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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro studies have shown that exogenously supplied amino acids are transferred into the malaria-infected cell, where they are incorporated into proteins. Most amino acids appear to enter the cell by facilitated or simple diffusion; however, the high distribution ratios seen in Plasmodium knowlesi-infected cells are difficult to explain on this basis. The changes (leakiness) observed in amino acid transport in P. lophurae infected cells are probably the result of ATP depletion in the host cell as well as the elaboration of plasmodial substances. Depletion of isoleucine, methionine, and cysteine from the medium strikingly depresses the in vitro growth of P. knowlesi. The degree of amino acid incorporation into the malaria-infected cell is not correlated with the amount of a particular amino acid in the host cell haemoglobin, the decline of that amino acid in the plasma of infected animals, or the ratio of free amino acids of the erythrocyte to those of the plasma. In erythrocyte-"free" P. lophurae, carrier-mediated transport is apparently limited to a small number of amino acids; all others seem to enter by simple diffusion.Malaria-infected erythrocytes transport exogenously supplied purines at substantially higher rates than uninfected red cells. The preferred purines are adenosine, hypoxanthine, and inosine. The only pyrimidine incorporated is orotic acid. Thymidine, cytidine, and uridine do not readily enter the red cell, and incorporation does not take place because the parasites lack the appropriate enzyme for conversion to nucleotides. Erythrocyte-"free" P. berghei and P. lophurae take up purines and orotic acid. It has been suggested that in vivo the preferred purines are hypoxanthine and inosine, and that the transport locus for erythrocytes is specific for 6-oxopurines. Similar results of purine incorporation are reported for the insect stages of P. cynomolgi and P. berghei, although transport studies have not been carried out.
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PMID:Transport of amino acids and nucleic acid precursors in malarial parasites. 33 80

Malaria-infected red cells and free parasites have limited capabilities for the biosynthesis of amino acids. Therefore, the principal amino acid sources for parasite protein synthesis are the plasma free amino acids and host cell haemoglobin. Infected cells and plasmodia incorporate exogenously supplied amino acids into protein. However, the hypothesis that amino acid utilization (from an external source) is related to availability of that amino acid in haemoglobin is without universal support: it is true for isoleucine and for Plasmodium knowlesi and P. falciparum, but not for methionine, cysteine, and other amino acids, and it does not apply to P. lophurae. More by default than by direct evidence, haemoglobin is believed to be the main amino acid reservoir available to the intraerythrocytic plasmodium. Haemoglobin, ingested via the cytostome, is held in food vacuoles where auto-oxidation takes place. As a consequence, haem is released and accumulates in the vacuole as particulate haemozoin (= malaria pigment). Current evidence favours the view that haemozoin is mainly haematin. Acid and alkaline proteases (identified in crude extracts from mammalian and avian malarias) are presumably secreted directly into the food vacuole. They then digest the denatured globin and the resulting amino acids are incorporated into parasite protein. Cell-free protein synthesizing systems have been developed using P. knowlesi and P. lophurae ribosomes. In the main these systems are typically eukaryotic.Studies of amino acid metabolism are exceedingly limited. Arginine, lysine, methionine, and proline are incorporated into protein, whereas glutamic acid is metabolized via an NADP-specific glutamic dehydrogenase. Glutamate oxidation generates NADPH and auxiliary energy (in the form of alpha-ketoglutarate). The role of red cell glutathione in the economy of the parasite remains obscure. Important goals for future research should be: quantitative assessment of the relative importance of amino acid sources for parasite protein synthesis; purification and characterization of plasmodial proteinases; and in vitro translation of parasite messenger RNA.
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PMID:Amino acid metabolism and protein synthesis in malarial parasites. 33 83

A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 microM). Administration of one of the compounds, MDL 27695, which is N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% alpha-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria.
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PMID:Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria. 246 35

