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)

Macrophage activation was examined in resistant C57BL/6 and susceptible A/J mice during the course of blood-stage infection with Plasmodium chabaudi AS. Three parameters of macrophage activation (lipopolysaccharide [LPS]- and malaria antigen-induced tumor necrosis factor [TNF] production in vitro, phorbol myristate acetate [PMA]-induced production of oxygen metabolites in vitro, and Ia antigen expression) were assessed during infection in populations of peritoneal and splenic macrophages recovered from infected mice of the two strains. The peak level of LPS-induced TNF production in vitro by splenic macrophages from both infected C57BL/6 and infected A/J mice occurred on day 7, which was 3 days before the peak of parasitemia. Although the kinetics of TNF production in vitro in response to either LPS, soluble malaria antigen, or intact parasitized erythrocytes varied in some of the other macrophage populations during infection, there was no significant difference in the peak level of production. Peritoneal and splenic macrophages from infected C57BL/6 mice exhibited significantly increased PMA-induced production of H2O2 in vitro on day 7. Peritoneal macrophages from infected A/J mice also exhibited significant PMA-induced H2O2 production on day 7, while production by splenic macrophages from these hosts was not increased in comparison with production by cells from normal animals. Only peritoneal macrophages from infected C57BL/6 mice produced significantly increased levels of O2-, and this occurred on day 7 postinfection. Ia antigen expression by both peritoneal and splenic macrophages from resistant C57BL/6 and susceptible A/J mice was significantly increased during P. chabaudi AS infection. However, the percentage of Ia+ peritoneal macrophages on days 8 and 10 postinfection and Ia+ splenic macrophages on day 3 postinfection was significantly higher in C57BL/6 than in A/J mice. Thus, these results demonstrate that macrophages from P. chabaudi AS-infected A/J mice exhibit defects in oxygen metabolism and Ia antigen expression which may contribute to the susceptibility of these hosts to this intraerythrocytic parasite. The cause-and-effect relationship between these defects and the susceptibility of A/J mice to P. chabaudi AS is unknown.
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PMID:Macrophage activation during Plasmodium chabaudi AS infection in resistant C57BL/6 and susceptible A/J mice. 131 5

Because subunit vaccines may create artificial epitopes, the goal of this study was to concentrate the immune response toward protective epitopes contained in a peptide, [(NAGG)5]Y. This peptide consisted of five repeat sequences of the immunodominant epitope of the circumsporozoite protein of the simian malaria parasite Plasmodium cynomolgi and a terminal tyrosine. It was conjugated to bovine serum albumin and mixed with various adjuvant formulations, including block copolymers L121, L141, L180.5 and a lipopolysaccharide (LPS). Outbred mice were vaccinated with seven vaccine formulations. Postvaccination sera from each group of mice were then pooled, and antibody responses against peptide [(NAGG)5]Y or (NAGG)5 were tested in an enzyme-linked immunosorbent assay and against sporozoites of P. cynomolgi in an indirect fluorescent antibody assay. Although all groups elicited a high antibody response to the peptide [(NAGG)5Y], the presence of the tyrosine induced a different antibody response to the peptide (NAGG)5, and formulations containing LPS alone did not induce an antibody response to either (NAGG)5 or P. cynomolgi sporozoites. The formulation including both LPS and the copolymer L121 was the only one to inhibit the development of P. cynomolgi sporozoites in rhesus monkey hepatocytes by 50%. These results suggest that vaccine formulations influence B-cell epitope selection.
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PMID:Effect of adjuvant formulations on the selection of B-cell epitopes expressed by a malaria peptide vaccine. 137 51

In patients with malaria, the clinical manifestations of the disease are associated with the presence of high concentrations of tumour necrosis factor (TNF) in the serum. Blood-stage parasites of human and rodent malarial parasites release serologically related exoantigens which induce the production of TNF in vitro and in vivo and which can kill mice made hypersensitive to TNF by pretreatment with D-galactosamine. They also elicit the production of T-independent antibody, which blocks these effects. The capacity of the exoantigens to stimulate macrophages to secrete TNF does not require the presence of protein or carbohydrate, but is associated with a lipid whose activity can be abolished by treatment with phospholipase C. Treatments of the exoantigens which destroyed their activity in vitro also abrogated their immunogenicity and their toxicity for mice. No TNF-inducing activity could be detected in preparations of parasitized erythrocytes that was not associated with phospholipid, and the TNF-inducing properties of the malarial phospholipids are quite distinct from those of bacterial lipopolysaccharide. We conclude that release of potentially toxic phospholipids by parasites may be responsible for some of the pathology of malaria.
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PMID:Tumour necrosis factor induction by malaria exoantigens depends upon phospholipid. 153 89

