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)

Schistosomiasis, the second major parasitic disease in the world after malaria affects at least 200 million people, 500 million being exposed to the risk of infection. It is widely agreed that a vaccine strategy which could lead to the induction of effector mechanisms reducing the level of reinfection and ideally parasite fecundity would deeply affect the incidence of pathological manifestations as well as the parasite transmission potentialities. Extensive studies performed in the rat model have allowed the identification of novel effector mechanisms involving IgE antibodies and various inflammatory cell populations (eosinophils, macrophages and platelets) whereas regulation of immune response by blocking antibodies has been evidenced. Recent epidemiological studies have now entirely confirmed in human populations the role of IgE antibodies in the acquisition of resistance and the association of IgG4 blocking antibodies with increased susceptibility. On the basis of these concepts, several schistosome target proteins have been identified and their encoding genes cloned. One of them, a schistosome glutathione S-transferase (Sm 28 GST) appears as a promising vaccine candidate. Immunization experiments have shown that two complementary goals can be achieved: (a) a partial but significant reduction of the worm population (up to 60% in rats); (b) a significant reduction of parasite fecundity (up to 70% in mice and 85% in cattle) and egg viability (up to 80%). At least two distinct immunological mechanisms account for these two effects. IgE antibodies appear as a major humoral component of acquired resistance whereas IgA antibodies appear as a major humoral factor affecting parasite fecundity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vaccine strategies against schistosomiasis. 134 2

A DNA fragment, designated as P190TR, encoding amino acid residues of the tripeptide region of the P190 antigen was amplified by polymerase chain reaction from genomic DNA of FCC1/HN Plasmodium falciparum isolated from Hainan Province, China. Upon comparison with the nucleotide sequences of MAD20 allele, it was found that there were five bases substitution in the P190TR which cause amino acid changes. The DNA fragment sequenced were ligated to BamHI and XbaI-digested pGEX-2T vector. Competent E. coli JM109 (DE3) were transformed with either parental or recombinant pGEX-2T for expression. Analysis of soluble cellular proteins revealed the high level expression of GST-P190TR as fusion proteins. Affinity purification of the fusion protein under nondenaturing condition resulted in the removal of almost all other E. coli proteins. The purified P190TR protein was highly immunogenic in rabbits. The antibodies against the recombinant protein recognized the malaria parasite with the titers at 1:320 measured by IFA and antisera from malarial patients reacted with the expressed protein in Western Blot.
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PMID:Expression and immunogenicity of tripeptide repeat region on P190 of Plasmodium falciparum. 778 21

Previously, the Plasmodium falciparum serine repeat antigen has been shown to be protective in primate models of malaria immunity and also to be a target of in vitro parasite-inhibitory antibodies. To further define parasite-inhibitory epitopes a series of deletions from the amino-terminal 47-kDa domain of the serine repeat antigen (SERA) were constructed as glutathione-S-transferase fusion proteins. Several GST-SERA fusion proteins were used to vaccinate mice with Freund's adjuvant and the resulting immune sera were used to assay for the inhibition of P. falciparum invasion of erythrocytes in vitro. The minimal epitope shown to be the target of invasion-blocking antibodies was SERA amino acids 17-165. Additional GST-SERA deletion constructs of the 47-kDa domain were developed and evaluated for reactivity, by Western immunoblot analysis, with a parasite-inhibitory murine monoclonal antibody (mAb 43E5), a parasite-inhibitory pooled goat polyclonal sera, and a pooled human Nigerian immune serum. The parasite-inhibitory epitope defined by mAb 43E5 was mapped to SERA amino acids 17-110 and, at least, part of the epitope was defined to include amino acids in the region of amino acids 59-72. The parasite-inhibitory epitope recognized by mAb 43E5 appears to be well conserved between diverse geographical isolates of P. falciparum. The results have relevance for malaria vaccine development and suggest that an appropriately designed recombinant SERA antigen produced from a synthetic gene in Escherichia coli may be an effective component of a candidate malaria vaccine.
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PMID:Plasmodium falciparum: an epitope within a highly conserved region of the 47-kDa amino-terminal domain of the serine repeat antigen is a target of parasite-inhibitory antibodies. 903 Jun 63

Severe Plasmodium falciparum malaria is characterized by excessive sequestration of infected and uninfected erythrocytes in the microvasculature of the affected organ. Rosetting, the adhesion of P. falciparum-infected erythrocytes to uninfected erythrocytes is a virulent parasite phenotype associated with the occurrence of severe malaria. Here we report on the identification by single-cell reverse transcriptase PCR and cDNA cloning of the adhesive ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1). Rosetting PfEMP1 contains clusters of glycosaminoglycan-binding motifs. A recombinant fusion protein (Duffy binding-like 1-glutathione S transferase; Duffy binding-like-1-GST) was found to adhere directly to normal erythrocytes, disrupt naturally formed rosettes, block rosette reformation, and bind to a heparin-Sepharose matrix. The adhesive interactions could be inhibited with heparan sulfate or enzymes that remove heparan sulfate from the cell surface whereas other enzymes or similar glycosaminoglycans of a like negative charge did not affect the binding. PfEMP1 is suggested to be the rosetting ligand and heparan sulfate, or a heparan sulfate-like molecule, the receptor both for PfEMP1 binding and naturally formed erythrocyte rosettes.
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PMID:Identification of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) as the rosetting ligand of the malaria parasite P. falciparum. 941 7

