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

The induction mechanism of gamete formation (gametogenesis) in a rodent malaria parasite, Plasmodium berghei, was investigated using Ca2+ antagonists, protein kinase inhibitors and amiloride, an inhibitor of monovalent cation/H+ exchange. Treatment with 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, a Ca2+ release inhibitor) and W-7/W-66 (calmodulin inhibitors) blocked formation of male gametes by inhibiting DNA synthesis from 1.5C to 8C level. In contrast, inhibitors of cAMP/cGMP-dependent protein kinases such as H-8, H-87, H-89 and staurosporine also ceased the development of gametocytes, but DNA synthesis in male gametocytes occurred as in the controls. Electron microscopy revealed that male gametocytes treated with TMB-8 and W-7 failed to enlarge nuclei and to form axonemes in the cytoplasm. In female gametocytes, treatment with both Ca2+ antagonists resulted in a dramatic morphological change in the endoplasmic reticulum (ER), which is thought to be a Ca2+ store. The ER network condensed near nuclei and was laminated by the abnormal attachment of ribosomes between two ER membranes. On the other hand, male gametocytes treated with protein kinase inhibitors or amiloride had enlarged nuclei and axonemes, but failed to develop further. The ER network in female gametocytes treated with these inhibitors was similar to that in the controls.
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PMID:The roles of Ca2+/calmodulin- and cGMP-dependent pathways in gametogenesis of a rodent malaria parasite, Plasmodium berghei. 838 16

To date, the circumsporozoite (CS) protein has been implicated in guiding malaria sporozoites to the liver [Cerami et al., Cell 70, 1992, 1021-1033]. Here we show that shortly after invasion, P. berghei and P. yoelii sporozoites lie free in the invaded cell and release considerable amounts of CS protein into the cytoplasm. The intracytoplasmic deposition of CS protein begins during the attachment of the sporozoite to the host cell surface and reaches its peak during the first 4-6 h after invasion. Initially, the CS protein spreads over the entire cytoplasm of the infected cell where it interacts with cytosolic as well as endoplasmic reticulum-associated ribosomes. During the subsequent development of the parasites to exoerythrocytic forms, the CS protein binding becomes gradually restricted to ribosomes lining the outer membrane of the nuclear envelope of the host cell. The distribution pattern of the parasite-released CS protein in the host cell cytoplasm is independent of the permissiveness of the host cell for the development of the parasites to exoerythrocytic forms. It requires neither the host cell metabolism nor does it involve the endocytotic machinery. Recombinant P. falciparum CS protein interacts with RNAse-sensitive sites on endoplasmic reticulum-associated ribosomes as shown by microinjection and immunoelectron microscopy. The generalized interaction of the CS protein with host cell ribosomes suggests that the CS protein has an intracellular function during the hepatic phase in the life cycle of Plasmodium and may also explain the generation of a CD8+ T cell response in the course of rodent malaria infections.
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PMID:Release of malaria circumsporozoite protein into the host cell cytoplasm and interaction with ribosomes. 889 31

The fluorescent indicator, fura-2, AM, was used to measure free calcium concentrations in the intraerythrocytic malaria parasites of Plasmodium chabaudi and Plasmodium falciparum. In both species the free cytosolic calcium concentration was maintained at low levels (between 40 and 100 nM throughout the maturation process. Digital image analysis of the indicator fluorescence was performed on parasites and evaluated with the aid of a calibration of the calcium response, based on permeabilized parasites, exposed to calcium buffers. This again revealed that free calcium concentrations in the intact parasite are maintained at a predetermined level, regardless of the free calcium in the surrounding milieu. Both species of parasites are thus capable of regulating their internal free calcium levels with high precision, presumably by means of calcium pump ATPases. A small but significant elevation of the cytosolic free calcium concentration by the tumor promoter, thapsigargin, may be taken to reflect the presence of calcium stores in the endoplasmic reticulum in P. falciparum.
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PMID:Calcium homeostasis in intraerythrocytic malaria parasites. 898 Sep 13

