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)

Generalized circulatory changes, manifesting as pulmonary oedema, acute renal failure, liver damage and severe hypotension, are well recognized aspects of acute falciparum malaria. The organ pathology is thought to be associated with a restricted local blood flow. These aspects of falciparum malaria are strikingly analogous to the shock syndrome which follows trauma, the injection of indotoxin, or some bacterial infections. Two of the cyclooxygenase products of arachidonic acid, thromboxane A2 and prostacyclin, acting through their opposing effects on vasoactivity and platelet aggregation, are emerging as the major controlling influences of vascular homeostasis. The effects of thromboxane, which constricts blood vessels and aggregates platelets, appear to dominate during traumatic or endotoxic shock. Thus thromboxane is potentially one of the main mediators of endotoxicity, and as such, from our previously published model, is likely to be important in the pathogenesis of the circulatory disturbances seen in acute malaria. This suggestion is consistent with earlier evidence that the autonomic nerve supply and bradykinin may have an important role in the pathogenesis of the haemodynamic changes in this disease. It also implies that pharmacological antagonists of thromboxane may provide useful specific therapy for the main life-threatening aspects of acute falciparum malaria.
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PMID:Thromboxane may be important in the organ damage and hypotension of malaria. 727 28

The mechanisms involved in the activation of the coagulation cascade in severe falciparum malaria were studied in 22 adult patients (19 male, three female) aged 18-45 (mean +/- SD 31 +/- 11) years. Of these, nine had multiple vital organ dysfunction, and bleeding occurred in four patients, two of whom died. During acute illness the reduction in plasma antithrombin III (AT III) concentrations and elevation in thrombin-AT III complexes were associated with significant reductions in factor XII and prekallikrein activities, and an increase in the C1 inhibitor antigen/activity ratio. Serial plasminogen activity remained within the normal range in all patients while protein C activity was significantly reduced. All patients had markedly elevated plasma polymorphonuclear leucocyte elastase (PMN-elastase) levels with mild depletion of alpha-2 macroglobulin but normal concentrations of alpha-1 antitrypsin. There was no correlation between PMN-elastase concentrations and any of the coagulation parameters or concentrations of proteinase inhibitors. These results suggest that the intrinsic pathway of the clotting cascade is activated in severe malaria. This may cause activation of the complement system and release of bradykinin and PMN-elastase and could contribute to the pathogenesis of severe malaria.
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PMID:Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway. 794 33

Recent results with primate plasmodia and rodent models of infection have focused attention on the C-terminal region of the merozoite surface protein-1 (MSP-1) as one of the leading candidates for vaccination against the erythrocytic stages of malaria. However, sequence heterogeneity of this region may compromise its use as a vaccine candidate. While the C-terminal region of MSP-1 from the two prototypic alleles of P. falciparum has been shown to be relatively conserved in laboratory-maintained strains, little data exist on sequence heterogeneity of this region in field isolates from diverse geographic areas. To address this question, DNA encoding the C-terminal, Cys-rich region of P. falciparum MSP-1 from field samples was analyzed by a polymerase chain reaction (PCR)-direct sequencing method. Sequence data were consistent with those obtained from laboratory-maintained strains. In 15 isolates from Africa, Asia and Latin America, only a few nucleotide changes were found leading to amino-acid alterations at four positions out of 102 residues. All the variations corresponded to the predicted amino-acid sequence of the other prototype, suggesting that these changes were possibly due to allelic recombinations. The four changes were E-->Q at position 1644 and TSR-->KNG, or KNG-->TSR at positions 1691, 1700 and 1701. Thus, only three patterns of the C-terminal, Cys-rich region of MSP-1, E-TSR, Q-KNG and Q-TSR, were detected. All the Cys residues were conserved. These results support the potential utility of the C-terminal region of MSP-1 as a vaccine candidate.
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PMID:Sequence heterogeneity of the C-terminal, Cys-rich region of the merozoite surface protein-1 (MSP-1) in field samples of Plasmodium falciparum. 857 18

