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The FEBS Journal Sep 2007Malaria is caused by protozoan parasites of the genus Plasmodium and is a major cause of mortality and morbidity worldwide. These parasites have a complex life cycle in... (Review)
Review
Malaria is caused by protozoan parasites of the genus Plasmodium and is a major cause of mortality and morbidity worldwide. These parasites have a complex life cycle in their mosquito vector and vertebrate hosts. The primary factors contributing to the resurgence of malaria are the appearance of drug-resistant strains of the parasite, the spread of insecticide-resistant strains of the mosquito and the lack of licensed malaria vaccines of proven efficacy. This minireview includes a summary of the disease, the life cycle of the parasite, information relating to the genome and proteome of the species lethal to humans, Plasmodium falciparum, together with other recent developments in the field.
Topics: Animals; Culicidae; Erythrocytes; Humans; Malaria; Plasmodium
PubMed: 17824953
DOI: 10.1111/j.1742-4658.2007.05997.x -
Infection, Genetics and Evolution :... Dec 2013The living world has evolved and is evolving through interspecific relationships between organisms. The diversity of these interactions is enormous going from mutualism... (Review)
Review
The living world has evolved and is evolving through interspecific relationships between organisms. The diversity of these interactions is enormous going from mutualism to parasitism. Humans live with a multitude of microorganisms, essential for their biology. However, interactions are not always advantageous. Indeed, many organisms might become pathogens, such as the Plasmodium species, the causative agents of malaria. Like many other microorganisms, they are «Machiavellian» in their capacity to elaborate a range of reproduction strategies, giving them a huge advantage in terms of adaptation. Here, we discuss the role played by parasites in the ecology and evolution of living organisms and particularly of humans. In the study of infectious diseases, humans are legitimately the focal point, although they represent only one ecosystem among many others and not taking this into account certainly biases our global view of the system. Indeed, we know only a minimal fraction of the microorganisms we live with. However, parasites have shaped and are still shaping the human genome. Several genetic signatures are the proofs of the selection pressures by parasites that humankind has endured during its evolution. But, ultimately, what are the solutionsfor living with pathogens? Should we eradicate them or should we learn how to control and manage them?
Topics: Ecosystem; Genome, Human; Genome, Protozoan; Host-Parasite Interactions; Humans; Malaria; Plasmodium
PubMed: 23954419
DOI: 10.1016/j.meegid.2013.08.005 -
Biochemical Society Transactions Apr 2024Malaria, a vector borne disease, is a major global health and socioeconomic problem caused by the apicomplexan protozoan parasite Plasmodium. The parasite alternates... (Review)
Review
Malaria, a vector borne disease, is a major global health and socioeconomic problem caused by the apicomplexan protozoan parasite Plasmodium. The parasite alternates between mosquito vector and vertebrate host, with meiosis in the mosquito and proliferative mitotic cell division in both hosts. In the canonical eukaryotic model, cell division is either by open or closed mitosis and karyokinesis is followed by cytokinesis; whereas in Plasmodium closed mitosis is not directly accompanied by concomitant cell division. Key molecular players and regulatory mechanisms of this process have been identified, but the pivotal role of certain protein complexes and the post-translational modifications that modulate their actions are still to be deciphered. Here, we discuss recent evidence for the function of known proteins in Plasmodium cell division and processes that are potential novel targets for therapeutic intervention. We also identify key questions to open new and exciting research to understand divergent Plasmodium cell division.
Topics: Plasmodium; Cell Division; Animals; Humans; Malaria; Protozoan Proteins; Mitosis; Cytokinesis; Meiosis; Protein Processing, Post-Translational; Host-Parasite Interactions
PubMed: 38563493
DOI: 10.1042/BST20230403 -
The FEBS Journal May 2017Proteasomes are multisubunit, energy-dependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes,... (Review)
Review
Proteasomes are multisubunit, energy-dependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes, archaea, and in some actinobacteria species. Inhibition of proteasome activity has emerged as a powerful strategy for anticancer therapy and three drugs have been approved for treatment of multiple myeloma. These compounds react covalently with a threonine residue located in the active site of a proteasome subunit to block protein degradation. Proteasomes in pathogenic organisms such as Mycobacterium tuberculosis and Plasmodium falciparum also have a nucleophilic threonine residue in the proteasome active site and are therefore sensitive to these anticancer drugs. This review summarizes efforts to validate the proteasome in pathogenic organisms as a therapeutic target. We describe several strategies that have been used to develop inhibitors with increased potency and selectivity for the pathogen proteasome relative to the human proteasome. In addition, we highlight a cell-based chemical screening approach that identified a potent, allosteric inhibitor of proteasomes found in Leishmania and Trypanosoma species. Finally, we discuss the development of proteasome inhibitors as anti-infective agents.
