the pAg fraction. These results provide the basis for the identification and characterization of potential vaccine antigens, selected solely for their ability to immunize against blood-stage malaria.
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PMID:Protective immunity against Plasmodium yoelii malaria induced by immunization with particulate blood-stage antigens. 923 66

Genetically determined differences in immune responses to environmental agents may underlie susceptibility to many autoimmune and infectious diseases. Leprosy provides an example of a polarity in the type of immune response made to an infectious agent, and there is evidence that the major histocompatibility complex is genetically linked to leprosy type. It was found that HLA-DR2 is associated with both tuberculoid and lepromatous types of leprosy; however, a variant at position -308 of the promoter of the neighboring tumor necrosis factor (TNF) gene was increased in frequency in lepromatous (odds ratio = 3.0, P = .02) but not tuberculoid leprosy. Some studies have found higher serum levels of TNF in lepromatous than tuberculoid leprosy, and high TNF levels are found in malaria and leishmaniasis, which are also associated with this TNF allele. It is speculated that this association reflects genetic variability in cytokine production, which influences the immune response to and clinical outcome of leprosy.
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PMID:Tumor necrosis factor promoter polymorphism and susceptibility to lepromatous leprosy. 923 25

Malarial pigment (haemozoin; HZ) is generally considered to be a non-toxic, high-molecular-weight storage form of undigested, toxic, host-haemoglobin haem. The available information on HZ indicates that it is a very heterozygous material. Its exact structure, in terms of constituent proteins (remnants of host globin v. parasite proteins), the type of linkage between the haem moieties (mu-oxo haem dimers further aggregated by non-covalent hydrophobic bonds v. mutually independent haematin monomers), iron status in the haem (penta-co-ordinated, high-spin ferriprotoporphyrin IX v. esa-co-ordinated, low-spin ferriprotoporphyrin IX), and compositions (beta-haematin-like structure without functionally relevant proteins or other constituents v. a ferriprotoporphyrin-IX core with aggregated proteins and phospholipids of host and parasite origin) remains a subject of controversy. When investigated by macrophages, HZ is not inert but affects a number of functional parameters. Crude pigment, as present in infected erythrocytes and shed after schizont rupture, may be considered the 'natural diet' ingested by macrophages in infected blood. It is a powerful source of radicals that may generate lipoperoxides and derived, toxic hydroxyaldehydes such as 4-hydroxynonenal (HNE). High concentrations of HNE, which have been detected in HZ-fed macrophages, inhibit protein kinase C (PKC). Complexes between HNE and PKC have also been detected in immunoprecipitated PKC from HZ-fed macrophages. HNE-mediated inhibition of PKC (and of other, as yet unidentified enzymes and processes) may explain HZ-mediated effects. HZ-mediated inhibition of NADPH-oxidase, the enzyme responsible for oxidative bursts, may only be partially explained by PKC inhibition. As Hz-laden human and murine macrophages produce increased amounts of tumour necrosis factor-alpha, interleukins 1 and 6, and macrophage inflammatory proteins 1 alpha and 1 beta, HZ-macrophage interactions may contribute to the cytokine-mediated manifestations of malaria.
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PMID:Malarial pigment (haemozoin): a very active 'inert' substance. 932 87

There is increasing evidence that inappropriate immune activation induced by parasite products occurs in malaria disease. To further elucidate the role of Plasmodium falciparum-derived products on host immune activation, we studied the expression of leukocyte adhesion molecules (CD11b/CD18 and LAM-1) on neutrophils and monocytes in response to malaria pigment using flow cytometry. Exposure of leukocytes to isolated malaria pigment derived from ruptured schizonts resulted in significant up-regulation of CD11b/CD18 expression and down-regulation of LAM-1 on both neutrophils and monocytes. In contrast, culture supernatants (pigment free) from ruptured schizonts did not alter the expression of CD11b/CD18 and LAM-1. The increase of CD11b/CD18 and the loss of LAM-1 expression occurred simultaneously with the earliest response detected at 10 min and a plateau reached by 60 min. The effect of malaria pigment on leukocyte adhesion molecules was inhibited by EDTA in a dose-dependent manner. Phagocytosis of malaria pigment was also suppressed by EDTA. This observation suggests that phagocytosis of malaria pigment may be a prerequisite for the effect of malaria pigment on the regulation of CD11b/CD18 and LAM-1 expression. Regulation of leukocyte adhesion molecules through up-regulation of CD11b/CD18 and down-regulation of LAM-1 by malaria pigment could promote leukocyte adherence to endothelium in vivo. This increased adherence of malaria pigment-activated leukocytes might induce cytokine (tumor necrosis factor alpha and interleukin-1beta)-mediated increases in capillary permeability resulting in local tissue edema, and a cytokine-mediated increase in adhesion molecule expression causing vascular clogging by adherent red blood cells, and in severe disease by adherent leukocytes.
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PMID:Regulation of leukocyte adhesion molecules CD11b/CD18 and leukocyte adhesion molecule-1 on phagocytic cells activated by malaria pigment. 934 50

Cerebral malaria (CM) remains a poorly understood and life-threatening complication of malaria caused by the parasite Plasmodium falciparum. The discovery that murine CM caused by Plasmodium berghei ANKA and human CM are both characterized by production of inflammatory cytokines, especially tumor necrosis factor alpha (TNF-alpha), led to a revival of the suggestion that P. berghei CM may have value as a model of the human disease. In this study, quantitative reverse transcription-PCR was used to measure levels of message for 18S rRNA of P. berghei and 10 cytokines in the brains, livers, and spleens of mice during the induction and course of CM. A coordinated increase in RNA of parasite and proinflammatory cytokines was observed in the brains of mice in parallel with onset of CM. Levels of message for parasite, TNF-alpha, and gamma interferon increased in the brains of mice from day 5 to death on day 7. These changes were observed only in the brain, and message for other cytokines remained near baseline levels. This demonstrated that parasite sequestration does take place in the brains of mice with CM. Histologically, CM was characterized by widespread damage to the microvasculature in the brain with focal infiltration of inflammatory cells. The pattern of cytokine production in the brain is characteristic of other murine encephalitides.
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PMID:Cytokine profile suggesting that murine cerebral malaria is an encephalitis. 935 82

Severe morbidity due to Plasmodium falciparum is a major health problem in African children. The patterns of morbidity in endemic areas are modified by the immune response, and vary markedly with transmission intensity. Severe disease falls into three overlapping syndromes: coma, respiratory distress, and severe anaemia. Recently, it has become clear that metabolic acidosis plays a major role in the pathogenesis of severe disease and is particularly important in the overlap between the different clinical syndromes. We propose that the different manifestations of severe malarial morbidity arise from the interaction of a limited number of pathogenic processes: red cell destruction, toxin-mediated activation of cytokine cascades, and infected cell sequestration in tissue microvascular beds. The pattern of severe morbidity varies with age within any one endemic area, with severe anaemia predominating in the youngest children and coma having its highest incidence in older children. Between endemic areas there is a marked variation in mean age of children with severe malaria, and therefore in the importance of different clinical syndromes. The shift in mean age is due to a combination of increased challenge and more rapid development of immunity at higher levels of transmission. Recent comparative studies indicate that at higher levels of transmission the net effect of these shifts may be a paradoxical reduction in total severe malarial morbidity.
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PMID:Host-parasite interaction and morbidity in malaria endemic areas. 935 31


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