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Experimental Parasitology Aug 1989Sequestration of Plasmodium falciparum-infected erythrocytes is crucial to parasite survival as it prevents destruction in the liver and spleen. Knobs have been...
Sequestration of Plasmodium falciparum-infected erythrocytes is crucial to parasite survival as it prevents destruction in the liver and spleen. Knobs have been considered necessary but not sufficient for cytoadherence to vascular endothelial cells in vivo and to melanoma or umbilical vein endothelial cells in vitro. We describe here a knobless clone that cytoadheres strongly to C32 melanoma cells. This clone cannot express the knob-associated histidine-rich protein (KAHRP) due to the deletion of the KAHRP gene. Our results raise the possibility of an alternative mechanism for in vitro cytoadherence and suggest that the use of long term cultured isolates and melanoma cells as a model for cytoadherence in vivo may be misleading.
Topics: Animals; Cell Adhesion; Chromosome Deletion; Humans; Peptides; Plasmodium falciparum; Protozoan Proteins
PubMed: 2666153
DOI: 10.1016/0014-4894(89)90187-2 -
Experimental Parasitology Oct 2001
Topics: Animals; Dose-Response Relationship, Radiation; Hypoxanthine; Plasmodium falciparum; Species Specificity
PubMed: 11748965
DOI: 10.1006/expr.2001.4649 -
Analysis of malaria parasite phenotypes using experimental genetic crosses of Plasmodium falciparum.International Journal For Parasitology May 2012We review the principles of linkage analysis of experimental genetic crosses and their application to Plasmodium falciparum. Three experimental genetic crosses have been... (Review)
Review
We review the principles of linkage analysis of experimental genetic crosses and their application to Plasmodium falciparum. Three experimental genetic crosses have been performed using the human malaria parasite P. falciparum. Linkage analysis of the progeny of these crosses has been used to identify parasite genes important in phenotypes such as drug resistance, parasite growth and virulence, and transmission to mosquitoes. The construction and analysis of genetic maps has been used to characterise recombination rates across the parasite genome and to identify hotspots of recombination.
Topics: Animals; Antimalarials; Crosses, Genetic; Culicidae; Drug Resistance; Genetic Linkage; Genotype; Humans; Phenotype; Plasmodium falciparum; Virulence
PubMed: 22475816
DOI: 10.1016/j.ijpara.2012.03.004 -
Malaria Journal Aug 2021Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible...
BACKGROUND
Plasmodium falciparum is an obligate intracellular parasite of humans that causes malaria. Falciparum malaria is a major public health threat to human life responsible for high mortality. Currently, the risk of multi-drug resistance of P. falciparum is rapidly increasing. There is a need to address new anti-malarial therapeutics strategies to combat the drug-resistance threat.
METHODS
The P. falciparum essential proteins were retrieved from the recently published studies. These proteins were initially scanned against human host and its gut microbiome proteome sets by comparative proteomics analyses. The human host non-homologs essential proteins of P. falciparum were additionally analysed for druggability potential via in silico methods to possibly identify novel therapeutic targets. Finally, the PfAp4AH target was prioritized for pharmacophore modelling based virtual screening and molecular docking analyses to identify potent inhibitors from drug-like compounds databases.
RESULTS
The analyses identified six P. falciparum essential and human host non-homolog proteins that follow the key druggability features. These druggable targets have not been catalogued so far in the Drugbank repository. These prioritized proteins seem novel and promising drug targets against P. falciparum due to their key protein-protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets. The pharmacophore features based virtual screening of Pharmit resource predicted a lead compound i.e. MolPort-045-917-542 as a promising inhibitor of PfAp4AH among prioritized targets.
CONCLUSION
The prioritized protein targets may worthy to test in malarial drug discovery programme to overcome the anti-malarial resistance issues. The in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.
Topics: Drug Delivery Systems; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum; Protein Conformation; Protein Interaction Domains and Motifs; Protozoan Proteins; Virulence Factors
PubMed: 34344361
DOI: 10.1186/s12936-021-03865-1 -
Malaria Journal Jun 2016Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in...
BACKGROUND
Western Cambodia is recognized as the epicentre of emergence of Plasmodium falciparum multi-drug resistance. The emergence of artemisinin resistance has been observed in this area since 2008-2009 and molecular signatures associated to artemisinin resistance have been characterized in k13 gene. At present, one of the major threats faced, is the possible spread of Asian artemisinin resistant parasites over the world threatening millions of people and jeopardizing malaria elimination programme efforts. To anticipate the diffusion of artemisinin resistance, the identification of the P. falciparum population structure and the gene flow among the parasite population in Cambodia are essential.
