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Yoko Kimata-Ariga, Shohei Yuasa, Takashi Saitoh, Haruka Fukuyama, Toshiharu Hase
The malaria parasite (Plasmodium falciparum) possesses a plastid-derived, essential organelle called the apicoplast, which contains a redox system comprising plant-type ferredoxin (Fd) and Fd-NADP+ reductase (FNR). This system supplies reducing power for the crucial metabolic pathways in this organelle. Electron transfer between P. falciparum Fd (PfFd) and FNR (PfFNR) is performed with higher affinity and specificity than that of plant Fd and FNR. To investigate the mechanism for such superior protein-protein interaction, we searched for the Fd interaction sites on the surface of PfFNR...
April 23, 2018: Journal of Biochemistry
Hoa Mai Nguyen, Shuxian Liu, Wassim Daher, Feng Tan, Sébastien Besteiro
Toxoplasma gondii is a parasitic protist possessing a limited set of proteins involved in the autophagy pathway, a self-degradative machinery for protein and organelle recycling. This distant eukaryote has even repurposed part of this machinery, centered on protein ATG8, for a non-degradative function related to the maintenance of the apicoplast, a parasite-specific organelle. However, some evidence also suggest Toxoplasma is able to generate autophagic vesicles upon stress, and that some autophagy-related proteins, such as ATG9, might be involved solely in the canonical autophagy function...
2018: PloS One
Gad Baneth
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...
April 30, 2018: Veterinary Parasitology
Wei Cong, Long Chen, Xiao-Feng Shan, Ai-Dong Qian, Qing-Feng Meng
Until now, limited information on the molecular epidemiology and genotypes of Toxoplasma gondii infection in donkeys is available in China. Thus, the present study was conducted to characterize T. gondii genotypes in donkeys, intended for human consumption in Shandong province, eastern China. A total of 618 muscle tissue samples of donkeys was collected in Shandong province from January 2016 to August 2017 and were used to detect the T. gondii B1 gene by a semi-nested PCR, and the positive samples were genotyped at 10 nuclear loci (i...
March 9, 2018: Infection, Genetics and Evolution
Viktorija Kirillova, Petras Prakas, Rafael Calero-Bernal, Inese Gavarāne, José Luis Fernández-García, Manuel Martínez-González, Eglė Rudaitytė-Lukošienė, Miguel Ángel Habela Martínez-Estéllez, Dalius Butkauskas, Muza Kirjušina
BACKGROUND: Typically, carnivores serve as definitive hosts for Sarcocystis spp. parasites; currently, their role as intermediate hosts is being elucidated. The present study aimed to identify and molecularly characterize Sarcocystis cysts detected in striated muscle of red foxes from different populations in Latvia, Lithuania and Spain. METHODS: Muscle samples from 411 red foxes (Vulpes vulpes) and 269 racoon dogs (Nyctereutes procyonoides) from Latvia, 41 red foxes from Lithuania and 22 red foxes from Spain were examined for the presence of Sarcocystis sarcocysts by light microscopy (LM)...
March 12, 2018: Parasites & Vectors
Teegan A Dellibovi-Ragheb, Hugo Jhun, Christopher D Goodman, Maroya S Walters, Daniel R T Ragheb, Krista A Matthews, Krithika Rajaram, Satish Mishra, Geoffrey I McFadden, Photini Sinnis, Sean T Prigge
Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that is the target of several classes of herbicides. Malaria parasites contain a plant-like ACC, and this is the only protein predicted to be biotinylated in the parasite. We found that ACC is expressed in the apicoplast organelle in liver- and blood-stage malaria parasites; however, it is activated through biotinylation only in the liver stages. Consistent with this observation, deletion of the biotin ligase responsible for ACC biotinylation does not impede blood-stage growth, but results in late liver-stage developmental defects...
February 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
Marco Biddau, Anne Bouchut, Jack Major, Tracy Saveria, Julie Tottey, Ojore Oka, Marcel van-Lith, Katherine Elizabeth Jennings, Jana Ovciarikova, Amy DeRocher, Boris Striepen, Ross Frederick Waller, Marilyn Parsons, Lilach Sheiner
Apicomplexan parasites are global killers, being the causative agents of diseases like toxoplasmosis and malaria. These parasites are known to be hypersensitive to redox imbalance, yet little is understood about the cellular roles of their various redox regulators. The apicoplast, an essential plastid organelle, is a verified apicomplexan drug target. Nuclear-encoded apicoplast proteins traffic through the ER and multiple apicoplast sub-compartments to their place of function. We propose that thioredoxins contribute to the control of protein trafficking and of protein function within these apicoplast compartments...