Using the incorporation of [3H]isoleucine or [3H]hypoxanthine into acid-insoluble products as indices of protein- and nucleic acid-synthetic activity, respectively, it was shown that seven plant-derived quassinoids with differing chemical substitutions all inhibited protein synthesis more rapidly than nucleic acid synthesis in human erythrocytes infected with Plasmodium falciparum, in vitro. Five quassinoids (ailanthinone, bruceantin, bruceine B, glaucarubinone and holacanthone) were effective within 30 min at doses 10 times their 48 hr in vitro IC50 values. Chaparrin and glaucarubol differed in that they did not inhibit protein synthesis during the time course of these experiments when applied at 10 times their in vitro IC50 values. When these compounds were used at 209 and 114 times their respective IC50 values, their observed effects were identical to those of the other quassinoids studied. The time (t50) at which nucleic acid synthesis was reduced to 50% of control was directly proportional to the t50 for protein synthesis, suggesting that failure of nucleic acid synthesis is a consequence of inhibition of protein synthesis. It is concluded that in the malaria parasite, as in eukaryote models, quassinoids are rapid and potent inhibitors of protein synthesis, and that this is most likely due to effects upon the ribosome, rather than upon nucleic acid metabolism.
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PMID:In vitro studies on the mode of action of quassinoids with activity against chloroquine-resistant Plasmodium falciparum. 269 Aug 30

The underlying cause of anemia is one of the problems to be solved in malaria research. Many factors are involved in reducing the quantity of uninfected red blood cells (RBC) in addition to those infected RBC destroyed by malaria parasites. In the Plasmodium yoelii (P.y.)-mouse model, the amount of [51Cr]-labelled normal mouse RBC destroyed in peripheral blood as well as the quantity phagocytized by spleen cells during acute and chronic infection in vivo is reported in this paper. Our results show that compensatory enlargement of the spleen, which cleans up a large amount of the damaged uninfected RBC, may be the major cause of anemia in chronic malaria infection. In acute malaria infection destruction of uninfected RBC in peripheral circulation is higher than that in normal mice. Neither malaria antigen, mouse autoantibody nor immune complex was detected on the surface of normal RBC from infected mice using indirect immunofluorescence assay (IFA) or [3H]-isoleucine-labelled P.y. antigen (P.y.Ag) in vitro. This suggests that malaria immune complexes do not play an important part in RBC destruction in circulating blood. Since no obvious hemolysis was observed by mixing RBC with P.y. culture supernatant in vitro, it is possible that physical and chemical changes in uninfected RBC induced by malaria metabolites are the prerequisite for their destruction in circulating blood in vivo. Hemolysis occurs due to external stresses, such as those incurred when damaged RBC run into each other in the blood stream or when they change their shape to pass through capillaries.
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PMID:Studies on the mechanism of anemia in rodent malaria. 279 98

The human malaria parasite Plasmodium falciparum synthesizes several proteins that are unusually rich in histidine. We therefore screened histidine analogues for their capacity to inhibit in vitro parasite growth. Analogues were added to cultures of ring-stage parasites, and parasite morphological development was assessed by light microscopy after a 22-hr culture. Inhibition of morphological development was identified as the appearance of condensed or pycnotic parasites rather than mature trophozoites. Inhibition of parasite protein synthesis was assessed by radioactivity counting of [3H] isoleucine incorporated into acid-insoluble products and by sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography of [3H]histidine-labeled malarial proteins. 2-F-L-Histidine and 2-I-D, L-histidine exerted the most pronounced inhibitory effects, the fluoro-analogue being the more effective of the two. At a 0.125 mM concentration, both compounds inhibited parasite growth and 2-F-L-histidine also inhibited protein synthesis. At a 1.0 mM concentration, 2-azido-L-histidine, alpha-methyl-L-histidine and WR 177589A also inhibited P. falciparum growth and protein synthesis. Twenty other histidine analogues, including 5-F-L-histidine and 5-I-L-histidine, showed little or no effect under these conditions. The inhibitory histidine analogues may be of interest for antimalarial chemotherapy if they should prove to have greater effect on P. falciparum protein synthesis than on host protein synthesis.
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PMID:Inhibitory effects of histidine analogues on growth and protein synthesis by Plasmodium falciparum in vitro. 351 22

