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Veterinary Parasitology Apr 2018Canine babesiosis is a tick-borne disease caused by several Babesia spp. which have different susceptebility to anti-protozoal drugs. A few drugs and drug combinations... (Review)
Review
Canine babesiosis is a tick-borne disease caused by several Babesia spp. which have different susceptebility to anti-protozoal drugs. A few drugs and drug combinations are used in the treatment of canine babesiosis often without complete parasite elimination leaving treated dogs as carriers which could relapse with clinical disease and also transmit infection further. Although the large form canine babesial species Babesia canis, Babesia vogeli and Babesia rossi are sensitive to the aromatic diamidines imidocarb dipropionate and diminazene aceturate, small form species such as Babesia gibsoni, Babesia conradae and Babesia vulpes (Theileria annae) are relatively resistant to these drugs and are treated with the combination of the hydroxynaphthoquinone atovaquone and the antibiotic azithromycin. Azithromycin and other antibiotics that have anti-protozoal properties target the apicoplast, a relict plastid found in protozoa, and exert a delayed death effect. The triple combination of clindamycin, diminazene aceturate and imidocarb dipropionate is also effective against B. gibsoni and used to treat atovaquone-resistant strains of this species. Novel drugs and the synergistic effects of drug combinations against Babesia infection should be explored further to find new treatments for canine babesiosis.
Topics: Animals; Antiprotozoal Agents; Babesia; Babesiosis; Dog Diseases; Dogs
PubMed: 29657012
DOI: 10.1016/j.vetpar.2018.03.001 -
Frontiers in Cellular and Infection... 2022The deadly malaria parasite, , contains a unique subcellular organelle termed the apicoplast, which is a clinically-proven antimalarial drug target. The apicoplast is a... (Review)
Review
The deadly malaria parasite, , contains a unique subcellular organelle termed the apicoplast, which is a clinically-proven antimalarial drug target. The apicoplast is a plastid with essential metabolic functions that evolved secondary endosymbiosis. As an ancient endosymbiont, the apicoplast retained its own genome and it must be inherited by daughter cells during cell division. During the asexual replication of inside human red blood cells, both the parasite, and the apicoplast inside it, undergo massive morphological changes, including DNA replication and division. The apicoplast is an integral part of the cell and thus its development is tightly synchronized with the cell cycle. At the same time, certain aspects of its dynamics are independent of nuclear division, representing a degree of autonomy in organelle biogenesis. Here, we review the different aspects of organelle dynamics during intraerythrocytic replication, summarize our current understanding of these processes, and describe the many open questions in this area of parasite basic cell biology.
Topics: Animals; Apicoplasts; Cell Cycle; Cell Division; Humans; Malaria, Falciparum; Parasites; Plasmodium; Plasmodium falciparum; Protozoan Proteins
PubMed: 35573785
DOI: 10.3389/fcimb.2022.864819 -
The Journal of Eukaryotic Microbiology Nov 2022Toxoplasma gondii belongs to the phylum Apicomplexa and is an important cause of congenital disease and infection in immunocompromised patients. T. gondii shares... (Review)
Review
Toxoplasma gondii belongs to the phylum Apicomplexa and is an important cause of congenital disease and infection in immunocompromised patients. T. gondii shares several characteristics with plants including a nonphotosynthetic plastid termed apicoplast and a multivesicular organelle that was named the plant-like vacuole (PLV) or vacuolar compartment (VAC). The name plant-like vacuole was selected based on its resemblance in composition and function to plant vacuoles. The name VAC represents its general vacuolar characteristics. We will refer to the organelle as PLVAC in this review. New findings in recent years have revealed that the PLVAC represents the lysosomal compartment of T. gondii which has adapted peculiarities to fulfill specific Toxoplasma needs. In this review, we discuss the composition and functions of the PLVAC highlighting its roles in ion storage and homeostasis, endocytosis, exocytosis, and autophagy.
