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)

Plasmodium coatneyi infection in rhesus monkeys has been used as a model for studying human malaria. Cytokine production in this model, however, has so far not been examined. In this study, four rhesus monkeys were infected with P. coatneyi, with another four animals serving as uninfected controls. Blood samples were taken for the determination of daily parasitemia, and cytokine and prostaglandin E2 (PGE2) levels at days 0, 3, 5, 7, and 10. All inoculated animals became infected, with synchronized appearance of ring-stage parasites. Infected monkeys had increased plasma levels of proinflammatory cytokines (interleukin-1beta, interferon-gamma, and tumor necrosis factor-alpha) during the late stage of the infection. They also had increased production of ciliary neurotrophic factor. In conjunction with the production of proinflammatory cytokines, infected monkeys also had gradual increases in the production of PGE2. A continued definition of the P. coatneyi/rhesus monkey animal model should be useful for the elucidation of the immunopathogenesis of human malaria.
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PMID:Cytokine production in rhesus monkeys infected with Plasmodium coatneyi. 1046 71

Pro- and antiinflammatory cytokines were measured on admission in 287 consecutive Vietnamese adults with severe falciparum malaria. Plasma interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha concentrations and the IL-6: IL-10 ratio were significantly higher in patients who died than in survivors (P<.001). On multivariate analysis, hyperparasitemia, jaundice, and shock were all associated independently with raised IL-6, IL-10, and interferon-gamma, and acute renal failure specifically with raised TNF-alpha levels. Cerebral malaria patients, particularly those without other vital organ dysfunction, had significantly lower levels of these cytokines (P=.006), reflecting a more localized pathology. Serial IL-6 and IL-10 measurements made on 43 patients who died and matched survivors indicated a relative deficiency in IL-10 production as death approached. Elevated plasma cytokines in severe malaria are associated with systemic pathologic abnormalities, not cerebral involvement. Both the overall magnitude of the cytokine responses and the eventual imbalance between the pro- and antiinflammatory responses are important determinants of mortality.
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PMID:The prognostic and pathophysiologic role of pro- and antiinflammatory cytokines in severe malaria. 1047 60

The frequency and level of cellular and humoral responses to seven synthetic peptides from asexual blood stages of Plasmodium falciparum were measured in two cohorts of children living in areas highly endemic for malaria in Gabon and Cameroon. A prospective longitudinal study was conducted for one year in these sites to examine the relationship between specific in vitro immune responses and susceptibility to clinical malaria. Clinical protection was related to high proliferative responses (merozoite surface antigen-1 [MSA-1] and MSA-2 peptides) as well as to elevated antibody levels (schizont extract, MSA-2, and rhoptry-associated protein-1 [RAP-1] peptides) in the village of Dienga, Gabon. Higher response rates of interferon-gamma but lower response rates of tumor necrosis factor-alpha to four and six peptides, respectively, were observed in Dienga than in Pouma that were independent of the older age of the Gabonese children. Age accounted only for the higher prevalence rate in Dienga of the antibody responders to the peptide from Pf155/ring-infected erythrocyte surface antigen (RESA). Our results support the inclusion of epitopes from MSA-1, MSA-2, RAP-1, and Pf155/RESA antigens in a subunit vaccine against malaria, but show that a longitudinal clinical, parasitologic, and immunologic study conducted according to identical criteria in two separate areas may lead to contrasting observations, demonstrating the geographic limitation of the interpretation of such results.
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PMID:Immune responses against Plasmodium falciparum asexual blood-stage antigens and disease susceptibility in Gabonese and Cameroonian children. 1049 96

We have designed a novel vaccine strategy which enables display of short peptides expressed from chimeras of the gene encoding the coat protein of the RNA bacteriophage MS2 and inserted foreign DNA. MS2 coat protein has a beta-hairpin loop at the N-terminus which forms the most radially distinct feature of the mature capsid. The coat protein gene was modified to enable insertion of DNA at the central part of the beta-hairpin loop. Upon expression of the recombinant gene in E. coli, the MS2 coat protein subunits self-assemble into capsids, each comprising 180 copies of the monomer. This system was used to produce chimeras containing a putatively protective epitope, T1, from the immunodominant liver stage antigen-1 (LSA-1) of the malaria parasite Plasmodium falciparum. The immunogenicity of the native MS2 capsid and the recombinant construct was investigated in BALB/c (H-2(d)) mice. The native protein appeared to elicit both humoral and cellular immune responses, observed as a predominance of type 2 cytokines but with a mixed profile of immunoglobulin isotypes. In contrast, the LSA-1 chimera stimulated a type 1-polarised response, with significant upregulation of interferon-gamma, a finding which corroborates naturally acquired resistance to liver stage malaria. These results validate RNA phage capsid display of immunogenic determinants as a basis for the development of novel peptide vaccines and indicate that further evaluation of MS2 coat protein as a vector for malaria epitopes is merited.
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PMID:Expression and immunogenicity of a liver stage malaria epitope presented as a foreign peptide on the surface of RNA-free MS2 bacteriophage capsids. 1050 49

