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

During intraerythrocytic development, the human malaria parasite, Plasmodium falciparum, establishes membrane-bound compartments, known as Maurer's clefts, outside the confines of its own plasma membrane. The Maurer's compartments are thought to be a crucial component of the machinery for protein sorting and trafficking; however, their ultrastructure is only partly defined. We have used electron tomography to image Maurer's clefts of 3D7 strain parasites. The compartments are revealed as flattened structures with a translucent lumen and a more electron-dense coat. They display a complex and convoluted morphology, and some regions are modified with surface nodules, each with a circular cross-section of approximately 25 nm. Individual 25 nm vesicle-like structures are also seen in the erythrocyte cytoplasm and associated with the red blood cell membrane. The Maurer's clefts are connected to the red blood cell membrane by regions with extended stalk-like profiles. Immunogold labelling with specific antibodies confirms differential labelling of the Maurer's clefts and the parasitophorous vacuole and erythrocyte membranes. Spot fluorescence photobleaching was used to demonstrate the absence of a lipid continuum between the Maurer's clefts and parasite membranes and the host plasma membrane.
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PMID:Electron tomography of the Maurer's cleft organelles of Plasmodium falciparum-infected erythrocytes reveals novel structural features. 1817 19

Mice have close genetic/physiological relationships to humans, breed rapidly, and can be genetically modified, making them the most used mammal in biomedical research. Because the red blood cell (RBC) is the sole gas transporter in vertebrates, diseases of the RBC are frequently severe; much research has therefore focused on RBC and cardiovascular disorders of mouse and humans. RBCs also host malaria parasites. Recently we presented an in-depth proteome for the human RBC. Here we present directly comparable data for the mouse RBC as membrane-only, soluble-only, and combined membrane-bound/soluble proteomes (comprising, respectively, 247, 232, and 165 proteins). All proteins were identified, validated, and categorized in terms of subcellular localization, protein family, and function, and in comparison with the human RBC, were classified as orthologs, family-related, or unique. Splice isoforms were identified, and polypeptides migrating with anomalous apparent molecular weights were grouped into putatively ubiquitinated or partially degraded complexes. Overall there was close concordance between mouse and human proteomes, confirming the unexpected RBC complexity. Several novel findings in the human proteome have been confirmed here. This comparison sheds light on several open issues in RBC biology and provides a departure point for more comprehensive understanding of RBC function.
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PMID:Deep coverage mouse red blood cell proteome: a first comparison with the human red blood cell. 1834 33

ATP-binding cassette transporters play an important role in drug resistance and nutrient transport. In the human malaria parasite Plasmodium falciparum, a homolog of the human p-glycoprotein (PfPgh-1) was shown to be involved in resistance to several drugs. More recently, many transporters were associated with higher IC(50) levels in responses to chloroquine (CQ) and quinine (QN) in field isolates. Subsequent studies, however, could not confirm the associations, although inaccuracy in drug tests in the later studies could contribute to the lack of associations. Here we disrupted a gene encoding a putative multidrug resistance-associated protein (PfMRP) that was previously shown to be associated with P. falciparum responses to CQ and QN. Parasites with disrupted PfMRP (W2/MRPDelta) could not grow to a parasitemia higher than 5% under normal culture conditions, possibly because of lower efficiency in removing toxic metabolites. The W2/MRPDelta parasite also accumulated more radioactive glutathione, CQ, and QN and became more sensitive to multiple antimalarial drugs, including CQ, QN, artemisinin, piperaquine, and primaquine. PfMRP was localized on the parasite surface membrane, within membrane-bound vesicles, and along the straight side of the D-shaped stage II gametocytes. The results suggest that PfMRP plays a role in the efflux of glutathione, CQ, and QN and contributes to parasite responses to multiple antimalarial drugs, possibly by pumping drugs outside the parasite.
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PMID:Disruption of a Plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione. 1911 44

Type II NADH: quinone oxidoreductases (ndh) are flavoenzymes found in a broad range of organisms including plants, fungi, protozoa, and bacteria. The ndh enzymes catalyze the oxidation of NADH with concomitant reduction of quinone (Q). These membrane-bound respiratory enzymes differ from the canonical NADH: dehydrogenase (complex I), because they are not involved in the vectorial transfer of protons across membranes. In Plasmodium falciparum and Mycobacterium tuberculosis, causative agents of malaria and tuberculosis, respectively, ndhs have aroused interest because of the essential role played in maintaining a reduced Q-pool during infection. In this chapter, we present methods for the measurement of steady-state parameters for ndhs from both pathogens, highlighting best practices and caveats. In addition, owing to the interest in ndhs as potential chemotherapeutic targets, we describe a miniaturized endpoint assay that is validated for high-throughput screening (HTS) of chemical libraries.
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PMID:Chapter 17 Type II NADH: quinone oxidoreductases of Plasmodium falciparum and Mycobacterium tuberculosis kinetic and high-throughput assays. 1934 96

