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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long chain polyunsaturated fatty acids derived from essential fatty acids have been shown to be toxic to Plasmodium falciparum both in vitro and in vivo. Here, we present evidence to suggest that in patients with Plasmodium falciparum malaria the levels of lipid peroxides (a marker of free radical generation) nitric oxide (a potent free radical with immunomodulatory actions), and concentrations of linoleic acid (LA) and alpha-linolenic acid (ALA) are low, whereas those of eicosapentaenoic acid (EPA) are high. The ability of the fatty acids to kill P. falciparum is dependent on their capacity to stimulate free radical generation in neutrophils and macrophages. EPA is more potent than LA in killing the parasite. In view of this, the results of the present study suggest that in patients with P. falciparum malaria the decreased levels of lipid peroxides and nitric oxide may contribute to the persistence of the infection, whereas elevated levels of EPA may be a feeble attempt to overcome this defect.
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PMID:Lipid peroxides, nitric oxide and essential fatty acids in patients with Plasmodium falciparum malaria. 1057 50

Infection-associated immunoincompetence during malaria might result from macrophage dysfunction. In the present study, we investigated the role of macrophages as target for immunosuppression during infection, using the murine Plasmodium c. chabaudi model. Special attention has been paid to the analysis of processing/presentation of protein antigens and presentation of peptides, using cocultures of peritoneal exudate cells (PECs) from infected mice and antigen-specific T-cell hybridomas. The results obtained indicate a defective processing of protein antigens that becomes maximal at acute parasitemias. In addition, macrophages from acutely infected mice suppress the interleukin-2 production by the antigen-activated T-cell hybridomas. This effect was independent of prostaglandin and nitric oxide production by the macrophage. The possible role of parasite components in the impaired accessory cell function of PECs was investigated and hemozoin, the end-product of the hemoglobin catabolism by intraerythrocytic malaria parasites, was found to induce similar infection-associated deficiencies in vitro. Moreover, hemozoin, was shown to mimic the immunosuppressive effects induced in PECs during in-vivo infections with P. chabaudi. In conclusion, we propose that hemozoin is a key factor in the malaria-associated immunosuppression, affecting both the antigen processing and immunomodulatory functions of macrophages.
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PMID:Hemozoin is a key factor in the induction of malaria-associated immunosuppression. 1058 55

To date, there have been conflicting reports concerning the clinical significance of nitric oxide (NO) in Plasmodium falciparum malaria. Some authors have proposed that NO contributes to the development of severe and complicated malaria, while others have argued that NO has a protective role. To investigate these apparently contradictory reports, reverse transcription-coupled PCR was used to study inducible NO synthase (iNOS) in whole-blood RNA samples from patients with severe and complicated malaria or uncomplicated malaria and from healthy donors. This work produced three principal findings. First, samples of patients with severe and complicated malaria were variably positive, with weak to moderate intensity. Markedly higher iNOS RNA levels were observed in samples of patients with uncomplicated malaria than in patients with severe and complicated malaria. Samples of healthy donors were uniformly negative. Second, since we initially demonstrated iNOS expression in whole-blood RNA samples, we extended our investigations to individual blood cells such as monocytes, lymphocytes, neutrophils, and platelets to identify the cellular source of iNOS. We found that iNOS was expressed predominantly in monocytes. Third, retrospective statistical analysis of monocyte counts clearly demonstrated that patients with uncomplicated malaria had higher monocyte counts at the time of presentation than patients with severe and complicated malaria. Taken together, our findings give room to the interpretation that NO may have a beneficial rather than a deleterious role in falciparum malaria.
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PMID:High levels of inducible nitric oxide synthase mRNA are associated with increased monocyte counts in blood and have a beneficial role in Plasmodium falciparum malaria. 1060 15

The pathology caused by acute Babesia bovis infection is similar to that seen in severe human malaria caused by Plasmodium falciparum infection, which is related to dysregulated production of inflammatory cytokines and nitric oxide (NO). We have observed induction of NO, inducible nitric oxide synthase (iNOS) and inflammatory cytokines in macrophages by B. bovis. Furthermore, proliferation of lymphocytes from individuals never exposed to certain protozoal pathogens can be induced by crude protozoal parasite extracts. We have repeatedly observed stimulation of naive PBMC from cattle to antigenic extracts of Babesia bovis. Based on recent studies demonstrating the mitogenicity of bacterial and other non-vertebrate DNAs for murine B cells and macrophages, the mitogenic properties of B. bovis DNA were examined. B. bovis and E. coli DNAs induced proliferation of PBMC and purified B cells from non-exposed cattle. Stimulatory activity was reduced by DNase treatment and methylation with CpG methylase, indicating the presence of stimulatory non-methylated CpG motifs in the B. bovis genome. B. bovis and E. coli DNAs enhanced IgG secretion by cultured B cells, stimulating IgG1 and more strongly, IgG2. Several hexameric CpG immunostimulatory sequences (ISS) active for murine B cells were identified in an 11 kb fragment of B. bovis DNA. An oligodeoxyribonucleotide containing one of these (AACGTT), located in the rhoptry associated protein-1 (rap-1) open reading frame, stimulated B cell proliferation. These studies identify a potential mechanism by which protozoal parasites may modulate host immune responses, leading to consequences such as hypergammaglobulinemia and splenomegaly. These results also support the use of ISS as vaccine adjuvants to enhance Type 1 immune responses in cattle.
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PMID:Modulation of host immune responses by protozoal DNA. 1061 97

