Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to evaluate nitric oxide (NO) activity in patients with uncomplicated malaria. Lipopolysaccharide and gamma interferon (IFN-gamma) are potent inducers of NO by inducing production of NO synthase. NO activity was determined by measuring serum levels of nitrite/nitrate (metabolic end products of NO), and IFN-gamma in patients with uncomplicated malaria, mostly caused by Plasmodium falciparum. Neither serum levels of nitrite/nitrate nor of IFN-gamma were significantly increased in patients with uncomplicated malaria, especially in patients with P. falciparum infection, and in those with high parasitaemia. These results show that NO cannot play a role in uncomplicated malaria, and it is still debatable if NO production in this infection has beneficial or detrimental effects.
 ...
PMID:Levels of circulating nitrate/nitrite and gamma interferon not increased in uncomplicated malaria. 979 89

We have sought to characterize Plasmodium chabaudi chabaudi infection in mice for use as a model for malaria pathology. Different mouse strains vary in their susceptibility to the erythrocytic stages of this parasite and this is manifested not only in the outcome of infection (survival versus death) but also by differences in the numbers of circulating parasites at the peak of infection. We have shown that regardless of final outcome, both resistant and susceptible mice exhibit other parameters of disease such as loss in body weight and anemia. By contrast, other parameters such as hypothermia appear more severe in susceptible mice. The severe symptoms coincide with high levels of inflammatory cytokines in the circulation of susceptible mice, not seen in H-2-matched resistant mice. However, levels of mRNA for the same cytokines, measured in the spleen of the same mice was not significantly different between the two strains. Neutralization of IFN-gamma in vivo led to an increase in parasitemia, in both susceptible and resistant mice, but did not affect the final outcome of disease. Indeed, symptoms were exacerbated in the absence of IFN-gamma, presumably because of larger numbers of circulating parasites. These data suggest that IFN-gamma does not directly contribute to the lethal outcome of infection in susceptible strains of mice.
 ...
PMID:Plasmodium chabaudi chabaudi (AS): inflammatory cytokines and pathology in an erythrocytic-stage infection in mice. 980 66

Plasmodium chabaudi infection of mice provides an excellent model for examining acquired immunity to the blood-borne stage of malaria infection. CD4+ T-cell receptor (TCR) alphabeta-bearing T lymphocytes play a critical role in mediating protection, ascribed to both T helper (Th) 1 and Th2 subsets. One factor that may influence the Th1/Th2 cell balance is infective dose. In this study, we found that the size of the infective dose of P. chabaudi, and thus the level of antigen presented to the immune system, correlated with the balance of responder CD4+ T-cell phenotypes. Increasing the infective dose in a resistant mouse strain enhanced the Th1 cytokine (interferon-gamma; IFN-gamma) response and reduced the Th2 cytokine (interleukin-4; IL-4) response. In contrast, increasing the infective dose in a susceptible mouse strain led to a prominent and accelerated up-regulation of IL-4 production. These data show that the dose of antigen can significantly affect the balance between Th1- and Th2-mediated immune functions during infection of the mammalian host with blood-stage malaria parasites. This demonstration that parasite numbers may modulate CD4+ T-cell regulation has novel implications for the successful implementation of antimalarial vaccination and chemotherapeutic strategies.
 ...
PMID:Infective dose modulates the balance between Th1- and Th2-regulated immune responses during blood-stage malaria infection. 982 63

The frequency of cytokine-producing T cells was assessed in patients of different age groups (29 infants, aged 1-5 years; 30 schoolchildren, aged 6-14 years; 26 adults, aged >15 years) with acute Plasmodium falciparum malaria from Gabon. By using flow cytometry for the intracellular detection of cytokines, a striking expansion was seen, in adults compared with children, of CD4+ and CD8+ T cells with the following profiles of type 1 cytokine production: interleukin (IL)-2-/interferon (IFN)-gamma+, IL-2+/IFN-gamma+, and IL-2+/IFN-gamma-. Patients with hyperparasitemia had a significantly lower frequency of IL-2-/IFN-gamma+ CD4+ cells. Type 2 cytokine expression (IL-4+/IFN-gamma-, IL-13+/IFN-gamma-) and type 0 cytokine expression (IL-4+/IFN-gamma+, IL-13+/IFN-gamma+) were also increased in adults within the CD4+ subset. Frequencies of IL-5+/IL-4+, IL-10+/IFN-gamma-, and IL-10+/IFN-gamma+ cells were similar in all groups. The increased frequency of both type 1 and type 2 cytokine-producing T cells in adults is likely to be of significance in the protection against P. falciparum malaria.
 ...
PMID:Frequency of cytokine-producing T cells in patients of different age groups with Plasmodium falciparum malaria. 984 41