The presence of a signal sequence preceding the gene encoding a target antigen in a DNA vaccine should facilitate secretion of the in vivo translated antigen. The immune responses elicited upon injection with such a vector could differ from those induced by the same vector lacking a signal sequence. In the present study, the humoral responses elicited in mice immunized with two plasmids, either containing or lacking the human tissue plasminogen activator signal sequence, were compared. Both plasmids encode the chimeric antigen ZZN4, containing a malaria antigen Pf332-derived sequence (N4) linked to a bacterial fusion partner (ZZ). In vitro transfection of COS cells with each plasmid and treatment of the transfectants with brefeldin A confirmed that secretion of ZZN4 via the endoplasmic reticulum and Golgi pathway only occurred in cells transfected with the signal peptide-encoding plasmid. Repeated intramuscular injections of mice with either of the plasmids elicited comparable antibody responses to ZZN4 with regard to kinetics, specific IgG levels and persistence. These results indicate that in vivo transfection of muscle cells by either of these two plasmids generated comparable levels of antigen available for B-cell recognition and for uptake by antigen-presenting cells, despite the differential intracellular targeting of the encoded antigen. The relevance of these findings for the design of DNA vaccine vectors is discussed.
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PMID:Comparative study of DNA-based immunization vectors: effect of secretion signals on the antibody responses in mice. 927 Nov 70

Non-mitochondrial calcium deposits were investigated in the intraerythrocytic malaria parasite Plasmodium chabaudi at the trophozoite stage by means of arsenazo III in the presence of ATP and the mitochondrial poisons, antimycin and oligomycin. Addition of vanadate and 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ), both known to interact with SERCA pump, induced calcium release by permeabilized parasites when the medium free calcium concentration was kept at 3.5 microM. The tumor promoter thapsigargin also caused elevation of the free calcium concentration in permeabilized parasites. Our results support the view that P. chabaudi sequesters calcium in an exchangeable form and maintains its calcium homeostasis by way of an endoplasmic reticulum Ca2+ pump.
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PMID:Characterization of Ca2+ transport activity associated with a non-mitochondrial calcium pool in the rodent malaria parasite P. chabaudi. 928 59

An endoplasmic reticulum-located, calcium-binding protein, with an apparent molecular weight (Mr) of approximately 40,000 (PfERC), has been identified in the asexual stages of the malaria parasite, Plasmodium falciparum. This protein appears to be equivalent to a previously described gametocyte protein, Pfs40, which was reported to be expressed on the gametocyte surface (Rawlings DJ, Kaslow DC. J Biol Chem 1992;267:3976-3982). Sequencing of the 3' end of the gene revealed the omission of a single base in the 3' region of the published sequence. The corrected gene sequence encodes a C-terminal IDEL motif, which indicates residency of the 40 kDa protein within the endoplasmic reticulum. The predicted C-terminal region also appears to contain a sixth EF-hand calcium-binding domain, which suggests that PfERC is related to previously reported ER-localized calcium-binding proteins, namely reticulocalbin and ERC-55 (Ozawa M. J. Biochem. 1995;117:1113-1119; Weis K, Griffiths G, Lamond AI. J. Biol. Chem. 1994;269:19142-19150). The presence of the 40 kDa calcium-binding protein in malaria parasites was confirmed using 45Ca2+-blotting and partial protein sequencing of the corresponding Coomassie blue-stained polypeptide. Confocal immunofluorescence microscopy of asexual stage parasites was used to show that PfERC co-localizes with the known ER-located protein, Pfgrp. Analysis of immunoblots of tightly synchronized parasites showed that expression of PfERC increases with increasing maturity of the parasite. We propose that PfERC is a member of the reticulocalbin family of calcium-binding proteins and may play a role in protein trafficking in the malaria parasite.
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PMID:Identification of an endoplasmic reticulum-resident calcium-binding protein with multiple EF-hand motifs in asexual stages of Plasmodium falciparum. 936 72

Penetration of the mosquito midgut epithelium is obligatory for the further development of Plasmodium parasites. Therefore, blocking the parasite from invading the midgut wall disrupts the transmission of malaria. Despite such a pivotal role in malaria transmission, the cellular and molecular interactions that occur during the invasion are not understood. Here, we demonstrate that the ookinetes of Plasmodium gallinaceum, which is related closely to the human malaria parasite Plasmodium falciparum, selectively invade a cell type in the Aedes aegypti midgut. These cells, unlike the majority of the cells in the midgut, do not stain with a basophilic dye (toluidine blue) and are less osmiophilic. In addition, they contain minimal endoplasmic reticulum, lack secretory granules, and have few microvilli. Instead, these cells are highly vacuolated and express large amounts of vesicular ATPase. The enzyme is associated with the apical plasma membrane, cytoplasmic vesicles, and tubular extensions of the basal membrane of the invaded cells. The high cost of insecticide use in endemic areas and the emergence of drug resistant malaria parasites call for alternative approaches such as modifying the mosquito to block the transmission of malaria. One of the targets for such modification is the parasite receptor on midgut cells. A step toward the identification of this receptor is the realization that malaria parasites invade a special cell type in the mosquito midgut.
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PMID:Plasmodium gallinaceum preferentially invades vesicular ATPase-expressing cells in Aedes aegypti midgut. 952 Mar 75