We have characterized the natural immune responses to the 19-kDa domain of merozoite surface protein 1 in individuals from an area of western Kenya in which malaria is holoendemic. We used the three known natural variant forms of the yeast-expressed recombinant 19-kDa fragment that are referred to as the E-KNG, Q-KNG, and E-TSR antigens. T-cell proliferative responses in individuals older than 15 years and the profile of immunoglobulin G (IgG) antibody isotypes in individuals from 2 to 74 years old were determined. Positive proliferative responses to the Q-KNG antigen were observed for 54% of the individuals, and 37 and 35% of the individuals responded to the E-KNG and E-TSR constructs, respectively. Considerable heterogeneity in the T-cell proliferative responses to these three variant antigens was observed in different individuals, suggesting that the 19-kDa antigen may contain variant-specific T epitopes. Among responses of the different isotypes of the IgG antibody, IgG1 and IgG3 isotype responses were predominant, and the prevalence and levels of the responses increased with age. We also found that a higher level of IgG1 antibody response correlated with lower parasite density among young age groups, suggesting that IgG1 antibody response may play a role in protection against malaria. However, there was no correlation between the IgG3 antibody level and protection. Furthermore, we observed that although the natural antibodies cross-reacted with all three variant 19-kDa antigens, IgG3 antibodies in 12 plasma samples recognized only the E-KNG and Q-KNG constructs and not the E-TSR antigen. This result suggests that the fine specificity of IgG3 antibodies differentiates among variant-specific natural B-cell determinants in the second epidermal growth factor domain (KNG and TSR) of the antigen.
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PMID:Natural immune response to the C-terminal 19-kilodalton domain of Plasmodium falciparum merozoite surface protein 1. 869

The 19-kDa antigenic domain of Plasmodium falciparum merozoite surface protein (MSP)-1 is a potential malaria vaccine candidate. Based on the amino acid substitution, four known alleles, E-TSR (PNG-MAD20 type), E-KNG (Uganda-PA type), Q-KNG (Wellcome type), and Q-TSR (Indo type) of this domain have been identified. Using single or double crossover recombinational events, we predicted the existence of additional alleles of this antigen. The presence of the predicted alleles was determined in parasite isolates from western Kenya, by undertaking a cross-sectional and a longitudinal study. Of the ten predicted alleles, we have revealed the presence of three new alleles: E-KSG-L (Kenya-1 type); E-KSR-L (Kenya-2 type); and E-KNG-F (Kenya-3 type). The results of this study suggest that it may be possible to predict the complexity of the genetic makeup of natural parasite populations.
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PMID:Predicted and observed alleles of Plasmodium falciparum merozoite surface protein-1 (MSP-1), a potential malaria vaccine antigen. 965 29

Infants born in areas of stable malaria transmission are relatively protected against severe morbidity and high density Plasmodium falciparum blood-stage infection. This protection may involve prenatal sensitization and immunologic reactivity to malaria surface ligands that participate in invasion of red cells. We examined cord blood T and B cell immunity to P. falciparum merozoite surface protein-1 (MSP-1) in infants born in an area of stable malaria transmission in Kenya. T cell cytokine responses to the C-terminal 19-kDa fragment of MSP-1 (MSP-1(19)) were detected in 24 of 92 (26%) newborns (4-192 IFN-gamma and 3-88 IL-4-secreting cells per 10(6)/cord blood lymphocytes). Peptide epitopes in the N-terminal block 3 region of MSP-1 also drove IFN-gamma and/or IL-13 production. There was no evidence of prenatal T cell sensitization to liver-stage Ag-1. A total of 5 of 86 (6%) newborns had cord blood anti-MSP-1(19) IgM Abs, an Ig isotype that does not cross the placenta and is therefore of fetal origin. The frequency of neonatal B cell sensitization was higher than that indicated by serology alone, as 5 of 27 (18%) cord blood samples contained B cells that produced IgG when stimulated with MSP-1(19) in vitro. Neonatal B cell IgG responses were restricted to the Q-KNG allele of MSP-1(19), the major variant in this endemic area, whereas T cells responded to all four MSP-1(19) alleles evaluated. In utero sensitization to MSP-1 correlated with the presence of malaria parasites in cord blood (chi(2) = 20, p < 0.0001). These data indicate that prenatal sensitization to blood-stage Ags occurs in infants born in malaria endemic areas.
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PMID:Acquired immune responses to Plasmodium falciparum merozoite surface protein-1 in the human fetus. 1175 81