February 2018: PLoS Pathogens
Sofía M García-Mauriño, Antonio Díaz-Quintana, Francisco Rivero-Rodríguez, Isabel Cruz-Gallardo, Christian Grüttner, Marian Hernández-Vellisca, Irene Díaz-Moreno
Malaria is caused by Apicomplexa protozoans from the Plasmodium genus entering the bloodstream of humans and animals through the bite of the female mosquitoes. The annotation of the Plasmodium vivax genome revealed a putative RNA binding protein (apiRBP) that was predicted to be trafficked into the apicoplast, a plastid organelle unique to Apicomplexa protozoans. Although a 3D structural model of the apiRBP corresponds to a noncanonical RNA recognition motif with an additional C-terminal α-helix (α3), preliminary protein production trials were nevertheless unsuccessful...
February 2018: FEBS Open Bio
Gowtham Subramanian, Meenakshi A Belekar, Anurag Shukla, Jie Xin Tong, Ameya Sinha, Trang T T Chu, Akshay S Kulkarni, Peter R Preiser, D Srinivasa Reddy, Kevin S W Tan, Dhanasekaran Shanmugam, Rajesh Chandramohanadas
The Malaria Box collection includes 400 chemically diverse small molecules with documented potency against malaria parasite growth, but the underlying modes of action are largely unknown. Using complementary phenotypic screens against Plasmodium falciparum and Toxoplasma gondii , we report phenotype-specific hits based on inhibition of overall parasite growth, apicoplast segregation, and egress or host invasion, providing hitherto unavailable insights into the possible mechanisms affected. First, the Malaria Box library was screened against tachyzoite stage T...
January 2018: MSphere
Cletus A Wezena, Romy Alisch, Alexandra Golzmann, Linda Liedgens, Verena Staudacher, Gabriele Pradel, Marcel Deponte
The enzymes glyoxalase 1 and 2 (Glo1 and Glo2) are found in most eukaryotes and catalyze the glutathione-dependent conversion of 2-oxoaldehydes to 2-hydroxycarboxylic acids. Four glyoxalases are encoded in the genome of the malaria parasite Plasmodium falciparum , the cytosolic enzymes PfGlo1 and PfcGlo2, the apicoplast enzyme PftGlo2, and an inactive Glo1-like protein that also carries an apicoplast-targeting sequence. Inhibition or knockout of the Plasmodium glyoxalases was hypothesized to lead to an accumulation of 2-oxoaldehydes and advanced glycation end-products (AGE) in the host-parasite unit and to result in parasite death...
November 20, 2017: Microbial Cell
Marvin Duvalsaint, Dennis E Kyle
Many organisms undergo dormancy as a stress response to survive under unfavorable conditions that might impede development. This is observed in seeds and buds of plants and has been proposed as a mechanism of drug evasion and resistance formation in Plasmodium falciparum We explored the effects of the phytohormones abscisic acid (ABA) and gibberellic acid (GA) on dihydroartemisinin (DHA)-induced dormant erythrocytic stages of P. falciparum parasites. Dormant ring stages exposed to ABA and GA recovered from dormancy up to 48 h earlier than parasites exposed to DHA alone...
March 2018: Antimicrobial Agents and Chemotherapy
Marta Walczak, Suresh M Ganesan, Jacquin C Niles, Ellen Yeh
Plasmodium parasites and related pathogens contain an essential nonphotosynthetic plastid organelle, the apicoplast, derived from secondary endosymbiosis. Intriguingly, a highly conserved eukaryotic protein, autophagy-related protein 8 (ATG8), has an autophagy-independent function in the apicoplast. Little is known about the novel apicoplast function of ATG8 and its importance in blood-stage Plasmodium falciparum Using a P. falciparum strain in which ATG8 expression was conditionally regulated, we showed that P...
January 2, 2018: MBio
Leanne M Low, Danielle I Stanisic, Michael F Good
The apicoplast, a relic plastid found in most Apicomplexan parasites, is a notable drug target. Certain antibiotics elicit a delayed death phenotype by targeting this organelle. Here, we review apicoplast-targeting drugs and their targets, particularly those that cause delayed death, and highlight its potential uses in malaria vaccine development.
