Journal articles: 'Metabolism in Toxoplasma Gondii'

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Krug, E. C., J. J. Marr, and R. L. Berens. "Purine Metabolism in Toxoplasma gondii." Journal of Biological Chemistry 264, no. 18 (June 1989): 10601–7. http://dx.doi.org/10.1016/s0021-9258(18)81663-5.

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Chang, Hernán R., and Jean-Claude Pechère. "Macrophage oxidative metabolism and intracellular Toxoplasma gondii." Microbial Pathogenesis 7, no. 1 (July 1989): 37–44. http://dx.doi.org/10.1016/0882-4010(89)90109-5.

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Chen, Min, Lijuan Zhou, Shengmin Li, Hiaxia Wei, Jiating Chen, Pei Yang, and Hongjuan Peng. "Toxoplasma gondii DNA methyltransferases regulate parasitic energy metabolism." Acta Tropica 229 (May 2022): 106329. http://dx.doi.org/10.1016/j.actatropica.2022.106329.

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Prandovszky, Emese, Elizabeth Gaskell, Heather Martin, J. P. Dubey, Joanne P. Webster, and Glenn A. McConkey. "The Neurotropic Parasite Toxoplasma Gondii Increases Dopamine Metabolism." PLoS ONE 6, no. 9 (September 21, 2011): e23866. http://dx.doi.org/10.1371/journal.pone.0023866.

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Sonda, Sabrina, Giusy Sala, Riccardo Ghidoni, Andrew Hemphill, and Jean Pieters. "Inhibitory Effect of Aureobasidin A on Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 49, no. 5 (May 2005): 1794–801. http://dx.doi.org/10.1128/aac.49.5.1794-1801.2005.

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ABSTRACT The apicomplexan parasite Toxoplasma gondii is a leading opportunistic pathogen associated with AIDS and congenital birth defects. Due to the need for identifying new parasite-specific treatments, the possibility of targeting sphingolipid biosynthesis in the parasite was investigated. Aureobasidin A, an inhibitor of the enzyme synthesizing the sphingolipid inositol phosphorylceramide, which is present in fungi, plants, and some protozoa but absent in mammalian cells, was found to block in vitro T. gondii replication without affecting host cell metabolism. Aureobasidin A treatment did not induce tachyzoite to bradyzoite stage conversion in T. gondii but resulted in a loss of intracellular structures and vacuolization within the parasite. In addition, aureobasidin A inhibited sphingolipid synthesis in T. gondii. Sphingolipid biosynthetic pathways may therefore be considered targets for the development of anti-T. gondii agents.

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Mageed, Sarmad N., Fraser Cunningham, Alvin Wei Hung, Hernani Leonardo Silvestre, Shijun Wen, Tom L. Blundell, Chris Abell, and Glenn A. McConkey. "Pantothenic Acid Biosynthesis in the Parasite Toxoplasma gondii: a Target for Chemotherapy." Antimicrobial Agents and Chemotherapy 58, no. 11 (July 21, 2014): 6345–53. http://dx.doi.org/10.1128/aac.02640-14.

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ABSTRACTToxoplasma gondiiis a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B5) biosynthesis inT. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to coenzyme A were identified and are expressed inT. gondii. A panel of inhibitors developed to targetMycobacterium tuberculosispantothenate synthetase were tested and found to exhibit a range of values for inhibition ofT. gondiigrowth. Two inhibitors exhibited lower effective concentrations than the currently used toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway, as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence,T. gondiiencodes and expresses the enzymes for pantothenate synthesis, and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target.

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el Kouni, Mahmoud. "Adenosine Metabolism in Toxoplasma gondii: Potential Targets for Chemotherapy." Current Pharmaceutical Design 13, no. 6 (February 1, 2007): 581–97. http://dx.doi.org/10.2174/138161207780162836.

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Weilhammer, Dina R., Anthony T. Iavarone, Eric N. Villegas, George A. Brooks, Anthony P. Sinai, and William C. Sha. "Host metabolism regulates growth and differentiation of Toxoplasma gondii." International Journal for Parasitology 42, no. 10 (September 2012): 947–59. http://dx.doi.org/10.1016/j.ijpara.2012.07.011.

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Wu, Liang, Lipei Wu, Chenyu Tang, Jiajian Wang, Xiaoling Jin, Xugan Jiang, and Shengxia Chen. "Induction of FAS II Metabolic Disorders to Cause Delayed Death of Toxoplasma gondii." Journal of Nanoscience and Nanotechnology 18, no. 12 (December 1, 2018): 8155–59. http://dx.doi.org/10.1166/jnn.2018.16396.

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The exact mechanism of delayed death of Toxoplasma gondii is not known. FAS II synthesis in the apicoplast of T. gondii is essential for the survival of Toxoplasma gondii, while β-hydroxyacylacyl carrier protein dehydratase (FabZ) is indispensable for fatty acid synthesis. The present study investigated the relationship between the delayed death of T. gondii by inducing metabolic disorders due to suppression the expression of FabZ. A tetracycline-induced knockout vector inserted with T. gondii fabZ gene was constructed, and transfected into T. gondii TATi strain by electroporation. The stable mutants with tetracycline-induced knockout were selected, expression of FabZ was suppressed by using anhydrotetracycline (ATc), and FAS II deficient tachyzoites were prepared. The Western blot and qPCR results revealed that proliferation of FAS II deficient tachyzoites was not significantly different compared to the normal tachyzoites at 24 h and 48 h; however, after 72 h, the number of T. gondii tachyzoites in the ATc treated group was significantly (p < 0.05) less than that of non-treated group, indicating the delayed death of T. gondii caused by the loss of apicoplast and decrease in the expression of FabZ, which inhibited the FAS II metabolism. The results of this study can be used for prevention of toxoplasmosis by inducing delayed death of T. gondii.

