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)

A case of fulminant falciparum malaria with a 35% parasitaemia, shock and subcoma was treated successfully by using parenteral chemotherapy, exchange transfusion, dexamethasone, circulatory support and mechanical ventilation. Pathophysiology and complications of falciparum malaria are discussed. The treatment of severe malaria should aim for a fast reduction in parasitaemia and toxic products. An exchange transfusion can be additive to parenteral chemotherapy. Blocking the over-reacting cell-mediated immune response, aggressive shock treatment, prevention of secondary infections and maintaining normoglycaemia might reduce morbidity and mortality of fulminant falciparum malaria.
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PMID:Fulminant falciparum malaria. 228 34

Immunization with extracellular sexual stages of the malaria parasites can induce the production of antibodies which block the development of the parasites in the midgut of a mosquito after a blood meal. We have generated a number of monoclonal antibodies against gametes and zygotes of the human malaria Plasmodium falciparum. Two monoclonal antibodies (mAb) reacting with a 230-kDa gamete surface protein (mAb 1B3 and 2B4 both isotype IgG2a) were found to block transmission of P. falciparum to mosquitoes. Blocking was complement dependent and this was verified in vitro by the rapid lysis of newly formed gametes and zygotes in the presence of the mAb and active complement. Both mAb reacted by immunofluorescence with the surface of gametes and zygotes from isolates of P. falciparum from various geographical areas. Each mAb immunoprecipitated a 230-kDa protein from 125I-labeled surface proteins of newly formed gametes and zygotes and immunoblotted a protein doublet of about molecular mass 260 and 230 kDa from gametocytes and gametes of P. falciparum. Only the 230-kDa protein is expressed on the surface of newly formed macrogametes and zygotes. The 230-kDa gamete surface protein forms a molecular complex with two proteins of 48 and 45 kDa. The 48- and 45-kDa gamete surface proteins have previously been shown to be targets of mAb which block infectivity of P. falciparum to mosquitoes. The present study now demonstrates that antibodies against the 230-kDa gamete surface protein block transmission of P. falciparum to mosquitoes. The 230-kDa gamete protein is thus a potential candidate for a gamete vaccine.
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PMID:The 230-kDa gamete surface protein of Plasmodium falciparum is also a target for transmission-blocking antibodies. 244 64

In the experimental Plasmodium berghei mouse model, as in human malaria, reduced maternal responsiveness and even loss of immunity were observed during pregnancy. Loss of immunity in the second half of pregnancy occurred during a period of elevated plasma corticoid levels. Further analysis showed that plasma corticoid levels were significantly higher in immunodepressed mice than in mice that remained immune throughout pregnancy. Plasma corticosterone levels differed increasingly from those in mice with persistent immunity towards recrudescence. In nonimmune infected controls, however, only a slight increase in plasma corticosterone, already present during the subpatent period, was measured. Blocking the maternal corticoid production by adrenalectomy delayed the increase of plasma corticosterone (fetoplacental origin) and reduced the number of mice that lost immunity during pregnancy considerably. The role of various plasma corticoid levels in the regulation of effector function of immunity during pregnancy is discussed.
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PMID:Corticosterone regulation of the effector function of malarial immunity during pregnancy. 704 72

We have constructed a second generation malaria transmission-blocking vaccine candidate based on Pfs25, the predominate surface protein of Plasmodium falciparum zygotes, to overcome potential production problems with the original construct. Four modifications were made: (1) addition of the last cysteine residue of the fourth epidermal growth factor like-domain of Pfs25; (2) mutagenesis of asparagine-linked glycosylation sites with glutamine rather than alanine; (3) addition of a six histidine tag at the carboxy-terminus for highly efficient purification of recombinant protein on nickel-NTA agarose; and (4) fermentation that combines continuous glucose fed-batch methodology with pH-controlled glucose addition and a terminal ethanol feed. The resulting product, TBV25H (Transmission-Blocking Vaccine based on Pfs25 with a Histidine tag), appears to be a more potent antigen and immunogen than the original construct, and the fermentation and post-fermentation processing methodology easily lend themselves to technology transfer to the ultimate users, newly industrialized countries.
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PMID:Production, purification and immunogenicity of a malaria transmission-blocking vaccine candidate: TBV25H expressed in yeast and purified using nickel-NTA agarose. 776 8