December 26, 2017: Microbes and Infection
Shinuo Cao, Nali Du, Heming Chen, Yu Pang, Zhaoxia Zhang, Jun Zheng, Honglin Jia
Caseinolytic peptidase B (ClpB) plays a pivotal role in suppressing and reversing protein aggregation. Toxoplasma gondii is an intracellular parasitic protozoan that infects a wide variety of mammals and birds and therefore is exposed to a broad range of living condition. We screened ToxoDB ( and identified 10 putative T. gondii genes encoding members of the Clp superfamily of caseinolytic proteases and chaperones. Of these, we focused on characterizing the Class I ATP-dependent molecular chaperones Tg ClpB1, Tg ClpB2, and Tg ClpB3...
October 17, 2017: Oncotarget
Zeinab Ebrahimzadeh, Angana Mukherjee, Dave Richard
Despite representing a small percentage of the cellular lipids of eukaryotic cells, phosphoinositides (PIPs) are critical in various processes such as intracellular trafficking and signal transduction. Central to their various functions is the differential distribution of PIP species to specific membrane compartments through the actions of kinases, phosphatases and lipases. Despite their importance in the malaria parasite lifecycle, the subcellular distribution of most PIP species in this organism is still unknown...
January 2018: International Journal for Parasitology
Anat Florentin, David W Cobb, Jillian D Fishburn, Michael J Cipriano, Paul S Kim, Manuel A Fierro, Boris Striepen, Vasant Muralidharan
The deadly malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid, known as the apicoplast, that functions to produce essential metabolites, and drugs that target the apicoplast are clinically effective. Several prokaryotic caseinolytic protease (Clp) genes have been identified in the Plasmodium genome. Using phylogenetic analysis, we focused on the Clp members that may form a regulated proteolytic complex in the apicoplast. We genetically targeted members of this complex and generated conditional mutants of the apicoplast-localized PfClpC chaperone and PfClpP protease...
November 14, 2017: Cell Reports
Taher Uddin, Geoffrey Ian McFadden, Christopher Dean Goodman
Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast-perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a nonapicoplast target...
January 2018: Antimicrobial Agents and Chemotherapy
Sonja Rueckert, Aleš Horák
BACKGROUND: Gregarines represent an important transition step from free-living predatory (colpodellids s.l.) and/or photosynthetic (Chromera and Vitrella) apicomplexan lineages to the most important pathogens, obligate intracellular parasites of humans and domestic animals such as coccidians and haemosporidians (Plasmodium, Toxoplasma, Eimeria, Babesia, etc.). While dozens of genomes of other apicomplexan groups are available, gregarines are barely entering the molecular age. Among the gregarines, archigregarines possess a unique mixture of ancestral (myzocytosis) and derived (lack of apicoplast, presence of subpellicular microtubules) features...
2017: PloS One
Sébastien Besteiro
Autophagy is a highly conserved eukaryotic degradation process that permits the recycling of intracellular components. The molecular machinery and the functions of autophagy have been classically characterized in mammalian cells and yeast, but have long remained unexplored in less-studied eukaryotes. Apicomplexan parasites are early-diverging eukaryotes responsible for a number of important human and veterinary diseases. In light of recent investigations into autophagy function in two of these pathogens, Plasmodium and Toxoplasma, it seems their autophagy-related machinery could be involved in both a canonical degradative function, and a non-canonical role related to the apicoplast, a metabolically important organelle of endosymbiotic origin...
December 2017: Current Opinion in Microbiology
Priyanka Bansal, Anuj Tripathi, Vandana Thakur, Asif Mohmmed, Pushkar Sharma
Mechanisms by which 3'-phosphorylated phosphoinositides (3'-PIPs) regulate the development of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii are poorly understood. The catabolic process of autophagy, which is dependent on autophagy-related proteins (ATGs), is one of the major targets of 3'-PIPs in yeast and mammals. In the present study, we identified autophagy-related protein ATG18 as an effector of 3'-PIPs in these parasites. P falciparum ATG18 (PfATG18) and T gondii ATG18 (TgATG18) interact with 3'-PIPs but exhibited differences in their specificity of interaction with the ligand PIP...
October 31, 2017: MBio
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