Some of the available information on the genetics of Plasmodium is reviewed, and some of its peculiarities are emphasized. Genetic factors in the human host that may affect susceptibility to malaria are critically evaluated. Most of the studies thus far have been concerned with the genetics of host erythrocytes but there is recent evidence that genes affecting immune processes may also be involved. At least two genes affecting red cells confer relative resistance to P. falciparum: the autosomal gene for haemoglobin S (Hb S) and the sex-linked gene for the glucose-6-phosphate dehydrogenase (G6PD) variant known as A(-). Whereas malaria selection can be regarded as established for these genes, it still remains a hypothesis for some other polymorphic traits of red cells. Differential susceptibility to P. falciparum of red cells with different genotypes has been tested by in vitro cultures, in which the invasion of new cells and intracellular development of the parasite can be followed by parasite counts and by (14)C-isoleucine uptake. A model that relates genetic factors in Plasmodium and in man and that may account for certain features of host-parasite interactions is presented.
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PMID:Genetic factors in malaria. 461 2

Invasion of erythrocytes by malaria parasites is known to be blocked by proteolytic digestion of merozoite receptors allegedly present in red cell membranes. This information was used in the present work to develop a simple and convenient assay for parasite invasion into red blood cells and for evaluating the role played by red cell membrane components in this process. Synchronized in vitro cultures of Plasmodium falciparum containing only ring stages were subjected to either trypsin or pronase digestion, a treatment that neither affected ring development into schizonts nor mature merozoite release. Cells from this culture were not invaded by the released merozoites. However, upon addition of untreated human red blood cells, marked invasion was observed, either microscopically or as [3H]isoleucine incorporation. The new assay circumvents the need for separating schizonts from uninfected cells and provides a convenient means for assessing how chemical and biochemical manipulation of red blood cells affects their invasiveness by parasites. Using this assay, we verified that sheep and rabbit erythrocytes were resistant to invasion, as were human erythrocytes which had been treated with trypsin, pronase or neuraminidase. Chymotrypsin digestion of human erythrocytes was without effect on invasion. Human erythrocytes which were chemically modified with the impermeant amino reactive reagent H2DIDS, or with the crosslinker of spectrin, TCEA, were found to resist invasion. The results underscore the involvement of surface membrane components as well as of elements of the cytoskeleton in the process of parasite invasion into erythrocytes.
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PMID:An assay of malaria parasite invasion into human erythrocytes. The effects of chemical and enzymatic modification of erythrocyte membrane components. 633 31

Serum samples from Aotus trivirgatus subsp. griseimembra monkeys obtained at different stages of a vaccination experiment were analyzed for total antibody titer to Plasmodium falciparum and were used for identifying protective antigens of the human malaria parasite. Total malarial antibody titers were higher in serum samples from protected monkeys (vaccinated with antigen in an adjuvant) than in those from unprotected monkeys (vaccinated with either antigen or adjuvant only). Parasite proteins were labeled with [3H]isoleucine, solubilized with nonionic detergent, and reacted with immune Aotus sera. Immunoprecipitates obtained were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography. Thirteen protein antigen bands in the molecular weight range 73,000 to 180,000 were resolved. Serum samples obtained from protected Aotus monkeys reacted more intensely with these proteins than samples from unprotected monkeys did. Evidence is presented that the protective antigen is not a single, normally nonimmunogenic, protein that is recognized only in protected monkeys. Rather, the present data indicate that a heightened immune response to multiple proteins correlated with in vivo protection to P. falciparum in Aotus monkeys. This finding may have a significant bearing on strategies for the development of a human P. falciparum vaccine.
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PMID:Plasmodium falciparum: protein antigens identified by analysis of serum samples from vaccinated Aotus monkeys. 636 Sep 1

Infection with Plasmodium berghei malaria is severely inhibited in rats fed on a low protein diet. A range of amino acid supplements was added to a 4.2% casein diet to determine whether the relationship between level of infection and protein content could be attributed to the dietary amounts of the essential amino acids. Significant increases in levels of infection were achieved by supplementation with specific combinations of amino acids. Threonine was most effective in increasing the degree of parasitaemia but its effect was further enhanced when it was combined with dietary excess of certain other amino acids, notably valine, isoleucine and methionine.
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PMID:Increased severity of malaria infection in rats fed supplementary amino acids. 639 37


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