Topics: Humans; Toxoplasma; Vacuoles; Protozoan Proteins; Apicoplasts; Plants
PubMed: 36218001
DOI: 10.1111/jeu.12951 -
MBio Aug 2021Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites... (Review)
Review
Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum, are the cause of many important human and animal diseases. While T. gondii tachyzoites replicate through endodyogeny, during which two daughter cells are formed within the parental cell, P. falciparum replicates through schizogony, where up to 32 parasites are formed in a single infected red blood cell and even thousands of daughter cells during mosquito- or liver-stage development. These processes require a tightly orchestrated division and distribution over the daughter parasites of one-per-cell organelles such as the mitochondrion and apicoplast. Although proper organelle segregation is highly essential, the molecular mechanism and the key proteins involved remain largely unknown. In this review, we describe organelle dynamics during cell division in T. gondii and P. falciparum, summarize the current understanding of the molecular mechanisms underlying organelle fission in these parasites, and introduce candidate fission proteins.
Topics: Animals; Apicoplasts; Erythrocytes; Humans; Mitochondria; Parasites; Plasmodium falciparum; Protozoan Proteins; Toxoplasma
PubMed: 34425697
DOI: 10.1128/mBio.01409-21 -
Biochemical Society Transactions Aug 2019Malaria continues to be one of the leading causes of human mortality in the world, and the therapies available are insufficient for eradication. Severe malaria is caused... (Review)
Review
Malaria continues to be one of the leading causes of human mortality in the world, and the therapies available are insufficient for eradication. Severe malaria is caused by the apicomplexan parasite Apicomplexan parasites, including the spp., are descendants of photosynthetic algae, and therefore they possess an essential plastid organelle, named the apicoplast. Since humans and animals have no plastids, the apicoplast is an attractive target for drug development. Indeed, after its discovery, the apicoplast was found to host the target pathways of some known antimalarial drugs, which motivated efforts for further research into its biological functions and biogenesis. Initially, many apicoplast inhibitions were found to result in 'delayed death', whereby parasite killing is seen only at the end of one invasion-egress cycle. This slow action is not in line with the current standard for antimalarials, which seeded scepticism about the potential of compounds targeting apicoplast functions as good candidates for drug development. Intriguingly, recent evidence of apicoplast inhibitors causing rapid killing could put this organelle back in the spotlight. We provide an overview of drugs known to inhibit apicoplast pathways, alongside recent findings in apicoplast biology that may provide new avenues for drug development.
Topics: Animals; Antimalarials; Apicoplasts; Humans; Malaria; Oxidation-Reduction; Plasmodium
PubMed: 31383817
DOI: 10.1042/BST20170563 -
International Journal For Parasitology Feb 2017Parasites such as Plasmodium and Toxoplasma possess a vestigial plastid homologous to the chloroplasts of algae and plants. The plastid (known as the apicoplast; for... (Review)
Review
Parasites such as Plasmodium and Toxoplasma possess a vestigial plastid homologous to the chloroplasts of algae and plants. The plastid (known as the apicoplast; for apicomplexan plastid) is non-photosynthetic and very much reduced, but has clear endosymbiotic ancestry including a circular genome that encodes RNAs and proteins and a suite of bacterial biosynthetic pathways. Here we review the initial discovery of the apicoplast, and recount the major new insights into apicoplast origin, biogenesis and function. We conclude by examining how the apicoplast can be removed from malaria parasites in vitro, ultimately completing its reduction by chemical supplementation.
Topics: Animals; Apicoplasts; Biological Evolution; Humans; Plasmodium; Symbiosis
PubMed: 27773518
DOI: 10.1016/j.ijpara.2016.08.005 -
PLoS Pathogens Nov 2022Many apicomplexan parasites harbor a non-photosynthetic plastid called the apicoplast, which hosts important metabolic pathways like the methylerythritol 4-phosphate...