As liver can be an important target organ in malaria, we performed an ultrastructural study of hepatic alterations in the final stage of Plasmodium berghei infection in mice. Significant hepatocyte abnormalities were found. An elevated number of cells showed mitochondria with a high electron-dense matrix and multiple changes in shape and size, alterations in the structure of Golgi complex, swelling and disorganisation of both rough and smooth-surfaced endoplasmic reticulum, differently shaped peroxisome nucleoids, and disappearance of glycogen granules. In other areas the hepatocytes were significantly altered with diminished microvilli and exhibited myelin-like figures, autophagic vacuoles, abundant lipid droplets, and swollen mitochondria in their cytoplasm. Necrotic and atrophied hepatocytes with scarce microvilli in the Disse space and biliary canaliculi could be seen. Parasitised red blood cells and parasite debris were found inside degenerated hepatocytes. Alterations were also noticed in microvasculature, including thickened endothelial cells with swollen mitochondria, lysosomes and autophagic vacuoles in their cytoplasm. Our results demonstrate that hepatocyte damage is an important finding associated with the advanced stages of P. berghei malarial infection, which may lead to liver dysfunction in this disease.
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PMID:Liver ultrastructural pathology in mice infected with Plasmodium berghei. 964 94

The intraerythrocytic location of the malaria parasite necessitates modification of the host cell. These alterations are mediated either directly or indirectly by parasite proteins exported to specific compartments within the host cell. However, little is known about how the parasite specifically targets proteins to locations beyond its plasma membrane. Mark Wiser, Norbert Lanners and Richard Bafford here propose an alternative secretory pathway for the export of parasite proteins into the host erythrocyte. The first step of this pathway is probably an endoplasmic reticulum (ER)-like organelle that is distinct from the normal ER. Possible mechanisms of protein trafficking in the infected erythrocyte are also discussed. The proposed ER-like organelle and alternative secretory pathway raise many questions about the cell biology of protein export and trafficking in Plasmodium.
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PMID:Export of proteins via a novel secretory pathway. 1032 53

We have identified a homologue of the GTP-binding protein, Sar1p, in Plasmodium falciparum. Sar1p is a small GTPase that is thought to play a crucial role in trafficking of proteins between the endoplasmic reticulum and the Golgi. The P.falciparum SAR1 gene is located on chromosome 4 and comprises two exons separated by a 508 bp intron. The deduced amino acid sequence of PfSar1p (GenBank accession number AF104306) shows 71% similarity (58% identity) to Sar1p from Saccharomyces cerevisiae. Expression of PfSar1p in erythrocytic stages of P. falciparum was confirmed by sequencing of a tryptic peptide derived from a polypeptide excised from an SDS-polyacrylamide gel. A recombinant protein corresponding to approximately 70% of the PfSar1p sequence was used to raise antibodies. The affinity-purified antiserum recognised a protein with an apparent molecular weight of 23 K in Western blots of malaria-infected erythrocytes but not in uninfected erythrocytes. PfSar1p was shown to be largely insoluble in non-ionic detergent and a low ionic strength buffer. Confocal immunofluorescence microscopy of malaria-infected erythrocytes was used to show that PfSar1p is located near the periphery of the parasite in discrete compartments, which appear to be distinct from the parasite endoplasmic reticulum. In addition, PfSar1p appears to be exported to structures outside the parasite in the erythrocyte cytoplasm. The export of PfSar1p to the erythrocyte cytosol is inhibited by treatment with brefeldin A. This provides the first evidence that the malaria parasite is capable of elaborating components of the classical vesicle-mediated trafficking machinery outside the boundaries of its own plasma membrane.
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PMID:A homologue of Sar1p localises to a novel trafficking pathway in malaria-infected erythrocytes. 1047 98


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