This study examined the evolution of immunoglobulin (Ig) G1 and IgG3 antibodies against the asexual stage Plasmodium falciparum protein, MSP1(19), before and after a heavy malaria transmission period in clinically immune Senegalese subjects living under different epidemiological conditions. Plasma was tested for antibodies to a yeast-produced, recombinant PfMSP1(19) antigen (the Q-KNG allelic variant) that has previously been demonstrated to react with IgG1, IgG3, or both in the majority of these people. Anti-P. falciparum antibodies of the IgG1 and IgG3 subclasses, previously reported to be associated with protection, were shown to evolve independently one from another after the transmission period in both settings. These results suggest differential regulation of MSP1(19)-specific IgG1 and IgG3. The precise role of these antibody isotypes in maintaining malaria immunity remains to be determined.
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PMID:Short report: differential evolution of immunoglobulin G1/G3 antibody responses to Plasmodium falciparum MSP1(19) over time in malaria-immune adult Senegalese patients. 1213 82

The effects of p-chlorophenylalanine, an inhibitor of serotonin synthesis, indomethacin, an inhibitor of prostaglandin synthesis, cyproheptadine, a serotonin, bradykinin and histamine antagonist, were assessed separately and in combination with chloroquine (CQ) in Vom strains of Swiss albino mice (18-22 g) of either sex infected intraperitoneally with 1 x 10(7) Plasmodium yoelii nigeriensis-induced malaria. As prophylactic, these agents reduced from 31.9 +/- 4.5 to 16.1 +/- 8.1% the level of parasitemia relative to control but had no appreciable activity as curative agents when administered subcutaneously once daily for 4 days after 72 h of parasites innoculum in vivo. However, CQ alone and the combination of these agents with CQ in curative and prophylactic treatments significantly reduced (from 50.3 +/- 5.8 to 4.9 +/- 0.75%) the level of parasitemia (P < 0.05), which was taken only once 72 h after the parasites innoculum. The prophylactic result was shown to produce better results than the curative treatment. The data indicate that inhibitors and an antagonist can reduce the parasitemia load (the extent of damage and the severity of infection) as well as enhance the effects of CQ when combined with it for malaria therapy. The study reveals that the production of autacoids in established infection renders autacoid inhibitors and an antagonist ineffective for radical cure in malarial mice; however, selective inhibition of local hormones implicated in the pathological manifestations of malaria infection by autacoid inhibitors and an antagonist may be a possible pathway to reduce the severity of infection and the associated tissue damage and to enhance the efficacy of available anti-malarials.
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PMID:Effects of autacoid inhibitors and of an antagonist on malaria infection in mice. 1527 21

Malaria parasites exhibit sequence diversity for a number of stage specific antigens. Several studies have proved that merozoite surface protein-1 (MSP-1) is an effective target eliciting a protective immune response. The MSP-1(42) region comprising two EGF-like domains is involved in generating protective immune response in humans and other experimental animals. Searching for point mutations in this region is essential in view of vaccine development. We have investigated the sequence variations in Plasmodium falciparum MSP-1 carboxy terminal region in field isolates from different regions in India. Our study reveals the presence of eight variant types of MSP-1(19) in the Indian sub-continent, which comprise of E-TSR-L, Q-TSR-L, E-TSG-L, Q-KNG-L, Q-KNG-F, E-KNG-L, E-KNG-F, and E-KYG-F. The last named allele is a novel variant being reported for the first time.
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PMID:Plasmodium falciparum: genetic diversity of C-terminal region of MSP-1 in isolates from Indian sub-continent. 1590 39

A new kallikrein-kinin system inhibitor, designated anophensin, was identified in the salivary glands of the malaria vector mosquito, Anopheles stephensi. In vitro reconstitution experiments showed that anophensin inhibits activation of the kallikrein-kinin system by inhibiting the reciprocal activation of factor XII (FXII) and prekallikrein (PK), and subsequent release of bradykinin. Additionally, anophensin inhibits activation of the kallikrein-kinin system on cultured human umbilical vein endothelial cells (HUVECs). Direct binding assays show that this inhibitory effect is due to Zn(2+)-dependent specific binding of anophensin to both FXII and high molecular weight kininogen (HK). Furthermore, anophensin interacts with both the N-terminus of FXII and domain D5 of HK, which are the binding domains for biological activating surfaces. These results suggest that anophensin inhibits activation of the kallikrein-kinin system by interfering with the association of FXII and HK with biological activating surfaces, resulting in the inhibition of bradykinin release in a host animal during insect blood-feeding.
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PMID:Identification and characterization of a new kallikrein-kinin system inhibitor from the salivary glands of the malaria vector mosquito Anopheles stephensi. 1745 41


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