METHODS
To this end, a mid-throughput PCR-LDR-FMA approach based on LUMINEX technology was developed to screen for genetic barcode in 533 blood samples collected in 2010-2011 from 16 health centres in malaria endemics areas in Cambodia.
RESULTS
Based on successful typing of 282 samples, subpopulations were characterized along the borders of the country. Each 11-loci barcode provides evidence supporting allele distribution gradient related to subpopulations and gene flow. The 11-loci barcode successfully identifies recently emerging parasite subpopulations in western Cambodia that are associated with the C580Y dominant allele for artemisinin resistance in k13 gene. A subpopulation was identified in northern Cambodia that was associated to artemisinin (R539T resistant allele of k13 gene) and mefloquine resistance.
CONCLUSIONS
The gene flow between these subpopulations might have driven the spread of artemisinin resistance over Cambodia.
Topics: Antimalarials; Cambodia; DNA Barcoding, Taxonomic; Drug Resistance; Gene Flow; Genetic Variation; Genotype; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 27301553
DOI: 10.1186/s12936-016-1370-y -
Molecular and Biochemical Parasitology Jul 2001The surface of the erythrocyte undergoes a number of modifications during infection by Plasmodium falciparum. These modifications are critical for pathogenesis of severe... (Review)
Review
The surface of the erythrocyte undergoes a number of modifications during infection by Plasmodium falciparum. These modifications are critical for pathogenesis of severe disease and the acquisition of host immunity through their role in interactions between the host and the parasite and in antigenic variation. Our knowledge of the molecular basis for these processes has increased dramatically over the last few years, through a combination of genomic and biochemical studies. This review provides a summary of the molecules involved in cytoadherence and antigenic variation in P. falciparum.
Topics: Animals; Antigenic Variation; Cell Adhesion; Erythrocytes; Humans; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins
PubMed: 11420100
DOI: 10.1016/s0166-6851(01)00275-4 -
Malaria Journal Mar 2019The malarial parasite Plasmodium falciparum is an auxotroph for purines, which are required for nucleic acid synthesis during the intra-erythrocytic developmental cycle...
BACKGROUND
The malarial parasite Plasmodium falciparum is an auxotroph for purines, which are required for nucleic acid synthesis during the intra-erythrocytic developmental cycle (IDC) of the parasite. The capabilities of the parasite and extent to which it can use compensatory mechanisms to adapt to purine deprivation were studied by examining changes in its metabolism under sub-optimal concentrations of hypoxanthine, the primary precursor utilized by the parasite for purine-based nucleic acid synthesis.
METHODS
The concentration of hypoxanthine that caused a moderate growth defect over the course of one IDC was determined. At this concentration of hypoxanthine (0.5 μM), transcriptomic and metabolomic data were collected during one IDC at multiple time points. These data were integrated with a metabolic network model of the parasite embedded in a red blood cell (RBC) to interpret the metabolic adaptation of P. falciparum to hypoxanthine deprivation.
RESULTS
At a hypoxanthine concentration of 0.5 μM, vacuole-like structures in the cytosol of many P. falciparum parasites were observed after the 24-h midpoint of the IDC. Parasites grown under these conditions experienced a slowdown in the progression of the IDC. After 72 h of deprivation, the parasite growth could not be recovered despite supplementation with 90 µM hypoxanthine. Simulations of P. falciparum metabolism suggested that alterations in ubiquinone, isoprenoid, shikimate, and mitochondrial metabolism occurred before the appearance of these vacuole-like structures. Alterations were found in metabolic reactions associated with fatty acid synthesis, the pentose phosphate pathway, methionine metabolism, and coenzyme A synthesis in the latter half of the IDC. Furthermore, gene set enrichment analysis revealed that P. falciparum activated genes associated with rosette formation, Maurer's cleft and protein export under two different nutrient-deprivation conditions (hypoxanthine and isoleucine).
CONCLUSIONS
The metabolic network analysis presented here suggests that P. falciparum invokes specific purine-recycling pathways to compensate for hypoxanthine deprivation and maintains a hypoxanthine pool for purine-based nucleic acid synthesis. However, this compensatory mechanism is not sufficient to maintain long-term viability of the parasite. Although P. falciparum can complete a full IDC in low hypoxanthine conditions, subsequent cycles are disrupted.
