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)

We have shown previously that at the time of peak primary parasitaemia of P. chabaudi infection in NIH mice, significant levels of nitric oxide are produced, detectable as nitrate in the serum, and that these contribute to the protective immune response to infection. Here, we demonstrate that following reinfection, mice show a markedly diminished ability to produce nitrate. However, if mice are treated with L-NG-monomethyl arginine specifically to block nitric oxide metabolism during the primary infection, and are then reinfected, production of nitrate is restored to levels approaching those attained at peak primary parasitaemia. These experiments, together with others we have reported, indicate that whereas nitric oxide appears to play a significant role in control of the primary parasitaemia of P. chabaudi infection, it performs no such function during subsequent patent parasitaemias. Furthermore, they suggest that factors as yet unknown may regulate nitric oxide activity during malaria infection, such that under normal circumstances its production comes under strict control. This is exemplified by the observation that after the burst of nitric oxide activity that coincides with peak primary parasitaemia, there follows a prolonged period of immunological tolerance during which nitrate levels remain low even at secondary challenge infection. This tolerized state is lifted only several months after initial infection, when the nitric oxide activity at reinfection appears to correlate with the size of the parasite challenge and the presence of a patent parasitaemia. The implications of these findings for protective immunity to malaria, malarial immunosuppression, and immunoregulation in general, are discussed.
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PMID:Kinetics of nitric oxide production during infection and reinfection of mice with Plasmodium chabaudi. 922 97

Swiss mice infected with multidrug-resistant Plasmodium yoelii nigeriensis were treated with polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose (Poly ICLC), a potent interferon (IFN) inducer and immune enhancer, in combination with chloroquine (CQ), which completely eliminated the malaria parasite from these animals. The enhancement of the antimalarial activity of poly ICLC was found to be completely reversed by the cytochrome P-450 inducer, phenobarbitone. No effect of Nw nitro-L-arginine (NLA), an inhibitor of nitric oxide, was seen on the enhancement of the antimalarial activity of CQ by Poly ICLC. These results suggest the possible involvement of cytochrome P-450 enzyme-mediated mechanism in the enhancement of the antimalarial activity of CQ by Poly ICLC.
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PMID:Poly ICLC enhances the antimalarial activity of chloroquine against multidrug-resistant Plasmodium yoelii nigeriensis in mice. 924 75

We have exploited the experimental accessibility of the protozoan parasite Toxoplasma gondii and its similarity to Plasmodium falciparum to investigate the influence of specific dihydrofolate reductase polymorphisms known from field isolates of drug-resistant malaria. By engineering appropriate recombinant shuttle vectors, it is feasible to examine mutations by transient or stable transformation of T. gondii parasites, in bacterial and yeast complementation assays, and through biochemical analysis of purified enzyme. A series of mutant alleles that mirror P. falciparum variants reveals that the key mutation Asn-108 (Asn-83 in T. gondii) probably confers resistance to pyrimethamine by affecting critical interactions in the ternary complex. Mutations such as Arg-59 (T. gondii 36) have limited effect in isolation, but in combination with other mutations they enhance the competitive ability of folate by increasing the speed of product turnover. Val-16 (T. gondii 10) confers low level resistance to cycloguanil but hypersensitivity to pyrimethamine. This mutation precludes Asn-108, probably because compression of the folate binding pocket introduced by this combination is incompatible with enzyme function. These studies permit detailed biochemical, kinetic, and structural analysis of drug resistance mutations and reconstruction of the probable phylogeny of antifolate resistance in malaria.
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PMID:A biochemical and genetic model for parasite resistance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum. 945 69

A series of experiments was carried out to investigate the involvement of the L-arginine-dependent effector mechanism (LADEM) in the killing of the blood stages of the rodent malaria parasite, Plasmodium vinckei petteri, by activated spleen macrophages in vitro. P.v.petteri-infected red blood cells were co-incubated with spleen macrophages from normal mice which had previously received 10(8) Mycobacterium bovis (BCG) 5 days earlier, in the presence of 0.1 microgram/ml LPS with and without 0.1 mM L-NMMA, an L-arginine analogue which inhibits LADEM, for 16 hours. The viability of the parasites was assessed according to their infectivity following inoculation into experimental mice. Incubation of parasites with spleen macrophages in the presence of LPS without L-NMMA reduced the parasite viability to about 3%. When L-NMMA was included in the culture, inhibition of parasite killing was observed, resulting in an increase of parasite viability to about 21%. These data provide evidence to suggest that spleen macrophages play an important role as effector cells in the immune mechanisms against P.v.petteri infection, and that the parasite killing of these cells, at least in part, was mediated by LADEM.
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PMID:Killing of blood stage Plasmodium vinckei petteri by spleen macrophages through L-arginine dependent mechanism. 956 97