Recent studies have implicated non-specific mediators associated with CD4+ T cells of the T helper 1 subset in resistance to experimental malarias. As part of continuing studies into the multifactorial role of nitric oxide and other contributors to the innate immune response in control of acute-phase malaria infection, the production of the acute-phase proteins, caeruloplasmin and serum amyloid P, following infection of naive mice with blood stages of the rodent malaria parasite Plasmodium chabaudi was investigated. Levels of both acute-phase proteins in the serum of infected mice were significantly elevated on days 7-12 post-infection compared both to other times of infection, and to background levels detected in uninfected control mice. These times corresponded to the ascending and peak primary parasitaemia, when production of interferon-gamma, tumour necrosis factor-alpha and nitric oxide is known to be raised. Although it is not apparent whether the production of caeruloplasmin and serum amyloid P has a causal effect in reducing parasitaemia or is simply a by-product of innate immunity, the detection of increased levels of circulating acute-phase proteins may act as a useful surrogate marker of high level parasitaemia, and therefore, of blood-borne malaria pathology.
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PMID:Increased production of acute-phase proteins corresponds to the peak parasitaemia of primary malaria infection. 1072 93

The role of neutrophils in experimental cerebral malaria (ECM) is not well understood. In this study we used a MoAb, RB6-8C5, to deplete the peripheral neutrophils of ECM-susceptible CBA/NSlc mice 24 h before Plasmodium berghei ANKA (PbA) infection. We found that early neutrophil depletion prevented the development of ECM and dramatically decreased the sequestration of monocytes and microhaemorrhage in the brain. The depletion of neutrophils also down-regulated tumour necrosis factor-alpha, interferon-gamma and IL-2 mRNAs and abrogated IL-12p40 mRNA expression in the brain as examined by competitive reverse transcriptase-polymerase chain reaction. Although depletion of neutrophils decreased the expression of Th1 cytokines in both spleen and brain, our results did not show the shift of a Th1 to a Th2 immune response since there was no obvious augmentation of expression of Th2 cytokine mRNAs (IL-4 and IL-10). We conclude that neutrophils play a role in the pathogenesis of ECM via enhancement of the expression of Th1 cytokines in the brain.
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PMID:Neutrophils play a critical role in the pathogenesis of experimental cerebral malaria. 1075 73

Exposure to irradiated Plasmodium sporozoites (gamma-spz) results in protection against malaria. Like infectious spz, gamma-spz colonize hepatocytes to undergo maturation. Disruption of liver stage development prevents the generation of protection, which appears, therefore, to depend on liver stage antigens. Although some mechanisms of protection have been identified, they do not include a role for intrahepatic mononuclear cells (IHMC). We demonstrated that P. berghei gamma-spz-immune murine IHMC adoptively transfer protection to naive recipients. Characterization of intrahepatic CD4+ T cells revealed an immediate, albeit transient, response to gamma-spz, while the response of CD8+ T cells is delayed until acquisition of protection. It is presumed that activated CD8+ T cells home to the liver to die; gamma-spz-induced CD8+CD45RB(lo)CD44(hi) T cells, however, persist in the liver, but not the spleen, during protracted protection. The association between CD8+CD45RB(lo)CD44(hi) T cells and protection has been verified using MHC class I and CD1 knockout mice and mice with disrupted liver stage parasites. Based on kinetic studies, we propose that interferon-gamma, presumably released by intrahepatic effector CD8+ T cells, mediates protection; the persistence of CD8+ T cells is, in turn, linked to Plasmodium antigen depots and cytokines released by CD4+ T cells and/or NK T cells.
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PMID:The role of intrahepatic lymphocytes in mediating protective immunity induced by attenuated Plasmodium berghei sporozoites. 1080 12