Many apicomplexan parasites harbor a non-photosynthetic plastid called the apicoplast, which hosts important metabolic pathways like the methylerythritol 4-phosphate (MEP) pathway that synthesizes isoprenoid precursors. Yet many details in apicoplast metabolism are not well understood. In this study, we examined the physiological roles of four glycolytic enzymes in the apicoplast of Toxoplasma gondii. Many glycolytic enzymes in T. gondii have two or more isoforms. Endogenous tagging each of these enzymes found that four of them were localized to the apicoplast, including pyruvate kinase2 (PYK2), phosphoglycerate kinase 2 (PGK2), triosephosphate isomerase 2 (TPI2) and phosphoglyceraldehyde dehydrogenase 2 (GAPDH2). The ATP generating enzymes PYK2 and PGK2 were thought to be the main energy source of the apicoplast. Surprisingly, deleting PYK2 and PGK2 individually or simultaneously did not cause major defects on parasite growth or virulence. In contrast, TPI2 and GAPDH2 are critical for tachyzoite proliferation. Conditional depletion of TPI2 caused significant reduction in the levels of MEP pathway intermediates and led to parasite growth arrest. Reconstitution of another isoprenoid precursor synthesis pathway called the mevalonate pathway in the TPI2 depletion mutant partially rescued its growth defects. Similarly, knocking down the GAPDH2 enzyme that produces NADPH also reduced isoprenoid precursor synthesis through the MEP pathway and inhibited parasite proliferation. In addition, it reduced de novo fatty acid synthesis in the apicoplast. Together, these data suggest a model that the apicoplast dwelling TPI2 provides carbon source for the synthesis of isoprenoid precursor, whereas GAPDH2 supplies reducing power for pathways like MEP, fatty acid synthesis and ferredoxin redox system in T. gondii. As such, both enzymes are critical for parasite growth and serve as potential targets for anti-toxoplasmic intervention designs. On the other hand, the dispensability of PYK2 and PGK2 suggest additional sources for energy in the apicoplast, which deserves further investigation.
Topics: Animals; Toxoplasma; Apicoplasts; Metabolic Networks and Pathways; Parasites; Pyruvic Acid; Fatty Acids; Protozoan Proteins
PubMed: 36449552
DOI: 10.1371/journal.ppat.1011009 -
Current Opinion in Microbiology Oct 2021The apicoplast is the relict of a plastid organelle found in several disease-causing apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii. In these... (Review)
Review
The apicoplast is the relict of a plastid organelle found in several disease-causing apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii. In these organisms, the organelle has lost its photosynthetic capability but harbours several fitness-conferring or essential metabolic pathways. Although maintaining the apicoplast and fuelling the metabolic pathways within requires the challenging constant import and export of numerous metabolites across its four membranes, only few apicoplast transporters have been identified to date, most of which are orphan transporters. Here we review the roles of metabolic pathways within the apicoplast and what is currently known about the few identified apicoplast metabolite transporters. We discuss what metabolites must get in and out of the apicoplast, the many transporters that are yet to be discovered, and what role these might play in parasite metabolism and as putative drug targets.
Topics: Animals; Apicomplexa; Apicoplasts; Metabolic Networks and Pathways; Parasites; Plasmodium; Toxoplasma
PubMed: 34455306
DOI: 10.1016/j.mib.2021.07.016 -
Malaria Journal Mar 2016Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is... (Review)
Review
Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2α cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance.
Topics: Antimalarials; Artemisinins; Drug Resistance; Humans; Malaria, Falciparum; Models, Biological; Plasmodium falciparum
PubMed: 26955948
DOI: 10.1186/s12936-016-1206-9 -
Life (Basel, Switzerland) Sep 2021is a unicellular eukaryote with a very polarized secretory system composed of micronemes rhoptries and dense granules that are required for host cell invasion. , like... (Review)
Review
is a unicellular eukaryote with a very polarized secretory system composed of micronemes rhoptries and dense granules that are required for host cell invasion. , like its relative , uses the endolysosomal system to produce the secretory organelles and to ingest host cell proteins. The parasite also has an apicoplast, a secondary endosymbiotic organelle, which depends on vesicular trafficking for appropriate incorporation of nuclear-encoded proteins into the apicoplast. Recently, the central molecules responsible for sorting and trafficking in and have been characterized. From these studies, it is now evident that has repurposed the molecules of the endosomal system to the secretory pathway. Additionally, the sorting and vesicular trafficking mechanism seem to be conserved among apicomplexans. This review described the most recent findings on the molecular mechanisms of protein sorting and vesicular trafficking in and revealed that has an amazing secretory machinery that has been cleverly modified to its intracellular lifestyle.
PubMed: 34575086
DOI: 10.3390/life11090937