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Trends in Parasitology Apr 2016A highly-effective, long-lasting vaccine, targeting multiple stages of the Plasmodium falciparum life cycle, is likely to be important for the elimination of this... (Review)
Review
A highly-effective, long-lasting vaccine, targeting multiple stages of the Plasmodium falciparum life cycle, is likely to be important for the elimination of this pathogen. Key antigens of this vaccine would produce host antibodies that block the ligands required for merozoite invasion of erythrocytes, thereby curtailing the expansion of parasitemia and symptomatic disease. Recent live cell imaging of invading Plasmodium falciparum merozoites with various receptor-ligand interactions inhibited has provided new information about the function, sequence, and timing of these events, providing a rationale for a vaccine containing multiple antigens that inhibit the sequential steps of invasion.
Topics: Erythrocytes; Humans; Life Cycle Stages; Ligands; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins
PubMed: 26778295
DOI: 10.1016/j.pt.2015.12.007 -
Malaria Journal Dec 2019Malaria continues to be endemic in the coast and Amazon regions of Ecuador. Clarifying current Plasmodium falciparum resistance in the country will support malaria...
BACKGROUND
Malaria continues to be endemic in the coast and Amazon regions of Ecuador. Clarifying current Plasmodium falciparum resistance in the country will support malaria elimination efforts. In this study, Ecuadorian P. falciparum parasites were analysed to determine their drug resistance genotypes and phenotypes.
METHODS
Molecular analyses were performed to search for mutations in known resistance markers (Pfcrt, Pfdhfr, Pfdhps, Pfmdr1, k13). Pfmdr1 copy number was determined by qPCR. PFMDR1 transporter activity was characterized in live parasites using live cell imaging in combination with the Fluo-4 transport assay. Chloroquine, quinine, lumefantrine, mefloquine, dihydroartemisinin, and artemether sensitivities were measured by in vitro assays.
RESULTS
The majority of samples from this study presented the CVMNT genotype for Pfcrt (72-26), NEDF SDFD mutations in Pfmdr1 and wild type genotypes for Pfdhfr, Pfdhps and k13. The Ecuadorian P. falciparum strain ESM-2013 showed in vitro resistance to chloroquine, but sensitivity to quinine, lumefantrine, mefloquine, dihydroartemisinin and artemether. In addition, transport of the fluorochrome Fluo-4 from the cytosol into the digestive vacuole (DV) of the ESM-2013 strain was minimally detected in the DV. All analysed samples revealed one copy of Pfmdr1.
CONCLUSION
This study indicates that Ecuadorian parasites presented the genotype and phenotype for chloroquine resistance and were found to be sensitive to SP, artemether-lumefantrine, quinine, mefloquine, and dihydroartemisinin. The results suggest that the current malaria treatment employed in the country remains effective. This study clarifies the status of anti-malarial resistance in Ecuador and informs the P. falciparum elimination campaigns in the country.
Topics: Antimalarials; Drug Resistance; Ecuador; Genotype; Humans; Malaria, Falciparum; Parasitic Sensitivity Tests; Phenotype; Plasmodium falciparum; Protozoan Proteins
PubMed: 31822269
DOI: 10.1186/s12936-019-3044-z -
Current Protein & Peptide Science 2016Malaria, a deadly infectious parasitic disease, is a major issue of public health in the world today and already produces serious economic constraints in the endemic... (Review)
Review
Malaria, a deadly infectious parasitic disease, is a major issue of public health in the world today and already produces serious economic constraints in the endemic countries. Most of the malarial infections and deaths are due to Plasmodium falciparum and Plasmodium vivax species. The recent emergence of resistance necessitates the search for new antimalarial drugs, which overcome the resistance and act through new mechanisms. Although much effort has been directed towards the discovery of novel antimalarial drugs. 4-anilino quinolone triazines as potent antimalarial agents, their in silico modelling and bioevaluation as Plasmodium falciparum transketolase and β-hematin inhibitors has been reported. This review is primarily focused on the drug discovery of the recent advances in the development of antimalarial agents and their mechanism of action.
Topics: Animals; Antimalarials; Drug Discovery; Humans; Plasmodium falciparum
PubMed: 26796302
DOI: 10.2174/1389203717999160226180543 -
Indian Journal of Medical Microbiology 2020Prohibitins (PHBs) are evolutionarily conserved mitochondrial integral membrane proteins, shown to regulate mitochondrial structure and function, and can be classified...