objective To investigate if severe malarial anaemia is associated with a specific immune response pattern, we determined serum levels of neopterin (a marker of activation of macrophages by interferon-gamma) and of the anti-inflammatory cytokines, interleukins 4 and 10. methods Zambian children < 6 years of age presenting to a rural hospital with cerebral malaria were studied. Twenty-one children with admission haemoglobin concentrations </= 5 g/dl were classified as having severe anaemia and 40 with haemoglobin concentrations >/= 7 g/dl served as a control group. results Logistic regression modelling indicated that a 10-fold rise in serum neopterin concentrations was associated with a 50-fold increase in the estimated odds of having severe anaemia (P = 0.015), while a 10-fold rise in serum interleukin 4 concentrations was associated with a 10-fold decrease in the estimated odds of having severe anaemia (P = 0.023). Increasing serum interleukin 10 concentrations, measured in less than half of the subjects, were associated with a nonsignificant reduction in the odds of having severe anaemia (P = 0.095). conclusion Development of severe malarial anaemia may be directly associated with serum neopterin concentrations and inversely correlated with serum interleukin 4 levels.
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PMID:Markers of inflammation in children with severe malarial anaemia 1081 20

Our previous reports indicated that C57BL/6 mice infected with a lethal variant of Plasmodium yoelii 17X (P. yoelii 17XL) produced high levels of interleukin 10 (IL-10) and interferon-gamma (IFN-gamma) while mice infected with the nonlethal variant of the parasite did not produce detectable levels of IL-10. In the present study, the involvement of IL-10 and IFN-gamma in exacerbation or regulation of blood-stage malaria was investigated by using the lethal variant of P. yoelii 17XL and monoclonal antibodies (mAb) against the cytokines. C57BL/6 mice were injected intraperitoneally with a neutralizing anti-IL-10 mAb or anti-IFN-gamma mAb after inoculation with P. yoelii 17XL. Treatment of mice with anti-IL-10 mAb resulted in substantial prolongation of survival and 60% of treated mice survived while 100% of control mice died by day 11. On the contrary, treatment of mice with anti-IFN-gamma mAb exacerbated infection and all mice died after an earlier period than those treated with normal rat Ig. No differences in parasitemias were found between treated and untreated mice. To elucidate the involvement of nitric oxide in the host protection or exacerbation, mice were treated with aminoguanidine, an inhibitor of nitric oxide synthetase, after inoculation of P. yoelii 17XL. Neither mortality nor parasitemia was influenced by the treatment. These results indicate that an IFN-gamma response is associated with protective immunity in mice infected with P. yoelii 17XL, while an IL-10 response is associated with disease exacerbation during the infection.
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PMID:Effects of in vivo administration of anti-IL-10 or anti-IFN-gamma monoclonal antibody on the host defense mechanism against Plasmodium yoelii yoelii infection. 1090 83

Mice deficient of functional interferon regulatory factor-1 (IRF-1-/-) by targeted gene disruption infected with a lethal murine malaria strain, Plasmodium berghei ANKA survived longer than its wild-type littermates despite the inability to induce appreciable amounts of interferon-gamma (IFN-gamma) and nitric oxide. In addition, infected IRF-1-/- mice displayed less organ injury with reduced necrosis and inflammation. Both wild-type and IRF-1-/- mice treated with exogenous interleukin-12 (IL-12) suffered extensive organ damage with corresponding up regulation of IFN-gamma, suggesting the pathogenic potential of IL-12 and IFN-gamma. IL-10 is a cytokine produced by CD4+ T lymphocytes belonging to the Th2 subset. Expression of IL-10 in the wild-type mice correlated with the severity of the infection, with higher mRNA expression towards the later stage of infection. In contrast to the wild-type mice, IL-10 levels in the IRF-1-/- mice were induced early in the infection and decreased gradually as the infection progressed. Both untreated and IL-12 treated wild-type mice appeared to follow a Th1-like immune response early in the infection and a Th2-like immune response later in the infection. However, the IRF-1-/- mice were able to launch an altered immune response with a Th2-like immune response early in the infection. These findings suggest that IL-10 expression in the IRF-1-/- mice during the early stage of P. berghei ANKA infection could play an important role in suppressing pathogenic effects of a cell mediated immune response and promoting protective immunity against the parasite.
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PMID:Differential interleukin-10 expression in interferon regulatory factor-1 deficient mice during Plasmodium berghei blood-stage infection. 1097 49


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