Research relating to host inflammatory processes during malaria infection has focused on Toll-like receptors, membrane-bound receptors implicated in innate sensing, and phagocytosis of parasitized erythrocytes by host cells. This is the first study to examine the role of Nod proteins, members of the Nod-like receptor (NLR) family of cytoplasmic proteins involved in pathogen recognition, in a murine model of cerebral malaria (Plasmodium berghei ANKA, PbA). Here, we find that nod1nod2(-/-) mice infected with PbA show no difference in survival or parasitemia compared with wild-type infected animals. However, cytokine levels, notably those associated with NLR activation including interleukin (IL)1-beta, KC, and MCP-1, and proteins linked to malaria pathogenesis, such as interferon-gamma (IFN-gamma), were decreased in the nod-1nod2(-/-) animals. We therefore demonstrate for the first time that Nod proteins are activated in response to parasites, and they play a role in regulating host inflammatory responses during malaria infection.
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PMID:Disruption of Nod-like receptors alters inflammatory response to infection but does not confer protection in experimental cerebral malaria. 1940 12

Mosquito larvae use a digestive strategy that is relatively rare in nature. The anterior half of the larval mosquito midgut has a luminal pH that ranges between 10.5 and 11.5. Most other organisms, both large and small, initiate digestion in an acid medium. The relative uniqueness of the highly alkaline digestive strategy has been a long-standing research focus in larval lepidopterans. More recently, the disease vector potential of mosquitoes has fueled specific interest in larval mosquito biology and the alkaline digestive environment in the midgut. The probable principle anion influencing the highly alkaline gut lumen is bicarbonate/carbonate. Bicarbonate/carbonate is regulated at least in part by the activity of carbonic anhydrases. Hence, we have focused attention on the carbonic anhydrases of the mosquito larva. Anopheles gambiae, the major malaria mosquito of Africa, is an organism with a published genome which has facilitated molecular analyses of the 12 carbonic anhydrase genes annotated for this mosquito. Microarray expression analyses, tissue-specific quantitative RT-PCR, and antibody localization have been used to generate a picture of carbonic anhydrase distribution in the larval mosquito. Cytoplasmic, GPI-linked extracellular membrane-bound and soluble extracellular carbonic anhydrases have been located in the midgut and hindgut. The distribution of the enzymes is consistent with an anion regulatory system in which carbonic anhydrases provide a continuous source of bicarbonate/carbonate from the intracellular compartments of certain epithelial cells to the ectoperitrophic space between the epithelial cells and the acellular membrane separating the food bolus from the gut cells and finally into the gut lumen. Carbonic anhydrase in specialized cells of the hindgut (rectum) probably plays a final role in excretion of bicarbonate/carbonate into the aquatic environment of the larva. Detection and characterization of classic anion exchangers of the SLC4A family in the midgut has been problematic. The distribution of carbonic anhydrases in the system may obviate the requirement for such transporters, making the system more dependent on simple carbon dioxide diffusion and ionization via the activity of the enzyme.
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PMID:Carbonic anhydrases and anion transport in mosquito midgut pH regulation. 1944 76

The Apicomplexan parasite responsible for the most virulent form of malaria, Plasmodium falciparum, invades human erythrocytes through multiple ligand-receptor interactions. The P. falciparum reticulocyte-binding protein homologue (PfRh or PfRBL) family have been implicated in the invasion process but their exact role is unknown. PfRh1 and PfRh4, members of this protein family, bind to red blood cells and function in merozoite invasion during which they undergo a series of proteolytic cleavage events before and during entry into the host cell. The ectodomain of PfRh1 and PfRh4 are processed to produce fragments consistent with cleavage in the transmembrane domain and released into the supernatant, at about the time of invasion, in a manner consistent with rhomboid protease cleavage. Processing of both PfRh1 and PfRh4, and by extrapolation all membrane-bound members of this protein family, is important for function and release of these proteins on the merozoite surface and they along with EBA-175 are important components of the tight junction, the transient structure that links the erythrocyte via receptor-ligand interactions to the actin-myosin motor in the invading merozoite.
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PMID:Reticulocyte binding protein homologues are key adhesins during erythrocyte invasion by Plasmodium falciparum. 1961 65