We have previously shown that malaria parasites liberate exoantigens which, through a phospholipid component, stimulate mouse macrophages to secrete tumor necrosis factor (TNF), which are toxic to D-galactosamine-sensitized mice, and which therefore might be involved in pathology. Plasmodium yoelii exoantigens detoxified by dephosphorylation or digestion with lipases do not induce TNF production. However, these partial structures inhibited its production in response to the exoantigens, although not to bacterial lipopolysaccharide (LPS). When pure phospholipids were tested in a macrophage assay, none stimulated the production of TNF, but phosphatidylinositol (PI) inhibited TNF induction by P. yoelii exoantigens. Moreover, inositol monophosphate (IMP) was the only one of a number of monophosphate saccharides tested which was inhibitory; inositol was not. Macrophages pretreated with PI, IMP, or detoxified exoantigens and then incubated with parasite exoantigens also yielded much less TNF. PI, IMP, and lipase-digested exoantigens of P. yoelii similarly inhibited the TNF-inducing activity of exoantigens of the human parasites Plasmodium falciparum and Plasmodium vivax. Neither PI nor IMP diminished TNF production in response to LPS, in contrast to a platelet-activating factor antagonist [1-O-hexadecyl-2-acetyl- sn-glycero-3-phospho(N,N,N-trimethyl hexanolamine)] which inhibited both exoantigen- and LPS-induced production of TNF. We conclude that at least two different parts of the molecule are involved in the induction of TNF secretion by parasite exoantigens: one requires the presence of a phosphate bound to inositol, and, since dephosphorylated exoantigens were also inhibitory, one does not. It would seem that both affect interactions between parasite-derived exoantigens and the macrophage receptors.
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PMID:Detoxified exoantigens and phosphatidylinositol derivatives inhibit tumor necrosis factor induction by malarial exoantigens. 156 80

Dietary fish-oil supplementation interferes with eicosanoid production and appears to decrease production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). The effect of fish oil was investigated in an intramuscular Klebsiella pneumoniae infection in Swiss mice and in cerebral malaria induced by Plasmodium berghei in C57B1/6 mice. After a low inoculum of K. pneumoniae, 90% of fish oil-fed mice survived; survival in control mice fed equal amounts of corn or palm oil or normal chow was 30%, 40%, and 0, respectively. Cerebral malaria occurred in only 23% of fish oil-fed mice; in the controls, cerebral malaria developed in 61%, 81%, and 78%, respectively. Contrary to what was expected, lipopolysaccharide-induced ex vivo production of IL-1 alpha and TNF alpha by peritoneal cells was significantly enhanced in fish oil-fed mice compared with controls. Indomethacin treatment did not alter the outcome in these two infections, thus arguing against reduced prostaglandin synthesis as an explanation for the increase in resistance to infection.
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PMID:Dietary fish-oil supplementation in experimental gram-negative infection and in cerebral malaria in mice. 156 40

Some soluble exoantigens of Plasmodium have lipopolysaccharide (LPS)-like properties and are believed to contribute to the pathogenesis of acute malaria. We have studied cellular and humoral immune responses to several purified exoantigens of Plasmodium falciparum in a cohort of children and compared these responses with their subsequent susceptibility to malaria infection and clinical disease. We found no evidence that either lymphoproliferative or interferon-gamma (IFN-gamma) responses to these antigens were associated with protective immunity. On the contrary, children whose cells produced IFN-gamma after in vitro activation with one of the soluble antigens (Ag7) were more likely to experience clinical manifestations of malaria infection (fever and malaise) than were children whose cells did not produce IFN-gamma. It is possible that exoantigen-induced IFN-gamma may exacerbate the LPS-like effects of these antigens. However, serum antibodies to another antigen (Ag2) were more prevalent in children with asymptomatic infections or low parasitemia than in children with fever and higher parasitemia (confirmed clinical malaria), suggesting that these antibodies may contribute to the development of protective immunity.
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PMID:Immune response to soluble exoantigens of Plasmodium falciparum may contribute to both pathogenesis and protection in clinical malaria: evidence from a longitudinal, prospective study of semi-immune African children. 190 73

The role of gamma interferon (IFN-gamma), a pluripotent lymphokine capable of activating macrophages, in acquired immunity to blood-stage malaria was investigated. C57BL-derived, lipopolysaccharide-resistant C57BL/10ScN mice, which were found to be resistant to intraperitoneal (i.p.) infection with 10(6) Plasmodium chabaudi AS parasitized erythrocytes, were treated with monoclonal anti-IFN-gamma antibody (MAb). Two MAbs were used: R4-6A2, a rat anti-mouse, neutralizing immunoglobulin G1, which was prepared against natural murine IFN-gamma, and DB-1, a murine anti-rat immunoglobulin G1 prepared against recombinant rat IFN-gamma, which can neutralize the murine molecule as well as the rat molecule. C57BL/10ScNH mice were injected i.p. with 200 micrograms of R4-6A2 1 day before infection and every 3 days through day 21. Control mice were treated with normal rat serum. In separate experiments, DB-1 (1.0 mg per week for 4 weeks) was administered i.p. to C57BL/10ScNH mice beginning on the day of infection; control mice were untreated. Control and MAb-treated mice were infected i.p. with 10(6) P. chabaudi AS parasitized erythrocytes, and the course and outcome of infection were determined. Control mice exhibited a course of infection that was characterized by a peak parasitemia between 30 and 40% parasitized erythrocytes and elimination of the parasite by 4 weeks. MAb-treated mice exhibited a significantly greater parasitemia 1 to 2 days before the peak parasitemia as well as a significantly greater peak parasitemia but also completely cleared the infection by 4 weeks. Thus, these results suggest that treatment with anti-IFN-gamma MAb impairs but does not completely abrogate host resistance to P. chabaudi AS. We also examined the kinetics of IFN-gamma production by spleen cells cultured in vitro with malaria antigen or concanavalin A. Spleen cells were recovered from individual C57BL/6 mice at various times after i.p. infection with 10(6) P. chabaudi AS parasitized erythrocytes. The amount of IFN-gamma produced was quantitated by enzyme-linked immunosorbent assay. In each case, the peak of IFN-gamma production occurred just before the peak parasitemia, followed by a decrease to little or no IFN-gamma production through 42 days postinfection. There was thus a parallel between the kinetics of production of IFN-gamma in vitro by spleen cells from infected animals and the requirement in vivo for the endogenous molecule just before and at the time of peak parasitemia. In conclusion, these results suggest that IFN-gamma-dependent and -independent mechanisms contribute to host resistance to P. chabaudi AS.
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PMID:Role of endogenous gamma interferon in host response to infection with blood-stage Plasmodium chabaudi AS. 211 42

