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Trends in Parasitology Oct 2023Meiosis is sexual cell division, a process in eukaryotes whereby haploid gametes are produced. Compared to canonical model eukaryotes, meiosis in apicomplexan parasites... (Review)
Review
Meiosis is sexual cell division, a process in eukaryotes whereby haploid gametes are produced. Compared to canonical model eukaryotes, meiosis in apicomplexan parasites appears to diverge from the process with respect to the molecular mechanisms involved; the biology of Plasmodium meiosis, and its regulation by means of post-translational modification, are largely unexplored. Here, we discuss the impact of technological advances in cell biology, evolutionary bioinformatics, and genome-wide functional studies on our understanding of meiosis in the Apicomplexa. These parasites, including Plasmodium falciparum, Toxoplasma gondii, and Eimeria spp., have significant socioeconomic impact on human and animal health. Understanding this key stage during the parasite's life cycle may well reveal attractive targets for therapeutic intervention.
Topics: Animals; Humans; Plasmodium; Eukaryota; Plasmodium falciparum; Meiosis; Toxoplasma
PubMed: 37541799
DOI: 10.1016/j.pt.2023.07.002 -
Genes May 2021Genomics has revolutionised the study of the biology of parasitic diseases. The first Eukaryotic parasite to have its genome sequenced was the malaria parasite . Since... (Review)
Review
Genomics has revolutionised the study of the biology of parasitic diseases. The first Eukaryotic parasite to have its genome sequenced was the malaria parasite . Since then, genomics has continued to lead the way in the study of the genome biology of parasites, both in breadth-the number of species' genomes sequenced-and in depth-massive-scale genome re-sequencing of several key species. Here, we review some of the insights into the biology, evolution and population genetics of gained from genome sequencing, and look at potential new avenues in the future genome-scale study of its biology.
Topics: Epigenome; Genome, Protozoan; Humans; Malaria; Plasmodium falciparum; Polymorphism, Genetic
PubMed: 34070769
DOI: 10.3390/genes12060843 -
PLoS Pathogens Dec 2021Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all... (Review)
Review
Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
Topics: Animals; Chagas Disease; Humans; Leishmaniasis; Mycobacterium tuberculosis; Plasmodium falciparum; Proteasome Endopeptidase Complex; Proteasome Inhibitors
PubMed: 34882737
DOI: 10.1371/journal.ppat.1010058 -
Frontiers in Cellular and Infection... 2021Blocking malaria transmission is critical to malaria control programs but remains a major challenge especially in endemic regions with high levels of asymptomatic... (Review)
Review
Blocking malaria transmission is critical to malaria control programs but remains a major challenge especially in endemic regions with high levels of asymptomatic infections. New strategies targeting the transmissible sexual stages of the parasite, called gametocytes, are needed. This review focuses on gametocytogenesis and . Highlighting advances made elucidating genes required for gametocyte production and identifying key questions that remain unanswered such as the factors and regulatory mechanisms that contribute to gametocyte induction, and the mechanism of sequestration. Tools available to begin to address these issues are also described to facilitate advances in our understanding of this important stage of the life cycle.
Topics: Animals; Asymptomatic Infections; Life Cycle Stages; Malaria; Malaria, Falciparum; Plasmodium falciparum
PubMed: 34926328
DOI: 10.3389/fcimb.2021.790067 -
Microbiology Spectrum Jun 2023Cyclic invasion of red blood cells (RBCs) by merozoites is associated with the symptoms and pathology of malaria. Merozoite invasion is powered actively and rapidly by...
Cyclic invasion of red blood cells (RBCs) by merozoites is associated with the symptoms and pathology of malaria. Merozoite invasion is powered actively and rapidly by a parasite actomyosin motor called the glideosome. The ability of the glideosome to generate force to support merozoite entry into the host RBCs is thought to rely on its stable anchoring within the inner membrane complex (IMC) through membrane-resident proteins, such as GAP50 and GAP40. Using a conditional knockdown (KD) approach, we determined that PfGAP40 was required for asexual blood-stage replication. PfGAP40 is not needed for merozoite egress from host RBCs or for the attachment of merozoites to new RBCs. PfGAP40 coprecipitates with PfGAP45 and PfGAP50. During merozoite invasion, PfGAP40 is associated strongly with stabilizing the expression levels of PfGAP45 and PfGAP50 in the schizont stage. Although PfGAP40 KD did not influence IMC integrity, it impaired the maturation of gametocytes. In addition, PfGAP40 is phosphorylated, and mutations that block phosphorylation of PfGAP40 at the C-terminal serine residues S370, S372, S376, S405, S409, S420, and S445 reduced merozoite invasion efficiency. Overall, our findings implicate PfGAP40 as an important regulator for the gliding activity of merozoites and suggest that phosphorylation is required for PfGAP40 function. Red blood cell invasion is central to the pathogenesis of the malaria parasite, and the parasite proteins involved in this process are potential therapeutic targets. Gliding motility powers merozoite invasion and is driven by a unique molecular motor termed the glideosome. The glideosome is stably anchored to the parasite inner membrane complex (IMC) through membrane-resident proteins. In the present study, we demonstrate the importance of an IMC-resident glideosome component, PfGAP40, that plays a critical role in stabilizing the expression levels of glideosome components in the schizont stage. We determined that phosphorylation of PfGAP40 at C-terminal residues is required for efficient merozoite invasion.
