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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 -
The Korean Journal of Parasitology Apr 2022Drug resistance is an important problem hindering malaria elimination in tropical areas. Point mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and...
Drug resistance is an important problem hindering malaria elimination in tropical areas. Point mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes confer resistance to antifolate drug, sulfadoxine-pyrimethamine (SP) while P. falciparum chloroquine-resistant transporter (Pfcrt) genes caused resistance to chloroquine (CQ). Decline in Pfdhfr/Pfdhps and Pfcrt mutations after withdrawal of SP and CQ has been reported. The aim of present study was to investigate the prevalence of Pfdhfr, Pfdhps, and Pfcrt mutation from 2 endemic areas of Thailand. All of 200 blood samples collected from western area (Thai-Myanmar) and southern area (Thai-Malaysian) contained multiple mutations in Pfdhfr and Pfdhps genes. The most prevalent haplotypes for Pfdhfr and Pfdhps were quadruple and double mutations, respectively. The quadruple and triple mutations of Pfdhfr and Pfdhps were common in western samples, whereas low frequency of triple and double mutations was found in southern samples, respectively. The Pfcrt 76T mutation was present in all samples examined. Malaria isolated from 2 different endemic regions of Thailand had high mutation rates in the Pfdhfr, Pfdhps, and Pfcrt genes. These findings highlighted the fixation of mutant alleles causing resistance of SP and CQ in this area. It is necessary to monitor the re-emergence of SP and CQ sensitive parasites in this area.
Topics: Antimalarials; Chloroquine; Drug Combinations; Drug Resistance; Humans; Malaria, Falciparum; Plasmodium falciparum; Pyrimethamine; Sulfadoxine; Thailand
PubMed: 35500892
DOI: 10.3347/kjp.2022.60.2.109 -
Parasitology Oct 2020Plasmodium falciparum is the main cause of severe malaria in humans that can lead to death. There is growing evidence of drug-resistance in P. falciparum treatment, and... (Review)
Review
Plasmodium falciparum is the main cause of severe malaria in humans that can lead to death. There is growing evidence of drug-resistance in P. falciparum treatment, and the design of effective vaccines remains an ongoing strategy to control the disease. On the other hand, the recognition of specific diagnostic markers for P. falciparum can accelerate the diagnosis of this parasite in the early stages of infection. Therefore, the identification of novel antigenic proteins especially by proteomic tools is urgent for vaccination and diagnosis of P. falciparum. The proteome diversity of the life cycle stages of P. falciparum, the altered proteome of P. falciparum-infected human sera and altered proteins in P. falciparum-infected erythrocytes could be proposed as appropriate proteins for the aforementioned aims. Accordingly, this review highlights and proposes different proteins identified using proteomic approaches as promising markers in the diagnosis and vaccination of P. falciparum. It seems that most of the candidates identified in this study were able to elicit immune responses in the P. falciparum-infected hosts and they also played major roles in the life cycle, pathogenicity and key pathways of this parasite.
Topics: Animals; Antimalarials; Biomarkers; Drug Resistance; Erythrocytes; Genes, Protozoan; Humans; Life Cycle Stages; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Proteome; Proteomics; Protozoan Proteins
PubMed: 32618524
DOI: 10.1017/S003118202000102X -
The American Journal of Tropical... Dec 2019In this review, we provide an epidemiological history of the emergence and ongoing spread of evolving artemisinin resistance (ARTR). Southeast Asia has been the focal... (Review)
Review
In this review, we provide an epidemiological history of the emergence and ongoing spread of evolving artemisinin resistance (ARTR). Southeast Asia has been the focal point for emergence and spread of multiple antimalarial drug resistance phenomena, and is once again for evolving ARTR, also known as the "delayed clearance phenotype" (DCP). The five countries most impacted, Cambodia, Thailand, Myanmar, Laos, and Vietnam, each have complex histories of antimalarial drug use over many decades, which have in part molded the use of various artemisinin combination therapies (ACTs) within each country. We catalog the use of ACTs, evolving loss of ACT efficacy, and the frequency of mutations (mutations associated with ARTR) in the Greater Mekong Subregion and map the historical spread of ARTR/DCP parasites. These data should assist improved surveillance and deployment of next-generation ACTs.
Topics: Artemisinins; Asia, Southeastern; Drug Resistance; Drug Therapy, Combination; Genotype; Humans; Malaria, Falciparum; Mutation; Phenotype; Plasmodium falciparum
PubMed: 31642425
DOI: 10.4269/ajtmh.19-0379 -
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 Jul 2021Early malaria diagnosis and its profiling require the development of new sensing platforms enabling rapid and early analysis of parasites in blood or saliva, aside the...
BACKGROUND
Early malaria diagnosis and its profiling require the development of new sensing platforms enabling rapid and early analysis of parasites in blood or saliva, aside the widespread rapid diagnostic tests (RDTs).
METHODS
This study shows the performance of a cost-effective optical fiber-based solution to target the presence of Plasmodium falciparum histidine-rich protein 2 (PfHRP2). Unclad multimode optical fiber probes are coated with a thin gold film to excite Surface Plasmon Resonance (SPR) yielding high sensitivity to bio-interactions between targets and bioreceptors grafted on the metal surface.
RESULTS
Their performances are presented in laboratory conditions using PBS spiked with growing concentrations of purified target proteins and within in vitro cultures. Two probe configurations are studied through label-free detection and amplification using secondary antibodies to show the possibility to lower the intrisic limit of detection.
CONCLUSIONS
As malaria hits millions of people worldwide, the improvement and multiplexing of this optical fiber technique can be of great interest, especially for a future purpose of using multiple receptors on the fiber surface or several coated-nanoparticles as amplifiers.