The human malaria parasite Plasmodium falciparum exports an interconnected network of tubovesicular membranes (the TVM) that extends from the parasite's vacuolar membrane to the periphery of the red cell. Here it is shown that extracellular solutes such as Lucifer yellow enter the TVM and are delivered to the parasite. Blocking the assembly of the network blocked the delivery of exogenous Lucifer yellow, nucleosides, and amino acids to the parasite without inhibiting secretion of plasmodial proteins. These data suggest that the TVM is a transport network that allows nutrients efficient access to the parasite and could be used to deliver antimalarial drugs directly into the parasite.
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PMID:A membrane network for nutrient import in red cells infected with the malaria parasite. 917 38

Merozoite surface protein-1 (MSP-1) of the human malaria parasite Plasmodium falciparum undergoes at least two endoproteolytic cleavage events during merozoite maturation and release, and erythrocyte invasion. We have previously demonstrated that mAbs which inhibit erythrocyte invasion and are specific for epitopes within a membrane-proximal, COOH-terminal domain of MSP-1 (MSP-119) prevent the critical secondary processing step which occurs on the surface of the extracellular merozoite at around the time of erythrocyte invasion. Certain other anti-MSP-119 mAbs, which themselves inhibit neither erythrocyte invasion nor MSP-1 secondary processing, block the processing-inhibitory activity of the first group of antibodies and are termed blocking antibodies. We have now directly quantitated antibody-mediated inhibition of MSP-1 secondary processing and invasion, and the effects on this of blocking antibodies. We show that blocking antibodies function by competing with the binding of processing-inhibitory antibodies to their epitopes on the merozoite. Polyclonal rabbit antibodies specific for certain MSP-1 sequences outside of MSP-119 also act as blocking antibodies. Most significantly, affinity-purified, naturally acquired human antibodies specific for epitopes within the NH2-terminal 83-kD domain of MSP-1 very effectively block the processing-inhibitory activity of the anti-MSP-119 mAb 12.8. The presence of these blocking antibodies also completely abrogates the inhibitory effect of mAb 12.8 on erythrocyte invasion by the parasite in vitro. Blocking antibodies therefore (a) are part of the human response to malarial infection; (b) can be induced by MSP-1 structures unrelated to the MSP-119 target of processing-inhibitory antibodies; and (c) have the potential to abolish protection mediated by anti-MSP-119 antibodies. Our results suggest that an effective MSP-119-based falciparum malaria vaccine should aim to induce an antibody response that prevents MSP-1 processing on the merozoite surface.
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PMID:Antibodies that inhibit malaria merozoite surface protein-1 processing and erythrocyte invasion are blocked by naturally acquired human antibodies. 936 29

CD4+ T cells have been implicated in immunity to the blood stages of malaria and cytokines associated with both monocyte and T cell activation have been implicated in disease. To determine whether specific T cells capable of inhibiting parasite growth can also mediate pathology we have transfused populations of Plasmodium berghei-specific T cells into normal and immunodeficient naive mice. We observed that they could inhibit parasite growth but were unable to save the animals which exhibited significantly greater anaemia and weight loss than control infected animals receiving either no T cells or T cells specific for ovalbumin. T cell-dependent tomour necrosis factor (TNF)alpha was a critical component in both parasite killing and disease promotion. Experiments with blocking antibodies demonstrated that all T-cell mediated antiparasitic immunity and all T-cell mediated weight loss was TNF-dependent. Blocking TNF-alpha in mice that received parasite-specific T cells prolonged the survival of the mice. Nitric oxide demonstrated no antiparasite effect, but was involved in the regulation of T-cell mediated weight loss. The data thus show that while parasite-specific CD4+ T cells can significantly limit parasite growth, such an effect need not be beneficial to the host, and that TNF-alpha and nitric oxide are critical effector molecules operating downstream of parasite-specific T cells in both immunity and disease.
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PMID:Malaria parasite-specific Th1-like T cells simultaneously reduce parasitemia and promote disease. 1035 54