In Plasmodium falciparum-infected red blood cells (RBCs), the flavoenzyme glutathione reductase (GR) regenerates reduced glutathione, which is essential for antioxidant defense. GR utilizes NADPH produced in the pentose phosphate shunt by glucose-6-phosphate dehydrogenase (G6PD). Thus, conditions affecting host G6PD or GR induce increased sensitivity to oxidants. Hereditary G6PD deficiency is frequent in malaria endemic areas and provides protection against severe malaria. Furthermore, GR deficiency resulting from insufficient saturation of the enzyme with its prosthetic group FAD is common. Based on these naturally occurring phenomena, GR of malaria parasites and their host cells represent attractive antimalarial drug targets. Recently we were given the opportunity to examine invasion, growth, and drug sensitivity of three P. falciparum strains (3D7, K1, and Palo Alto) in the RBCs from three homozygous individuals with total GR deficiency resulting from mutations in the apoprotein. Invasion or growth in the GR-deficient RBCs was not impaired for any of the parasite strains tested. Drug sensitivity to chloroquine, artemisinin, and methylene blue was comparable to parasites grown in GR-sufficient RBCs and sensitivity towards paraquat and sodium nitroprusside was only slightly enhanced. In contrast, membrane deposition of hemichromes as well as the opsonizing complement C3b fragments and phagocytosis were strongly increased in ring-infected RBCs of the GR-deficient individuals compared to ring-infected normal RBCs. Also, in one of the individuals, membrane-bound autologous IgGs were significantly enhanced. Thus, based on our in vitro data, GR deficiency and drug-induced GR inhibition may protect from malaria by inducing enhanced ring stage phagocytosis rather than by impairing parasite growth directly.
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PMID:Inherited glutathione reductase deficiency and Plasmodium falciparum malaria--a case study. 1980 91

The importance of innate immunity in malaria has been suggested for early protection from maturation and multiplication of Plasmodium parasites injected via infected mosquitoes. In this study, the killer cell immunoglobulin-like receptor (KIR) genes in innate immunity were investigated for an association with malaria in the comparison between Plasmodium-positive and Plasmodium-negative Melanesian individuals in the Solomon Islands, one of the most hyperendemic malaria regions in the world. The higher frequency of a pair of KIR3DL1 and KIR2DS4 was observed in the Plasmodium-positive individuals, which led to the investigation of KIR3DL1/S1 genotypes in concert with KIR2DS4 allelic variants. The positive individuals showed the highest frequency of KIR3DL1/KIR3DS1 heterozygosity, which might suggest the masking of activating KIR3DS1 by inhibitory KIR3DL1 at allelic levels to maintain the KIR3DS1-driven activation of natural killer cells diminished in controlling Plasmodium proliferation. The extended analysis with A/B genotypes further revealed the trend of parasitic positive individuals to be KIR3DL1/KIR3DS1 heterozygous in pair with KIR2DS4 nondeleted variants in a set of KIR genes inheritable as the AB genotypes. To the best of our knowledge, this study is the first KIR investigation of the malaria-infected population, which strengthened the potential associations of KIR with malaria pathogenesis. The balance of inhibitory and activating KIR3D genes (KIR3DL1/S1) and membrane-bound or secreted status of KIR2DS4 alleles in the interaction with the other KIR genes in the AB genotypes might constitute a part of KIR characteristics to determine resistance or susceptibility to Plasmodium parasitic infection.
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PMID:KIR3DL1/S1 genotypes and KIR2DS4 allelic variants in the AB KIR genotypes are associated with Plasmodium-positive individuals in malaria infection. 1985 4

The liver is the first organ infected by Plasmodium sporozoites during malaria infection. In the infected hepatocytes, sporozoites undergo a complex developmental program to eventually generate hepatic merozoites that are released into the bloodstream in membrane-bound vesicles termed merosomes. Parasites blocked at an early developmental stage inside hepatocytes elicit a protective host immune response, making them attractive targets in the effort to develop a pre-erythrocytic stage vaccine. Here, we generated parasites blocked at a late developmental stage inside hepatocytes by conditionally disrupting the Plasmodium berghei cGMP-dependent protein kinase in sporozoites. Mutant sporozoites are able to invade hepatocytes and undergo intracellular development. However, they remain blocked as late liver stages that do not release merosomes into the medium. These late arrested liver stages induce protection in immunized animals. This suggests that, similar to the well studied early liver stages, late stage liver stages too can confer protection from sporozoite challenge.
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PMID:Role of Plasmodium berghei cGMP-dependent protein kinase in late liver stage development. 1994 Jan 33


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