Topics: Antigens, Protozoan; Biosensing Techniques; Humans; Optical Fibers; Plasmodium falciparum; Protozoan Proteins
PubMed: 34320995
DOI: 10.1186/s12936-021-03863-3 -
EMBO Reports Mar 2021The intra-erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and...
The intra-erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a metabolic byproduct of glycolysis, is potentially toxic as it lowers the pH inside the parasite. Plasmodium falciparum formate-nitrite transporter (PfFNT), a 34-kDa transmembrane protein, has been identified as a novel drug target as it exports lactate from inside the parasite to the surrounding parasitophorous vacuole within the erythrocyte cytosol. The structure and detailed molecular mechanism of this membrane protein are not yet available. Here we present structures of PfFNT in the absence and presence of the functional inhibitor MMV007839 at resolutions of 2.56 Å and 2.78 Å using single-particle cryo-electron microscopy. Genetic analysis and transport assay indicate that PfFNT is able to transfer lactate across the membrane. Combined, our data suggest a stepwise displacement mechanism for substrate transport. The PfFNT membrane protein is capable of picking up lactate ions from the parasite's cytosol, converting them to lactic acids and then exporting these acids into the extracellular space.
Topics: Cryoelectron Microscopy; Formates; Nitrites; Plasmodium falciparum; Protozoan Proteins
PubMed: 33471955
DOI: 10.15252/embr.202051628 -
Journal of Proteome Research Aug 2022Histones are the building units of nucleosomes, which constitute chromatin. Histone post-translational modifications (PTMs) play an essential role in epigenetic gene...
Histones are the building units of nucleosomes, which constitute chromatin. Histone post-translational modifications (PTMs) play an essential role in epigenetic gene regulation. The genome encodes canonical and variant histones and a collection of conserved enzymes for histone PTMs and chromatin remodeling. Herein, we profiled the histone PTMs during the development of gametocytes, the obligatory stage for parasite transmission. Mass spectrometric analysis of histones extracted from the early, middle, and late stages of gametocytes identified 457 unique histone peptides with 90 PTMs, of which 50% were novel. The gametocyte histone PTMs display distinct patterns from asexual stages, with many new methylation sites in histones H3 and H3.3 (, K14, K18, and K37). Quantitative analyses revealed a high abundance of acetylation in H3 and H4, mono-methylation of H3/H3.3 K37, and ubiquitination of H3BK112, suggesting that these PTMs play critical roles in gametocytes. Gametocyte histones also showed extensive and unique combinations of PTMs. These data indicate that the parasite harbors distinct transcription regulation mechanisms during gametocyte development and lay the foundation for further characterization of epigenetic regulation in the life cycle of the malaria parasite.
Topics: Acetylation; Epigenesis, Genetic; Gametogenesis; Histones; Humans; Life Cycle Stages; Malaria, Falciparum; Plasmodium falciparum; Protein Processing, Post-Translational
PubMed: 35772009
DOI: 10.1021/acs.jproteome.2c00108 -
Current Opinion in Microbiology Dec 2020For malaria parasites regulating sexual commitment, the frequency with which asexual bloodstream forms differentiate into non-replicative male and female gametocytes, is... (Review)
Review
For malaria parasites regulating sexual commitment, the frequency with which asexual bloodstream forms differentiate into non-replicative male and female gametocytes, is critical because asexual replication is required to maintain a persistent infection of the human host while gametocytes are essential for infection of the mosquito vector and transmission. Here, we describe recent advances in understanding of the regulatory mechanisms controlling this key developmental decision. These include new insights into the mechanistic roles of the transcriptional master switch AP2-G and the epigenetic modulator GDV1, as well as the identification of defined metabolic signals that modulate their activity. Many of these metabolites are linked to parasite phospholipid biogenesis and we propose a model linking this pathway to the epigenetic regulation underlying sexual commitment in P. falciparum.
Topics: Animals; Epigenesis, Genetic; Germ Cells; Humans; Malaria, Falciparum; Plasmodium falciparum; Reproduction
PubMed: 33053503
DOI: 10.1016/j.mib.2020.09.004 -
Biomolecules Nov 2021Malaria remains by far one of the most threatening and dangerous illnesses caused by the plasmodium falciparum parasite. Chloroquine (CQ) and first-line...
Malaria remains by far one of the most threatening and dangerous illnesses caused by the plasmodium falciparum parasite. Chloroquine (CQ) and first-line artemisinin-based combination treatment (ACT) have long been the drug of choice for the treatment and controlling of malaria; however, the emergence of CQ-resistant and artemisinin resistance parasites is now present in most areas where malaria is endemic. In this work, we developed five machine learning models to predict antimalarial bioactivities of a drug against plasmodium falciparum from the features (i.e., molecular descriptors values) obtained from PaDEL software from SMILES of compounds and compare the machine learning models by experiments with our collected data of 4794 instances. As a consequence, we found that three models amongst the five, namely artificial neural network (ANN), extreme gradient boost (XGB), and random forest (RF), outperform the others in terms of accuracy while observing that, using roughly a quarter of the promising descriptors picked by the feature selection algorithm, the five models achieved equivalent and comparable performance. Nevertheless, the contribution of all molecular descriptors in the models was investigated through the comparison of their rank values by the feature selection algorithm and found that the most potent and relevant descriptors which come from the 'Autocorrelation' module contributed more while the 'Atom type electrotopological state' contributed the least to the model.
Topics: Algorithms; Antimalarials; Databases, Pharmaceutical; Drug Evaluation, Preclinical; Machine Learning; Neural Networks, Computer; Plasmodium falciparum
PubMed: 34944394
DOI: 10.3390/biom11121750