There is an urgent need for a vaccine against malaria and proteins on the surface of the merozoite are good targets for development as vaccine candidates because they are exposed to antibody. However, it is possible that the parasite has evolved mechanisms to evade a protective immune response to these proteins. Merozoite surface protein 1 (MSP-1) is a candidate for vaccine development and its C-terminal sequence is the target of protective antibody. MSP-1 is cleaved by proteases in two processing steps, the second step releases the bulk of the protein from the surface and goes to completion during successful red blood cell invasion. Antibodies binding to the C-terminus of Plasmodium falciparum MSP-1 can inhibit both the processing and erythrocyte invasion. Other antibodies that bind to either the C-terminal sequence or elsewhere in the molecule are 'blocking' antibodies, which on binding prevent the binding of the inhibitory antibodies. Blocking antibodies are a mechanism of immune evasion, which may be based on antigenic conservation rather than diversity. This mechanism has a number of implications for the study of protective immunity and the development of malaria vaccines, emphasising the need for appropriate functional assays and careful design of the antigen.
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PMID:Merozoite surface protein 1, immune evasion, and vaccines against asexual blood stage malaria. 1069 94

The mechanisms of malaria parasite clearance in the host are not well understood, but are ascribed to the intact spleen, the site for parasite clearance. The infection induces a huge increase in spleen volume and cellularity. There is, however, a lack of studies on the splenic production of chemokines, which are small proteins that control homing and activation of immune cells and must be crucial for organized tissue growth. We studied the spleen cell production of SDF-1, a primordial chemokine of the CXCL12 class, through mRNA Reverse transcriptase and polymerase chain reaction of both isoforms, alpha and beta, in lethal (Plasmodium berghei ANKA) and non-lethal recrudescent malaria (Plasmodium chabaudi CR) in BALB/c and C57BL/6 mouse strains. In non-lethal P. chabaudi malaria in C57BL/6 mice, SDF-1alpha mRNA production clearly peaked before the control of parasitemia, a fact not observed in the same mouse strain infected with lethal P. berghei, when this production was lower and without peaks. The infection of BALB/c mice infected with the same Plasmodium species led to a similar evolution of parasitemia and also chemokine production, albeit at lower levels. SDF-1beta synthesis was more constant and regular during both infections, presenting some variation but usually occurring at all the experimental times. Supplementation of lethal models with SDF-1alpha i.p., at the time when endogenous stromal cell chemokine production peaked in non-lethal models, induced a clear reduction in parasitemia, probably with prolonged host survival. Blocking SDF-1 action by administration of T-140, a CXCR4 receptor blocker, caused an increase in circulating parasites in the usually benign non-lethal P. chabaudi malaria in C57BL/6 mice, mainly at recrudescence of parasitemia. These data suggest that SDF-1alpha production in the spleen plays an important role in rodent malaria, and its supplementation was found to partially correct defects in the control of malaria in lethal models.
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PMID:Stromal cell derived factor 1 synthesis by spleen cells in rodent malaria, and the effects of in vivo supplementation of SDF-1alpha and CXCR4 receptor blocker. 1205 54

Incessant transmission of the parasite by mosquitoes makes most attempts to control malaria fail. Blocking of parasite transmission by mosquitoes therefore is a rational strategy to combat the disease. Upon ingestion of blood meal mosquitoes secrete chitinase into the midgut. This mosquito chitinase is a zymogen which is activated by the removal of a propeptide from the N-terminal. Since the midgut peritrophic matrix acts as a physical barrier, the activated chitinase is likely to contribute to the further development of the malaria parasite in the mosquito. Earlier it has been shown that inhibiting chitinase activity in the mosquito midgut blocked sporogonic development of the malaria parasite. Since synthetic propeptides of several zymogens have been found to be potent inhibitors of their respective enzymes, we tested propeptide of mosquito midgut chitinase as an inhibitor and found that the propeptide almost completely inhibited the recombinant or purified native Anopheles gambiae chitinase. We also examined the effect of the inhibitory peptide on malaria parasite development. The result showed that the synthetic propeptide blocked the development of human malaria parasite Plasmodium falciparum in the African malaria vector An. gambiae and avian malaria parasite Plasmodium gallinaceum in Aedes aegypti mosquitoes. This study implies that the expression of inhibitory mosquito midgut chitinase propeptide in response to blood meal may alter the mosquito's vectorial capacity. This may lead to developing novel strategies for controlling the spread of malaria.
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PMID:Synthetic propeptide inhibits mosquito midgut chitinase and blocks sporogonic development of malaria parasite. 1272 25


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