The balance between Th1 cytokines (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma) and Th2 cytokines (interleukin [IL]-10, -4) may be critical in the development of severe falciparum malaria. Therefore, plasma concentrations of these cytokines were determined in children with various manifestations of malaria. Plasma levels of IFN-gamma and IL-4 were undetectable in most children. However, TNF-alpha and IL-10 were significantly elevated in children with high-density parasitemia and malaria anemia compared with children in control groups. In children with mild malaria, IL-10, but not TNF-alpha, was significantly elevated. While the highest concentrations of TNF-alpha were found in children with malaria anemia, IL-10 levels were highest in children with high-density uncomplicated malaria. The mean ratio of IL-10 to TNF-alpha was significantly higher in children with mild and high-density parasitemia (4.64, P<.005) than in children with malaria anemia (1.77). Thus, higher levels of IL-10 over TNF-alpha may prevent development of malaria anemia by controlling the excessive inflammatory activities of TNF-alpha.
 ...
PMID:A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. 1051 52

The desirability of inducing cytotoxic T cell responses to defined epitopes in humans has led to the development of a variety of recombinant delivery systems. Recombinant protein particles derived from a yeast retrotransposon (Ty) and the modified Ankara vaccinia (MVA) virus can deliver large epitope strings or even whole proteins. Both have previously been administered safely in humans. Immunization with recombinant Ty and MVA containing a single Plasmodium berghei class I-binding epitope provided 95% sterile protection against malaria in mice. The sequence of immunization, Ty followed by MVA, was critical to elicit high levels of IFN-gamma-producing cells and protection. The reciprocal sequence (MVA/TY) or homologous boosting was not protective. Both constructs (Ty and MVA) contain the H-2Kd-restricted pb9 CTL epitope from the circumsporozoite protein of P. berghei among a string of 8-15 human P. falciparum-derived CTL epitopes restricted through 7 common HLA alleles as well as widely recognized CD4 T cell epitopes. Thus, the novel recombinant Ty/MVA prime/boost combination with these constructs provides a safe alternative for evaluation for human vaccination against P. falciparum malaria.
 ...
PMID:Protection from Plasmodium berghei infection by priming and boosting T cells to a single class I-restricted epitope with recombinant carriers suitable for human use. 986 71

Using strict inclusion criteria, we conducted a hospital-based, case-control study in which 100 Gabonese children with severe Plasmodium falciparum malaria were matched for age, gender and provenance with 100 children presenting with mild malaria. Parasite antigen-specific cellular and humoral immunological responses were measured and compared with post-treatment parasite clearance times in each group. Significantly faster parasite clearance times were associated with in vitro production of IL-10 by acute-phase peripheral blood mononuclear cells (PBMC) in response to both liver and asexual stage parasite antigens, but not with proliferative, IFN-gamma, or TNF responses to the same antigens. In addition, in those children with mild malaria, higher levels of acute-phase antibody responses to liver stage antigen-1 (LSA-1) were associated with faster parasite clearance times, and were correlated with the presence of IL-10 responses to the same antigen. No such associations were found for IL-10 or antibody responses to a range of asexual blood stage antigens. Those with severe malaria had significantly lower levels of anti-LSA-1 antibodies compared to their counterparts with mild malaria. In conclusion, the results of this study suggest that parasite antigen-specific IL-10-mediated antibody responses may play a role in the control of asexual stage parasite multiplication in P. falciparum malaria.
 ...
PMID:Parasite antigen-specific interleukin-10 and antibody reponses predict accelerated parasite clearance in Plasmodium falciparum malaria. 988 8