Heat-stable antigens of rodent malarial parasites induce the release of tumour necrosis factor (TNF) from mouse macrophages, in vitro and in vivo. We report here that analogous antigens of Plasmodium falciparum trigger the release of TNF from human monocytes in vitro, in conditions that exclude the effects of any contaminating endotoxin. These antigens also induced TNF release from a murine monocytic cell line and from the peritoneal macrophages of several strains of mice, including the LPS-hyporesponsive C3H/HeJ mice. Similarly, boiled soluble antigens from the rodent parasites P. yoelii and P. berghei also stimulated human monocytes. Antisera made by immunizing mice with boiled antigens of P. falciparum or P. yoelii inhibited the stimulation of TNF secretion by P. falciparum antigens. They did not block the induction of TNF by bacterial lipopolysaccharide. Thus mouse macrophages provide a convenient system for investigating the nature, cross-reactions and antigenic variation of human malarial soluble antigens. Since these are known to occur in the circulation of patients with malaria, they may be responsible for excess production of TNF, a mediator that is thought to play a central role in the pathogenesis of the disease.
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PMID:Human and murine macrophages produce TNF in response to soluble antigens of Plasmodium falciparum. 217 28

Monoclonal IgM rheumatoid factor-like anti-globulins were produced by in vitro stimulation of naive BALB/c spleen cells with lipopolysaccharide, and by hyperimmunization of mice with merozoites of Plasmodium falciparum, followed by fusion of the spleen cells to mouse myelomas. In vitro, these anti-globulins augmented the inhibitory effects of P. falciparum-specific polyclonal mouse sera and monoclonal IgG1 and IgG2b antibodies by binding to Fc fragments of IgG molecules attached to blood-stage parasites. In some instances, the presence of anti-globulins correlated with an increase in the number of schizonts which failed to disperse merozoites. In other cases, parasitaemia remained low in the absence of the schizont inhibition phenomenon, suggesting that anti-globulins contribute to host cell protection not only by agglutinating merozoites, but also by increasing the density of the antibody coat surrounding the parasites, thus interfering with parasite receptor-erythrocyte ligand interactions. The anti-globulins were not inhibitory when added to parasite cultures containing IgG not specific for P. falciparum. These results may help explain the function of IgM anti-globulins found at elevated serum levels in some patients with malaria or other chronic infectious diseases.
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PMID:Monoclonal IgM rheumatoid factor-like anti-globulins enhance the inhibitory effects of Plasmodium falciparum-specific monoclonal antibodies in vitro. 226 12

Heat-stable soluble products of rodent malarial parasites induce activated peritoneal macrophages to secrete tumour necrosis factor (TNF) in vitro. Since heat-stable parasite antigens are known to be present in the circulation of patients with malaria and it has been suggested that much of the pathology of malaria is due to TNF, we investigated the ability of such antigens to induce the production of TNF in vivo and to be toxic to mice. Injection of antigens obtained from Plasmodium yoelii or from P. berghei into mice which had previously received the macrophage-activating agent Propionibacterium acnes induced the release of TNF into the serum in amounts equivalent to the maximum release induced by bacterial lipopolysaccharide (LPS). Specific antiserum blocked the ability to the boiled soluble antigens, but not of LPS, to induce release of TNF. Similarly, vaccination specifically inhibited the release of TNF into the serum in response to subsequent stimulation with the antigens, but not with LPS. Mice made hypersensitive to the lethal action of TNF by pretreatment with D-galactosamine were killed in a dose-related fashion by administration of antigen preparations; addition of specific antiserum or prior vaccination with the antigens protected such mice, but not those given LPS, from death. We conclude that, in malaria, soluble antigens derived from the parasites may act like a toxin by stimulating the production of TNF, an important mediator of endotoxic shock, and that immunization with such antigens may diminish TNF secretion and consequently many of the clinical manifestations of the disease.
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PMID:Soluble malarial antigens are toxic and induce the production of tumour necrosis factor in vivo. 265 12


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