Topics: Animals; Plasmodium falciparum; Merozoites; Protozoan Proteins; Membrane Proteins; Malaria
PubMed: 37249423
DOI: 10.1128/spectrum.01434-23 -
International Journal of Molecular... May 2021The highly complex life cycle of the human malaria parasite, , is based on an orchestrated and tightly regulated gene expression program. In general, eukaryotic... (Review)
Review
The highly complex life cycle of the human malaria parasite, , is based on an orchestrated and tightly regulated gene expression program. In general, eukaryotic transcription regulation is determined by a combination of sequence-specific transcription factors binding to regulatory DNA elements and the packaging of DNA into chromatin as an additional layer. The accessibility of regulatory DNA elements is controlled by the nucleosome occupancy and changes of their positions by an active process called nucleosome remodeling. These epigenetic mechanisms are poorly explored in The parasite genome is characterized by an extraordinarily high AT-content and the distinct architecture of functional elements, and chromatin-related proteins also exhibit high sequence divergence compared to other eukaryotes. Together with the distinct biochemical properties of nucleosomes, these features suggest substantial differences in chromatin-dependent regulation. Here, we highlight the peculiarities of epigenetic mechanisms in , addressing chromatin structure and dynamics with respect to their impact on transcriptional control. We focus on the specialized chromatin remodeling enzymes and discuss their essential function in gene regulation.
Topics: Animals; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Gene Expression Regulation; Humans; Life Cycle Stages; Malaria, Falciparum; Plasmodium falciparum; Transcription, Genetic
PubMed: 34068393
DOI: 10.3390/ijms22105168 -
Trends in Parasitology Feb 2020The major growth in point-of-care malaria diagnosis over the past decade has been based on immunochromatographic malaria rapid diagnostic tests (mRDTs), which generally... (Review)
Review
The major growth in point-of-care malaria diagnosis over the past decade has been based on immunochromatographic malaria rapid diagnostic tests (mRDTs), which generally detect Plasmodium falciparum via its abundant histidine-rich protein 2 (HRP2). Here, we review the discovery and biology of HRP2, as well as the strengths and weaknesses of HRP2-based diagnosis compared with alternative antigens. We highlight recent studies describing HRP2 deletion in Latin America, Eritrea, and possibly other regions, and the methodological challenges of confirming deletion of the pfhrp2 gene. We also discuss the mechanism of persistent HRP2 positivity after effective antimalarial treatment, along with other emerging HRP2-based applications, including detection of submicroscopic malaria and diagnosis of severe malaria.
Topics: Antigens, Protozoan; Gene Deletion; Humans; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Research
PubMed: 31848119
DOI: 10.1016/j.pt.2019.12.004 -
Nature Communications May 2023In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite...
In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ~5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines. Upon challenge with the spiroindolone PfATP4-inhibitor KAE609, high-level resistance is obtained more rapidly and at lower inocula than wild-type parasites. Selections also yield mutants with resistance to an "irresistible" compound, MMV665794 that failed to yield resistance with other strains. We validate mutations in a previously uncharacterised gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), as causal for resistance to MMV665794 and a panel of quinoxaline analogues. The increased genetic repertoire available to this "mutator" parasite can be leveraged to drive P. falciparum resistome discovery.
Topics: Animals; Plasmodium falciparum; Parasites; Malaria, Falciparum; Antimalarials; Mutation; Drug Resistance; Protozoan Proteins
PubMed: 37244916
DOI: 10.1038/s41467-023-38774-1 -
Briefings in Functional Genomics Sep 2019Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all... (Review)
Review
Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.
Topics: Aminoquinolines; Anti-Bacterial Agents; Antimalarials; Artemisinins; Atovaquone; Drug Resistance; Drug Resistance, Multiple; Folic Acid Antagonists; Humans; Malaria; Plasmodium falciparum; Plasmodium vivax; Quinine
PubMed: 31119263
DOI: 10.1093/bfgp/elz008 -
MSphere Aug 2023Nonsense-mediated decay (NMD) is a conserved mRNA quality control process that eliminates transcripts bearing a premature termination codon. In addition to its role in...
Nonsense-mediated decay (NMD) is a conserved mRNA quality control process that eliminates transcripts bearing a premature termination codon. In addition to its role in removing erroneous transcripts, NMD is involved in post-transcriptional regulation of gene expression via programmed intron retention in metazoans. The apicomplexan parasite shows relatively high levels of intron retention, but it is unclear whether these variant transcripts are functional targets of NMD. In this study, we use CRISPR-Cas9 to disrupt and epitope-tag the orthologs of two core NMD components: UPF1 (PF3D7_1005500) and UPF2 (PF3D7_0925800). We localize both UPF1 and UPF2 to puncta within the parasite cytoplasm and show that these proteins interact with each other and other mRNA-binding proteins. Using RNA-seq, we find that although these core NMD orthologs are expressed and interact in , they are not required for degradation of nonsense transcripts. Furthermore, our work suggests that the majority of intron retention in has no functional role and that NMD is not required for parasite growth . IMPORTANCE In many organisms, the process of destroying nonsense transcripts is dependent on a small set of highly conserved proteins. We show that in the malaria parasite, these proteins do not impact the abundance of nonsense transcripts. Furthermore, we demonstrate efficient CRISPR-Cas9 editing of the malaria parasite using commercial Cas9 nuclease and synthetic guide RNA, streamlining genomic modifications in this genetically intractable organism.
Topics: Humans; Plasmodium falciparum; Nonsense Mediated mRNA Decay; Gene Expression Regulation; RNA, Messenger; Malaria
PubMed: 37366629
DOI: 10.1128/msphere.00233-23