Topics: Adaptation, Physiological; Animals; Gene Expression Profiling; Hypoxanthine; Metabolic Networks and Pathways; Metabolomics; Plasmodium falciparum; Survival; Time Factors
PubMed: 30890151
DOI: 10.1186/s12936-019-2720-3 -
Memorias Do Instituto Oswaldo Cruz Jul 2018The biochemical pathways involved in nicotinamide adenine dinucleotide (NAD) biosynthesis converge at the enzymatic step catalysed by nicotinamide mononucleotide...
The biochemical pathways involved in nicotinamide adenine dinucleotide (NAD) biosynthesis converge at the enzymatic step catalysed by nicotinamide mononucleotide adenylyltransferase (NMNAT, EC: 2.7.7.1). The majority of NMNATs are assembled into homo-oligomeric states that comprise 2-6 subunits. Recently, the NMNAT of Plasmodium falciparum (PfNMNAT) has been identified as a pharmacological target. The enzymatic characterisation, cellular location, and tertiary structure of the PfNMNAT protein have been reported. Nonetheless, its quaternary structure remains to be explored. The present study describes the oligomeric assembly of the 6 x His-PfNMNAT recombinant protein using immobilised metal affinity chromatography coupled with size exclusion chromatography (SEC) and native protein electrophoresis combined with Ferguson plot graphing. These chromatographic approaches resulted in the elution of an active monomer from the SEC column, whereas the Ferguson plot indicated a dimeric assembly of the 6 x His-PfNMNAT protein.
Topics: Chromatography, Affinity; Nicotinamide-Nucleotide Adenylyltransferase; Plasmodium falciparum
PubMed: 29995110
DOI: 10.1590/0074-02760180073 -
Trends in Parasitology May 2008Carbohydrate structures that decorate the surface of cells are increasingly recognized as playing important roles in the biology of host-pathogen interactions.... (Review)
Review
Carbohydrate structures that decorate the surface of cells are increasingly recognized as playing important roles in the biology of host-pathogen interactions. Plasmodium species have undergone a process of gene loss that has removed much of their capacity to produce complex glycoconjugates or glycosylated proteins other than the glycosylphosphatidyinositol (GPI) moiety that anchors the surface proteins of infective stages, including the merozoite. Instead, these parasites have elaborated a set of proteins with lectin-like properties that interact with mammalian and insect cell surfaces. An overview of this and other aspects of the glycobiology of Plasmodium is presented here.
Topics: Animals; Carbohydrate Sequence; Genome, Protozoan; Glycosylphosphatidylinositols; Malaria; Models, Molecular; Molecular Sequence Data; Plasmodium falciparum; Protozoan Proteins
PubMed: 18420458
DOI: 10.1016/j.pt.2008.02.007 -
Parasitology Research Oct 2019Plasmodium falciparum (Pf) refurbishes the infected erythrocytes by exporting a myriad of parasite proteins to the host cell. A novel exported protein family 'Plasmodium... (Review)
Review
Plasmodium falciparum (Pf) refurbishes the infected erythrocytes by exporting a myriad of parasite proteins to the host cell. A novel exported protein family 'Plasmodium Helical Interspersed Subtelomeric' (PHIST) has gained attention for its significant roles in parasite biology. Here, we have collected and analysed available information on PHIST members to enhance understanding of their functions, varied localization and structure-function correlation. Functional diversity of PHIST proteins is highlighted by their involvement in PfEMP1 (Pf erythrocyte membrane protein 1) expression, trafficking and switching. This family also contributes to cytoadherence, gametocytogenesis, host cell modification and generation of extracellular vesicles. While the PHIST domain forms the hallmark of this family, existence and functions of additional domains (LyMP, TIGR01639) and the MEC motif underscores its diversity further. Since specific PHIST proteins seem to form pairs with PfEMP1 members, we have used in silico tools to predict such potential partners in Pf. This information and our analysis of structural data on a PHIST member provide important insights into their functioning. This review overall enables readers to view the PHIST family comprehensively, while highlighting key knowledge gaps in the field.
Topics: Animals; Erythrocytes; Humans; Malaria, Falciparum; Multigene Family; Plasmodium falciparum; Protein Transport; Protozoan Proteins
PubMed: 31418110
DOI: 10.1007/s00436-019-06420-9