A basis for the intrinsic resistance of some Plasmodium vivax isolates to pyrimethamine is suggested following the isolation of the bifunctional gene encoding dihydrofolate reductase-thymidylate synthase (DHFR-TS) of this human malaria parasite. Malaria parasites are dependent on this enzyme for folate biosynthesis. Specific inhibition of the DHFR domain of the enzyme by pyrimethamine blocks pyrimidine biosynthesis, leading to an inhibition of DNA replication. The gene was isolated by the polymerase chain reaction (PCR) from genomic DNA using degenerate oligonucleotides designed to hybridize on the highly conserved regions of the sequence. The nucleotide sequence was completed by screening P. vivax genomic bank. Sequence analysis revealed an open reading frame (ORF) of 1872 nucleotides encoding a deduced protein of 623 amino acids (aa). Alignment with other malarial DHFR-TS genes showed that a 237-residue DHFR domain and a 286-residue TS domain were separated by a 100-aa linker region. Comparison with other malarial species showed low and essentially no isology in the DHFR and junctional domains, respectively, whereas an extensive isology was observed in the TS domain. The characteristic features of the P. vivax DHFR-TS gene sequence include an insertion of a short repetitive tandem array within the DHFR domain that is absent in another human malaria parasite, P. falciparum, and a GC-biased aa composition, giving rise to highly GC-rich DHFR (50.8%), junctional (58.7%), and TS (40.5%) domains, as compared with other malaria parasites. Analysis of the 5' noncoding region revealed the presence of a putative TATA box at 116 nucleotides upstream of the ATG start codon as well as a putative GC box at -636. Comparison of the DHFR sequences from pyrimethamine-sensitive and pyrimethamine-resistant P. vivax isolates revealed two residue changes: Ser Arg-58 and Ser Asn-117. These aa residues correspond to codons 59 and 108 in the P. falciparum DHFR active site in which similar aa substitutions (Cys Arg-59 and Ser Asn-108) are associated with pyrimethamine resistance. These findings may explain the intrinsic resistance of some P. vivax isolates to pyrimethamine.
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PMID:Analysis of the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene sequence. 957 57

We have discovered that the mosquito Anopheles stephensi, a natural vector of human malaria, limits parasite development with inducible synthesis of nitric oxide (NO). Elevated expression of A. stephensi NO synthase (NOS), which is highly homologous to characterized NOS genes, was detected in the midgut and carcass soon after invasion of the midgut by Plasmodium. Early induction is likely primed by bacterial growth in the blood meal. Later increases in A. stephensi NOS expression and enzyme activity occurred at the beginning of sporozoite release. Circulating levels of nitrite/nitrate, end-products of NO synthesis, were significantly higher in Plasmodium-infected mosquitoes. Dietary provision of the NOS substrate L-arginine reduced Plasmodium infections in A. stephensi. In contrast, dietary provision of a NOS inhibitor significantly increased parasite numbers in infected mosquitoes, confirming that A. stephensi limits Plasmodium development with NO.
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PMID:The mosquito Anopheles stephensi limits malaria parasite development with inducible synthesis of nitric oxide. 957 47

The gene encoding dihydrofolate reductase-thymidylate synthase of the human malaria parasite, Plasmodium vivax, was isolated by polymerase chain reaction from genomic DNA and cloned. The sequences of the dihydrofolate reductase domain of 30 clinical isolates originating from various geographic areas were compared. Interstrain analysis revealed several genotypic variations, including short tandem repeat arrays which produced length polymorphism between different parasite isolates and point mutations in the putative dihydrofolate reductase active site cavity corresponding to those associated with pyrimethamine resistance in P. falciparum and rodent malaria parasites. Amino acid substitutions Ser-->Asn-117 and Ser-->Arg-58 were associated with decreased level of in vitro pyrimethamine sensitivity. These findings suggest that the P. vivax dihydrofolate reductase domain is characterized by polymorphism that has not been observed in P. falciparum and may explain the resistance of some P. vivax isolates to pyrimethamine. Nucleotide sequence data reported in this paper are available in the EMBL, GenBank and DDJB databases under the accession numbers X98123 (isolate ARI/Pakistan), AJ003050 (isolate CNC/Thailand), AJ003051 (isolate COU/unknown geographic origin), AJ003052 (isolate DUF/French Guiana), AJ003053 (isolate GRO/Madagascar), AJ003054 (isolate HRT/Comoros Islands), AJ003071 (isolate LFT/Cambodia), AJ003072 (isolate LGF/'India), AJ003073 (isolate MAN/Comoros Islands), AJ003074 (isolate MAT/Surinam), AJ003075 (isolate PHI/Djibouti), AJ003076 (isolate PIT/Madagascar), AJ003077 (isolate YTZ/Indonesia), AJ222630 (isolate Burma-1), AJ222631 (isolate Burma-151), AJ222632 (isolate Burma-5), AJ222633 (isolate Burma-6), AJ222634 (isolate Burma-98).
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PMID:Sequence variations in the Plasmodium vivax dihydrofolate reductase-thymidylate synthase gene and their relationship with pyrimethamine resistance. 965 31