Protective immune mechanisms to the asexual erythrocytic stages of the malaria parasite Plasmodium chabaudi AS strain include antibody-independent mechanisms. Nitric oxide (NO) is produced during the infection and indirect evidence suggests that it can contribute to the antiparasitic mechanisms. We examined the effect of an NO producer, S-nitroso-acetyl-penicillamine (SNAP), on the growth and survival in vitro of P. chabaudi AS, P. berghei and P. falciparum. Growth of the parasites was monitored by the uptake of tritiated hypoxanthine and, in the case of P. falciparum, by morphological examination in stained blood smears. DL-penicillamine and sodium nitrite, as controls, had no inhibitory activity at the concentrations used. The results showed that at SNAP concentrations of approximately 182 microM and above NO was cytotoxic to P. falciparum but, at lower concentrations, there was a cytostatic effect and some parasites resumed growth and division after NO production had ceased. Rings were less susceptible to NO effects than later stages in the asexual cycle. The antimalarial activity of NO from SNAP also extended to the rodent parasites but, under the experimental conditions used, they were less sensitive than the human species. In the cultures of P. chabaudi, increasing the numbers of noninfected erythrocytes present did not diminish the antimalarial activity of SNAP, suggesting that here at least haemoglobin was not scavenging NO significantly.
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PMID:The effect of nitric oxide on the growth of Plasmodium falciparum, P. chabaudi and P. berghei in vitro. 1065 22

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

While the effect of reactive nitrogen intermediates (RNI) against macrophage-dwelling protozoa, such as Leishmania and Toxoplasma has become established, the possible antiparasitic function of nitric oxide (NO) and RNI against the intracellular blood stages of malaria and babesia has, until recently, been less well accepted. This was, at least in part, due to the long-standing notion that haemoglobin (Hb) universally scavenges NO and thus that erythrocytes act as a permanent sink for this molecule. It is now known that NO can be released as well as scavenged by Hb, and that the less oxygenated the blood the lower the affinity of Hb for NO. As a consequence, NO is preferentially released by venous erythrocytes. Based on the increased sensitivity of Plasmodium falciparum -infected erythrocytes to RNI in venous blood that was recently demonstrated, it is proposed that the noted greater susceptibility of mature intra-erythrocytic forms of malaria, late-stage schizonts, is coincidental with their peripheral blood withdrawal by sequestration to deep-tissue capillaries. This environment is non NO-scavenging in nature and one which would bring schizonts and macrophages into intimate proximity, providing diffusion distances sufficiently short for RNI to be effective. Given its short half-life, this hypothesis explains the potential for NO to be toxic for malaria parasites in vivo, and suggests that sequestration, a mechanism adopted by the parasite to supposedly avoid immune surveillance, may in fact have a partially counteractive effect.
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PMID:The sequestration hypothesis: an explanation for the sensitivity of malaria parasites to nitric oxide-mediated immune effector function in vivo. 1085 56

The role of endogenous gamma interferon (IFN-gamma) in protective immunity against blood-stage Plasmodium chabaudi AS malaria was studied using IFN-gamma gene knockout (GKO) and wild-type (WT) C57BL/6 mice. Following infection with 10(6) parasitized erythrocytes, GKO mice developed significantly higher parasitemia during acute infection than WT mice and had severe mortality. In infected GKO mice, production of interleukin 12 (IL-12) p70 and tumor necrosis factor alpha in vivo and IL-12 p70 in vitro by splenic macrophages was significantly reduced compared to that in WT mice and the enhanced nitric oxide (NO) production observed in infected WT mice was completely absent. WT and GKO mice had comparable numbers of total nucleated spleen cells and B220(+) and Mac-1(+) spleen cells both before and after infection. Infected WT mice, however, had significantly more F4/80(+), NK1.1(+), and F4/80(+)Ia(+) spleen cells than infected GKO mice; male WT had more CD3(+) cells than male GKO mice. In comparison with those from WT mice, splenocytes from infected GKO mice had significantly higher proliferation in vitro in response to parasite antigen or concanavalin A stimulation and produced significantly higher levels of IL-10 in response to parasite antigen. Infected WT mice produced more parasite-specific immunoglobulin M (IgM), IgG2a, and IgG3 and less IgG1 than GKO mice. Significant gender differences in both GKO and WT mice in peak parasitemia levels, mortality, phenotypes of spleen cells, and proliferation of and cytokine production by splenocytes in vitro were apparent during infection. These results thus provide unequivocal evidence for the central role of endogenous IFN-gamma in the development of protective immunity against blood-stage P. chabaudi AS.
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PMID:Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection. 1089 36

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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