Topics: Animals; Anti-Infective Agents; Humans; Mycobacterium; Plasmodium; Proteasome Endopeptidase Complex; Schistosoma
PubMed: 28122162
DOI: 10.1111/febs.14029 -
FEMS Microbiology Reviews Nov 2017Five species of parasite cause malaria in humans with the most severe disease caused by Plasmodium falciparum. Many of the proteins encoded in the P. falciparum genome... (Review)
Review
Five species of parasite cause malaria in humans with the most severe disease caused by Plasmodium falciparum. Many of the proteins encoded in the P. falciparum genome are unusually enriched in repetitive low-complexity sequences containing a limited repertoire of amino acids. These repetitive sequences expand and contract dynamically and are among the most rapidly changing sequences in the genome. The simplest repetitive sequences consist of single amino acid repeats such as poly-asparagine tracts that are found in approximately 25% of P. falciparum proteins. More complex repeats of two or more amino acids are also common in diverse parasite protein families. There is no universal explanation for the occurrence of repetitive sequences and it is possible that many confer no function to the encoded protein and no selective advantage or disadvantage to the parasite. However, there are increasing numbers of examples where repetitive sequences are important for parasite protein function. We discuss the diverse roles of low-complexity repetitive sequences throughout the parasite life cycle, from mediating protein-protein interactions to enabling the parasite to evade the host immune system.
Topics: Plasmodium; Protozoan Proteins; Repetitive Sequences, Amino Acid
PubMed: 29077880
DOI: 10.1093/femsre/fux046 -
Parasites & Vectors Dec 2022The production of Plasmodium gametocytes in vitro is a real challenge. Many protocols have been described, but few have resulted in the production of viable and... (Review)
Review
BACKGROUND
The production of Plasmodium gametocytes in vitro is a real challenge. Many protocols have been described, but few have resulted in the production of viable and infectious gametocytes in sufficient quantities to conduct research on-but not limited to-transmission-blocking drug and vaccine development. The aim of this review was to identify and discuss gametocyte production protocols that have been developed over the last two decades.
METHODS
We analyzed the original gametocyte production protocols published from 2000 onwards based on a literature search and a thorough review. A systematic review was performed of relevant articles identified in the PubMed, Web of Sciences and ScienceDirect databases.
RESULTS
A total 23 studies on the production of Plasmodium gametocytes were identified, 19 involving in vitro Plasmodium falciparum, one involving Plasmodium knowlesi and three involving ex vivo Plasmodium vivax. Of the in vitro studies, 90% used environmental stressors to trigger gametocytogenesis. Mature gametocytemia of up to 4% was reported.
CONCLUSIONS
Several biological parameters contribute to an optimal production in vitro of viable and infectious mature gametocytes. The knowledge gained from this systematic review on the molecular mechanisms involved in gametocytogenesis enables reproducible gametocyte protocols with transgenic parasite lines to be set up. This review highlights the need for additional gametocyte production protocols for Plasmodium species other than P. falciparum.
Topics: Humans; Malaria, Falciparum; Plasmodium falciparum; Plasmodium knowlesi; Plasmodium vivax; Systematic Reviews as Topic
PubMed: 36471426
DOI: 10.1186/s13071-022-05566-3 -
PLoS Pathogens Apr 2023
Topics: Animals; Parasites; Plasmodium; Ribosomes
PubMed: 37053161
DOI: 10.1371/journal.ppat.1011267 -
Trends in Parasitology Jun 2020Artemisinins - the frontline antimalarial drug class - are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year.... (Review)
Review
Artemisinins - the frontline antimalarial drug class - are compromised by emerging resistance, putting at risk the lives of hundreds of thousands of people each year. Resistance is associated with mutations in a malaria parasite protein, called Kelch 13 (K13). Recent work suggests that K13 is located at the cytostome (cell mouth) that the parasite uses to take up hemoglobin. Here we explore the proposal that K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis. This model suggests that the resultant decrease in hemoglobin-derived heme reduces artemisinin activation, which is sufficient to enable parasite survival in the early ring stage of infection. A fuller understanding of the resistance mechanism will underpin efforts to develop alternative antimalarial strategies.