Two new dihydrofolate reductase (DHFR) mutations were recently discovered in Plasmodium falciparum samples from an area of Bolivia with high rates of in vivo resistance to pyrimethamine-sulfadoxine: a Cys-->Arg point mutation in codon 50 and a five amino acid insertion after codon 30, termed the Bolivia repeat. We used a yeast expression system to screen these new DHFR mutants, as well as all of the other known DHFR mutant genotypes, against four antifolates: pyrimethamine, cycloguanil, chlorcycloguanil, and WR99210. The prodrug proguanil was also evaluated. The primary 108-Asn mutation, the known secondary mutations 51-Ile, 59-Arg and 164-Leu, as well as the 50-Arg mutation, all progressively enhanced pyrimethamine resistance in naturally observed combinations with one another, with the presence of 164-Leu most significantly increasing resistance. Cycloguanil and chlorcycloguanil resistance were most impacted by 164-Leu and the paired 16-Val/108-Thr. Proguanil had no effect on malaria DHFR. All DHFRs analyzed were sensitive to WR99210. The Bolivia repeat did not markedly affect drug sensitivity. We conclude that malaria DHFR can be reliably, rapidly and inexpensively analyzed in yeast for activity against a broad spectrum of antifolates. This system may be useful for initially characterizing newly discovered genotypes before proceeding to P. falciparum transfection; for large-scale geographic surveys of drug resistance; and for screening new antifolates or new antifolate combinations for their effectiveness against a large panel of DHFR mutants.
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PMID:Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast. 974 71

An immunogenic aminopeptidase of Candida albicans was purified by high-performance liquid chromatography. It was then used for the development of an enzyme-linked immunosorbent assay to detect antibodies directed against this antigen in sera from patients with candidiasis. This enzyme specifically cleaves the L-Arg-7-amino-4-methyl-coumarin substrate at pH 7.4 and was detected in the crude extract of different C. albicans isolates. Sera used for this study were obtained from healthy blood donors or from patients with one of the following: systemic candidiasis, aspergillosis, cryptococcosis, toxoplasmosis, or malaria. The statistical analysis demonstrates significant differences between absorbency values obtained with sera from patients with candidiasis and with sera from the other groups (P = 0.000001). Diagnostic parameters show high diagnostic specificity of 97% and a sensitivity of 83% at a cutoff value of 0.425 and suggest the usefulness of this aminopeptidase for the diagnosis of systemic candidiasis.
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PMID:Improved immunodiagnosis of human candidiasis by an enzyme-linked immunosorbent assay using a Candida albicans 52-kilodalton metallopeptidase. 980 42

HLA-B*3910, which has only been found in African and African American individuals, differs from B*3901 by the single amino acid change of Cys67 to Tyr67. Sequence analysis of the B*3910-bound peptide pool and of several individual ligands revealed that this subtype has strong preference for peptides with Pro2. This is in contrast with the preference of B*3901 for peptides with basic residues (Arg and His) at this position, and indicates that the single amino acid substitution between B*3910 and B*3901 totally changes the repertoire of bound peptides. This is presumably due to the significant decrease in the size of the B pocket, and to its increased hydrophobicity, since Tyr67 takes part in this pocket. B*3910 is similar to various other class I proteins in its preference for peptides with Pro2 and nonpolar C-terminal residues, including HLA-B53, an antigen associated with protection against severe malaria. The role of these two motifs as major peptidic anchors suggests that B*3910 and HLA-B53 may bind common peptides.
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PMID:A single amino acid change makes the peptide specificity of B*3910 unrelated to B*3901 and closer to a group of HLA-B proteins including the malaria-protecting allotype HLA-B53. 986 30


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