The mechanisms by which Abs mediate protection during blood-stage malaria infections is controversial, with some evidence pointing to the direct effect of Abs on parasite invasion and growth, while other studies suggest that Abs act in cooperation with monocytes to achieve parasite inhibition. To determine whether the effector phase of protection in vivo to the rodent parasite Plasmodium yoelii yoelii requires Fc receptor bearing cells, we passively transferred immune sera into FcR gamma-chain knockout mice. Inflammatory macrophages from these knockout mice were unable to mediate phagocytosis or Ab-dependent cell-mediated cytotoxicity (ADCC) through Fc gamma RI, Fc gamma RII, or Fc gamma RIII. Passive transfer of either P. y. yoelii hyperimmune sera or anti-GST-PYC2 sera directed to the major merozoite surface protein (MSP-1) of this parasite enabled both BALB/cByJ mice and FcR gamma-chain-deficient mice to resist lethal P. y. yoelii 17XL (Py17XL) challenge. mAb302, a protective IgG3 Ab, also passively protected both strains of mice. Most of these samples contain Ab isotypes that would not be able to protect mice if their protective effects required Ab-dependent cell-mediated cytotoxicity. These results establish that, in this infection, protection is directly mediated by Abs and does not require the participation of Fc receptors.
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PMID:Fc receptors are not required for antibody-mediated protection against lethal malaria challenge in a mouse model. 971 60

The prevalence of antibodies to hepatitis E virus (HEV) has been examined in many countries, but such studies have generally been limited to majority populations such as those represented in healthy blood donors or cross sections of urban populations. Due to its major route of enteric transmission, large differences in HEV prevalence might be expected between populations in the same country but with different living conditions. Using an ELISA based on GST-ORF2.1 antigen, the prevalence of IgG-class antibodies to HEV was examined in three distinct populations in Malaysia: the normal (urban) blood donor population and two aboriginal communities located at Betau, Pahang and Parit Tanjung, Perak. IgG anti-HEV was detected in 45 (44%) of 102 samples from Betau and 15 (50%) of 30 samples from Parit Tanjung, compared to only 2 (2%) of 100 normal blood donors. The distribution of sample ELISA reactivities was also consistent with ongoing sporadic infection in the aboriginal communities, while there was no significant relationship between HEV exposure and age, sex, or malaria infection. The high prevalence of antibodies to HEV in the two aboriginal communities indicates that this group of people are at high risk of exposure to HEV compared to the general blood donors, and the results suggest that studies of HEV seroprevalence within countries must take into account the possibility of widely varying infection rates between populations with marked differences in living conditions.
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PMID:Seroprevalence of antibodies to hepatitis E virus in the normal blood donor population and two aboriginal communities in Malaysia. 1045 51

The genomic DNA of a GST class I alternative splicing gene has been characterized from Anopheles dirus, a Thai malaria vector. This gene organization is highly conserved in An. dirus and Anopheles gambiae (aggst1alpha), with >80% nucleotide identity in the coding region. Their gene organization contains six exons for four mature GST transcripts, which share exon 1 and exon 2 but vary between four different exon 3 sequences (exon 3A-3D). The deduced amino acid sequence of the GST transcripts from these two genes also shows very high conservation, with 85-93% identity for each orthologous gene. Two putative promoters and possible regulatory elements were predicted by a combination of the TSSW and MatInspector programs. The Ad214 promoter is proposed to be involved in developmental stage regulation. The Ad2112 promoter would appear to respond to intra- or extracellular stimuli. These two Anopheline species appear to have diverged in the distant past based on gene neighbors and phylogenetic data, yet these GST genes are still conserved. Therefore it is highly probable that this GST gene organization has one or more important roles.
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PMID:Genomic organization and putative promoters of highly conserved glutathione S-transferases originating by alternative splicing in Anopheles dirus. 1110 37