Prohibitins (PHBs) are evolutionarily conserved mitochondrial integral membrane proteins, shown to regulate mitochondrial structure and function, and can be classified into PHB1 and PHB2. PHB1 and PHB2 have been shown to interact with each other, and form heterodimers in mitochondrial inner membrane. Plasmodium falciparum has orthologues of PHB1 and PHB2 in its genome, and their role is unclear. Here, by homology modelling and yeast two-hybrid analysis, we show that putative Plasmodium PHBs (Pf PHB1 and Pf PHB2) interact with each other, which suggests that they could form supercomplexes of heterodimers in Plasmodium, the functional form required for optimum mitochondrial function.
Topics: Membrane Proteins; Mitochondria; Models, Molecular; Plasmodium falciparum; Prohibitins; Protein Conformation; Protein Multimerization; Protozoan Proteins; Repressor Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Two-Hybrid System Techniques
PubMed: 32883936
DOI: 10.4103/ijmm.IJMM_20_28 -
Translational Research : the Journal of... Aug 2018The proteasome plays a vital role throughout the life cycle as Plasmodium parasites quickly adapt to a new host and undergo a series of morphologic changes during... (Review)
Review
The proteasome plays a vital role throughout the life cycle as Plasmodium parasites quickly adapt to a new host and undergo a series of morphologic changes during asexual replication and sexual differentiation. Plasmodium carries 3 different types of protease complexes: typical eukaryotic proteasome (26S) that resides in the cytoplasm and the nucleus, a prokaryotic proteasome homolog ClpQ that resides in the mitochondria, and a caseinolytic protease complex ClpP that resides in the apicoplast. In silico prediction in conjunction with immunoprecipitation analysis of ubiquitin conjugates have suggested that over half of the Plasmodium falciparum proteome during asexual reproduction are potential targets for ubiquitination. The marked potency of multiple classes of proteasome inhibitors against all stages of the life cycle, synergy with the current frontline antimalarial, artemisinin, and recent advances identifying differences between Plasmodium and human proteasomes strongly support further drug development efforts.
Topics: Animals; Antimalarials; Humans; Life Cycle Stages; Malaria, Falciparum; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Reproduction, Asexual
PubMed: 30009761
DOI: 10.1016/j.trsl.2018.04.007 -
Cell Host & Microbe Dec 2021Amino acid deprivation from reduced hemoglobin degradation in Pfkelch13 artemisinin-resistant parasites reduces fitness. In this issue of Cell Host & Microbe,...
Amino acid deprivation from reduced hemoglobin degradation in Pfkelch13 artemisinin-resistant parasites reduces fitness. In this issue of Cell Host & Microbe, Mesén-Ramírez et al. decipher the role of nutrient permeable channel activity within the parasitophorous vacuolar membrane to compensate for this fitness cost in asexual blood-stage Plasmodium falciparum parasites.
Topics: Antimalarials; Artemisinins; Drug Resistance; Mutation; Plasmodium falciparum; Protozoan Proteins
PubMed: 34883062
DOI: 10.1016/j.chom.2021.11.007 -
Genetics Aug 2019Understanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology...
Understanding the relatedness of individuals within or between populations is a common goal in biology. Increasingly, relatedness features in genetic epidemiology studies of pathogens. These studies are relatively new compared to those in humans and other organisms, but are important for designing interventions and understanding pathogen transmission. Only recently have researchers begun to routinely apply relatedness to apicomplexan eukaryotic malaria parasites, and to date have used a range of different approaches on an basis. Therefore, it remains unclear how to compare different studies and which measures to use. Here, we systematically compare measures based on identity-by-state (IBS) and identity-by-descent (IBD) using a globally diverse data set of malaria parasites, and , and provide marker requirements for estimates based on IBD. We formally show that the informativeness of polyallelic markers for relatedness inference is maximized when alleles are equifrequent. Estimates based on IBS are sensitive to allele frequencies, which vary across populations and by experimental design. For portability across studies, we thus recommend estimates based on IBD. To generate estimates with errors below an arbitrary threshold of 0.1, we recommend ∼100 polyallelic or 200 biallelic markers. Marker requirements are immediately applicable to haploid malaria parasites and other haploid eukaryotes. C.I.s facilitate comparison when different marker sets are used. This is the first attempt to provide rigorous analysis of the reliability of, and requirements for, relatedness inference in malaria genetic epidemiology. We hope it will provide a basis for statistically informed prospective study design and surveillance strategies.