The immunoregulatory cytokine interleukin 12 (IL-12) induces host resistance against experimental malaria. In this study, we tested the feasibility of using IL-12 in combination with chloroquine (CQ) to rescue susceptible A/J mice from lethal blood-stage Plasmodium chabaudi AS infection. Combined treatment with low doses of CQ and IL-12 resulted in a >15-fold reduction in the parasite load and 100% survival of A/J mice with established infections. Compared to control mice, which succumbed to severe anemia, CQ-plus-IL-12-treated mice had significantly higher early- and late-stage erythroid-cell progenitors in the bone marrow and spleen, resulting in significantly higher hematocrits, erythrocyte counts, and percentages of reticulocytes. Production of parasite-specific gamma interferon (IFN-gamma) by splenocytes from these mice was upregulated >20-fold relative to controls in parallel with enhanced IFN-gamma mRNA expression. Further, enhanced responsiveness to IL-12 and increased downstream IFN-gamma production in CQ-plus-IL-12-treated mice was evident from increased mRNA expression for the beta1 and beta2 subunits of IL-12 receptor in the splenocytes. Moreover, this combined therapy induced higher levels of anti-malaria antibodies than did CQ alone as well as sterile immunity against reinfection. Because IL-12 can be used at low doses and is effective even in established infections, it may be feasible to use this immunochemotherapeutic approach in human malaria.
 ...
PMID:Therapy with a combination of low doses of interleukin 12 and chloroquine completely cures blood-stage malaria, prevents severe anemia, and induces immunity to reinfection. 991 53

As previously reported, blood-stage Plasmodium chabaudi AS malaria is lethal by days 10-12 postinfection in susceptible A/J mice that mount an early, predominantly Th2 response. In contrast, resistant C57BL/6 (B6) mice clear the infection by 4 wk with an early Th1 response. In this study, we analyzed in vivo production of IL-12, a potent Th1-inducing cytokine, during the first 5 days after P. chabaudi AS infection in these mice. By day 2, serum IL-12 p70 levels were significantly increased in B6 mice over basal levels and were also significantly higher compared with A/J mice that showed no significant changes in serum p70 levels after infection. Splenectomy of resistant B6 mice before infection demonstrated that the spleen is the major source of systemic IL-12 in these hosts. Splenic mRNA levels of both p40 and p35 were significantly higher in A/J mice; however, the ratios of p40/p35 mRNA levels were similarly up-regulated in both strains. Furthermore, B6 but not A/J mice showed significant up-regulation of splenic IL-12R beta2 mRNA over basal levels by days 3 and 4, coincident with sustained up-regulation of splenic IFN-gamma mRNA levels on days 3-5. However, IL-12R beta1 mRNA levels in the spleen were similarly up-regulated in both mouse strains by day 3. Taken together, these data suggest that high systemic IL-12 production, accompanied by an early and sustained up-regulation of both IL-12R beta1 and beta2 mRNA levels in the spleen, as occurs in resistant B6 mice, appears to preferentially induce protective Th1 responses against blood-stage malaria.
 ...
PMID:In vivo IL-12 production and IL-12 receptors beta1 and beta2 mRNA expression in the spleen are differentially up-regulated in resistant B6 and susceptible A/J mice during early blood-stage Plasmodium chabaudi AS malaria. 997 16

The contribution of T cell-mediated responses was studied with regard to resistance to reinfection in groups of Gabonese children participating in a prospective study of severe and mild malaria due to infection with Plasmodium falciparum. In those admitted with mild malaria, but not in those with severe malaria, production of IFN-gamma by peripheral blood mononuclear cells (PBMC) in response to either liver-stage or merozoite antigen peptides was associated with significantly delayed first reinfections and with significantly lower rates of reinfection. Proliferative or tumor necrosis factor responses to the same peptides showed no such associations. Production of interferon-gamma by PBMC in response to sporozoite and merozoite antigen peptides was observed in a higher proportion of those presenting with mild malaria. Differences in the Th1/Th2 cytokine balance may be linked to the ability to control parasite multiplication in these young children, helping to explain the marked differences observed in both susceptibility to infection as well as in clinical presentation.
 ...
PMID:Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children. 1006 95


<< Previous 1 2 3 4 5 6 7 8 9 10