By motif searching of the unfinished sequences in the Malaria Genome Sequencing Project databases we have identified a novel EGF-like domain-containing protein of Plasmodium falciparum. The sequence lies within a single open reading frame of 1791 bp and is predicted to encode a polypeptide of 597 amino acids. There are hydrophobic regions at the extreme N- and C-termini, which could represent secretory signal peptide and GPI attachment sites, respectively. Similar to MSP1, there are two EGF-like domains located near the C-terminus. RT-PCR analysis of the novel gene shows that it is transcribed in asexual stages of the malaria parasite. We have expressed portions of the protein as recombinant GST fusions in Escherichia coli and raised antisera in rabbits. Antibodies to the EGF-like domains of the novel protein are highly specific and do not cross-react with the EGF-like domains of MSP1, MSP4 or MSP5 expressed as GST fusion proteins. Antiserum raised to the most C-terminal region of the protein reacts with four bands of 98, 50, 25 and 19 kDa in P. falciparum parasite lysates whereas antisera to the N-terminal fusion proteins recognise the 98 and 50 kDa bands, suggesting that the novel protein may undergo processing in a similar way to MSP1. Immunoblot analysis of stage-specific parasite samples reveals that the protein is present throughout the parasite asexual life cycle and in isolated merozoites, with the smaller fragments present in ring stage parasites. The protein partitions in the detergent-enriched phase after Triton X-114 fractionation and is localized to the surfaces of trophozoites, schizonts and free merozoites by indirect immunofluorescence. Antisera to the C-terminus stain the surface of rings, whereas antisera to the N-terminus do not, suggesting that a fragment of the protein is carried into the developing ring stage parasite. Based on the accepted nomenclature in the field we designate this protein MSP8. We have shown that the MSP8 fusion proteins are in a conformation that can be recognised by human immune sera and that there is very limited diversity in the MSP8 gene sequences from various P. falciparum laboratory isolates. MSP8 shows significant similarity to the recently reported sequence of the protective P. yoelii merozoite surface protein pypAg-2 [Burns JM, Belk CC, Dunn PD. Infect Immun 2000;68:6189-95.] suggesting that the two proteins are homologues. Taken together, these findings suggest that MSP8/pypAg-2 may play an important role in the process of red cell invasion and is a potential malaria vaccine candidate.
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PMID:Merozoite surface protein 8 of Plasmodium falciparum contains two epidermal growth factor-like domains. 1137 1

Comparative DDT-susceptibility status as well as glutathione S-transferase activity and DDTase activity of Anopheles minimus (A). An. annularis and Culex quinquefasciatus were investigated to ascertain the role of these enzymes in DDT-resistance. The standard WHO susceptibility test kits was used to discriminate between resistant and susceptible populations. GST activity was measured in microtiter plates whereas DDTase activity was determined by HPLC quantitation of DDT metabolites. This is the first report of DDT-resistance in the Thai malaria vector, An. minimus species A. A positive correlation of DDT-resistance and DDTase activity was observed in this species as well as in the suspected vector, An. annularis. However, GST activity was not correlated to DDT-resistance in either species. Statistical analysis and scatter plots demonstrated the non-correlation between DDTase and GST activity in An. annularis. Studies in Culex quinquefisciatus revealed difference in GST/ DDTase and the relationship to DDT-resistance compared to the anopheline species. The Culex GST activity is correlated to DDTase activity. These results suggested that a positive correlation of GST and DDTase activity might be species dependent.
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PMID:Correlation of glutathione S-transferase and DDT dehydrochlorinase activities with DDT susceptibility in Anopheles and Culex mosquitos from northern Thailand. 1141 39

Western blot analysis was performed to diagnose vivax malaria using stage-specific recombinant antigens. Genomic DNA from the whole blood of a malaria patient was used as templates to amplify the coding regions for the antigenic domains of circumsporozoite protein (CSP-1), merozoite surface protein (MSP-1), apical merozoite antigen (AMA-1), serine repeat antigen (SERA), and exported antigen (EXP-1) of Plasmodium vivax. Each amplified DNA fragment was inserted into a pGEX-4T plasmid to induce the expression of GST fusion protein in Escherichia coli by IPTG. The bacterial cell extracts were separated on 10% SDS-PAGE followed by western blot analysis with patient sera which was confirmed by blood smear examination. When applied with patient sera, 147 (91.9%) out of 160 vivax malaria, 12 (92.3%) out of 13 falciparum malaria, and all 9 vivax/falciparum mixed malaria reacted with at least one antigen, while no reactions occurred with 20 normal uninfected sera. In the case of vivax malaria, CSP-1 reacted with 128 (80.0%) sera, MSP-1 with 102 (63.8%), AMA-1 with 128 (80.0%), SERA with 115 (71.9%), and EXP-1 with 89 (55.6%), respectively. We obtained higher detection rates when using 5 antigens (91.9%) rather than using each antigen solely (55.6-80%), a combination of 2 (76.3-87.5%), 3 (85.6-90.6%), or 4 antigens (89.4-91.3%). This method can be applied to serological diagnosis, mass screening in endemic regions, or safety test in transfusion of prevalent vivax malaria.
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PMID:Western blot diagnosis of vivax malaria with multiple stage-specific antigens of the parasite. 1144 4


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