Topics: Genome, Protozoan; Models, Genetic; Pedigree; Phylogeny; Plasmodium falciparum; Plasmodium vivax; Polymorphism, Single Nucleotide
PubMed: 31209105
DOI: 10.1534/genetics.119.302120 -
Chembiochem : a European Journal of... May 2019The protozoan parasite Plasmodium has evolved to survive in different hosts and environments. The diverse strategies of adaptation to different niches involve... (Review)
Review
The protozoan parasite Plasmodium has evolved to survive in different hosts and environments. The diverse strategies of adaptation to different niches involve differential gene expression mechanisms mediated by chromatin plasticity that are poorly characterized in Plasmodium. The parasite employs a wide variety of regulatory mechanisms to complete their life cycle and survive inside hosts. Among them, epigenetic-mediated mechanisms have been implicated for controlling chromatin organization, gene regulation, morphological differentiation, and antigenic variation. The differential gene expression in parasite is largely dependent on the nature of the chromatin structure. The histone core methylation marks and methyl mark readers contribute to chromatin dynamics. Here, we review the recent developments on various epigenetic marks and its enzymes in the Plasmodium falciparum, how these marks play a key role in the regulation of transcriptional activity of variable genes and coordinate the differential gene expression. We also discuss the possible roles of these epigenetic marks in chromatin structure regulation and plasticity at various stages of its development.
Topics: Chromatin; Epigenesis, Genetic; Gene Expression Regulation; Genome, Protozoan; Histones; Methylation; Plasmodium falciparum; Protozoan Proteins
PubMed: 30632244
DOI: 10.1002/cbic.201800718 -
PLoS Pathogens Jun 2020New techniques for obtaining electron microscopy data through the cell volume are being increasingly utilized to answer cell biologic questions. Here, we present a...
New techniques for obtaining electron microscopy data through the cell volume are being increasingly utilized to answer cell biologic questions. Here, we present a three-dimensional atlas of Plasmodium falciparum ultrastructure throughout parasite cell division. Multiple wild type schizonts at different stages of segmentation, or budding, were imaged and rendered, and the 3D structure of their organelles and daughter cells are shown. Our high-resolution volume electron microscopy both confirms previously described features in 3D and adds new layers to our understanding of Plasmodium nuclear division. Interestingly, we demonstrate asynchrony of the final nuclear division, a process that had previously been reported as synchronous. Use of volume electron microscopy techniques for biological imaging is gaining prominence, and there is much we can learn from applying them to answer questions about Plasmodium cell biology. We provide this resource to encourage readers to consider adding these techniques to their cell biology toolbox.
Topics: Cytokinesis; Humans; Plasmodium falciparum
PubMed: 32511279
DOI: 10.1371/journal.ppat.1008587 -
Malaria Journal Jun 2019The intensification of malaria control interventions has resulted in its global decline, but it remains a significant public health burden especially in sub-Saharan... (Review)
Review
The intensification of malaria control interventions has resulted in its global decline, but it remains a significant public health burden especially in sub-Saharan Africa (sSA). Knowledge on the parasite diversity, its transmission dynamics, mechanisms of adaptation to environmental and interventional pressures could help refine or develop new control and elimination strategies. Critical to this is the accurate assessment of the parasite's genetic diversity and monitoring of genetic markers of anti-malarial resistance across all susceptible populations. Such wide molecular surveillance will require selected tools and approaches from a variety of ever evolving advancements in technology and the changing epidemiology of malaria. The choice of an effective approach for specific endemic settings remains challenging, particularly for countries in sSA with limited access to advanced technologies. This article examines the current strategies and tools for Plasmodium falciparum genetic diversity typing and resistance monitoring and proposes how the different tools could be employed in resource-poor settings. Advanced approaches enabling targeted deep sequencing is valued as a sensitive method for assessing drug resistance and parasite diversity but remains out of the reach of most laboratories in sSA due to the high cost of development and maintenance. It is, however, feasible to equip a limited number of laboratories as Centres of Excellence in Africa (CEA), which will receive and process samples from a network of peripheral laboratories in the continent. Cheaper, sensitive and portable real-time PCR methods can be used in peripheral laboratories to pre-screen and select samples for targeted deep sequence or genome wide analyses at these CEAs.
Topics: Africa South of the Sahara; Antimalarials; Disease Eradication; Drug Resistance; Genetic Variation; Humans; Malaria, Falciparum; Plasmodium falciparum
PubMed: 31242921
DOI: 10.1186/s12936-019-2844-5