Topics: Antimalarials; Artemisinins; Drug Resistance; Heme; Humans; Mutation; Plasmodium; Protozoan Proteins
PubMed: 32359872
DOI: 10.1016/j.pt.2020.03.006 -
The Biochemical Journal Jul 2021During malarial infection, Plasmodium parasites digest human hemoglobin to obtain free amino acids for protein production and maintenance of osmotic pressure. The...
During malarial infection, Plasmodium parasites digest human hemoglobin to obtain free amino acids for protein production and maintenance of osmotic pressure. The Plasmodium M1 and M17 aminopeptidases are both postulated to have an essential role in the terminal stages of the hemoglobin digestion process and are validated drug targets for the design of new dual-target anti-malarial compounds. In this study, we profiled the substrate specificity fingerprints and kinetic behaviors of M1 and M17 aminopeptidases from Plasmodium falciparum and Plasmodium vivax, and the mouse model species, Plasmodium berghei. We found that although the Plasmodium M1 aminopeptidases share a largely similar, broad specificity at the P1 position, the P. falciparum M1 displays the greatest diversity in specificity and P. berghei M1 showing a preference for charged P1 residues. In contrast, the Plasmodium M17 aminopeptidases share a highly conserved preference for hydrophobic residues at the P1 position. The aminopeptidases also demonstrated intra-peptide sequence specificity, particularly the M1 aminopeptidases, which showed a definitive preference for peptides with fewer negatively charged intrapeptide residues. Overall, the P. vivax and P. berghei enzymes had a faster substrate turnover rate than the P. falciparum enzymes, which we postulate is due to subtle differences in structural dynamicity. Together, these results build a kinetic profile that allows us to better understand the catalytic nuances of the M1 and M17 aminopeptidases from different Plasmodium species.
Topics: Aminopeptidases; Animals; Biocatalysis; Humans; Isoenzymes; Kinetics; Leucine; Malaria; Mice; Peptides; Plasmodium; Plasmodium berghei; Plasmodium falciparum; Plasmodium vivax; Protease Inhibitors; Protozoan Proteins; Recombinant Proteins; Species Specificity; Substrate Specificity
PubMed: 34133730
DOI: 10.1042/BCJ20210172 -
Current Opinion in Microbiology Dec 2017Non-human primates harbor diverse species of malaria parasites, including the progenitors of Plasmodium falciparum and Plasmodium vivax. Cross-species transmission of... (Review)
Review
Non-human primates harbor diverse species of malaria parasites, including the progenitors of Plasmodium falciparum and Plasmodium vivax. Cross-species transmission of some malaria parasites-most notably the macaque parasite, Plasmodium knowlesi-continues to this day, compelling the scientific community to ask whether these zoonoses could impede malaria control efforts by acting as a source of recurrent human infection. Host-restriction varies considerably among parasite species and is governed by both ecological and molecular variables. In particular, the efficiency of red blood cell invasion constitutes a prominent barrier to zoonotic emergence. Although proteins expressed upon the erythrocyte surface exhibit considerable diversity both within and among hosts, malaria parasites have adapted to this heterogeneity via the expansion of protein families associated with invasion, offering redundant mechanisms of host cell entry. This molecular toolkit may enable some parasites to circumvent host barriers, potentially yielding host shifts upon subsequent adaptation. Recent studies have begun to elucidate the molecular determinants of host-specificity, as well as the mechanisms that malaria parasites use to overcome these restrictions. We review recent studies concerning host tropism in the context of erythrocyte invasion by focusing on three malaria parasites that span the zoonotic spectrum: P. falciparum, P. knowlesi, and P. vivax.
Topics: Animals; Erythrocytes; Host Specificity; Humans; Malaria; Plasmodium; Protozoan Proteins
PubMed: 29096194
DOI: 10.1016/j.mib.2017.10.006