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Li, Meiqi, Xiaoyu Sang, Xiaohan Zhang, Xiang Li, Ying Feng, Na Yang, and Tiantian Jiang. "A Metabolomic and Transcriptomic Study Revealed the Mechanisms of Lumefantrine Inhibition of Toxoplasma gondii." International Journal of Molecular Sciences 24, no. 5 (March 3, 2023): 4902. http://dx.doi.org/10.3390/ijms24054902.

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Toxoplasma gondii is an obligate protozoon that can infect all warm-blooded animals including humans. T. gondii afflicts one-third of the human population and is a detriment to the health of livestock and wildlife. Thus far, traditional drugs such as pyrimethamine and sulfadiazine used to treat T. gondii infection are inadequate as therapeutics due to relapse, long treatment period, and low efficacy in parasite clearance. Novel, efficacious drugs have not been available. Lumefantrine, as an antimalarial, is effective in killing T. gondii but has no known mechanism of action. We combined metabolomics with transcriptomics to investigate how lumefantrine inhibits T. gondii growth. We identified significant alternations in transcripts and metabolites and their associated functional pathways that are attributed to lumefantrine treatment. RH tachyzoites were used to infect Vero cells for three hours and subsequently treated with 900 ng/mL lumefantrine. Twenty-four hours post-drug treatment, we observed significant changes in transcripts associated with five DNA replication and repair pathways. Metabolomic data acquired through liquid chromatography-tandem mass spectrometry (LC-MS) showed that lumefantrine mainly affected sugar and amino acid metabolism, especially galactose and arginine. To investigate whether lumefantrine damages T. gondii DNA, we conducted a terminal transferase assay (TUNEL). TUNEL results showed that lumefantrine significantly induced apoptosis in a dose-dependent manner. Taken together, lumefantrine effectively inhibited T. gondii growth by damaging DNA, interfering with DNA replication and repair, and altering energy and amino acid metabolisms.

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el Kouni, Mahmoud H., Vincenzo Guarcello, Omar N. Al Safarjalani, and Fardos N. M. Naguib. "Metabolism and Selective Toxicity of 6-Nitrobenzylthioinosine in Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 43, no. 10 (October 1, 1999): 2437–43. http://dx.doi.org/10.1128/aac.43.10.2437.

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ABSTRACT The purine nucleoside analogue NBMPR {nitrobenzylthioinosine or 6-[(4-nitrobenzyl)thio]-9-β-d-ribofuranosylpurine} was selectively phosphorylated to its nucleoside 5′-monophosphate byToxoplasma gondii but not mammalian adenosine kinase (EC2.7.1.20). NBMPR was also cleaved in toxoplasma to its nucleobase, nitrobenzylmercaptopurine. However, nitrobenzylmercaptopurine was not a substrate for either adenosine kinase or hypoxanthine-guanine-xanthine phosphoribosyltransferase (EC 2.4.2.8). Because of this unique and previously unknown metabolism of NBMPR by the parasite, the effect of NBMPR as an antitoxoplasmic agent was tested. NBMPR killed T. gondii grown in human fibroblasts in a dose-dependent manner, with a 50% inhibitory concentration of approximately 10 μM and without apparent toxicity to host cells. Doses of up to 100 μM had no significant toxic effect on uninfected host cells. The promising antitoxoplasmic effect of NBMPR led to the testing of other 6-substituted 9-β-d-ribofuranosylpurines, which were shown to be good ligands of the parasite adenosine kinase (M. H. Iltzsch, S. S. Uber, K. O. Tankersley, and M. H. el Kouni, Biochem. Pharmacol. 49:1501–1512, 1995), as antitoxoplasmic agents. Among the analogues tested, 6-benzylthioinosine,p-nitrobenzyl-6-selenopurine riboside,N 6-(p-azidobenzyl)adenosine, andN 6-(p-nitrobenzyl)adenosine, like NBMPR, were selectively toxic to parasite-infected cells. Thus, it appears that the unique characteristics of purine metabolism inT. gondii render certain 6-substituted 9-β-d-ribofuranosylpurines promising antitoxoplasmic drugs.

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Xu, Qiong, Yin-Yan Duan, Ming Pan, Qi-Wang Jin, Jian-Ping Tao, and Si-Yang Huang. "In Vitro Evaluation Reveals Effect and Mechanism of Artemether against Toxoplasma gondii." Metabolites 13, no. 4 (March 27, 2023): 476. http://dx.doi.org/10.3390/metabo13040476.

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Due to the limited effectiveness of existing drugs for the treatment of toxoplasmosis, there is a dire need for the discovery of new therapeutic options. Artemether is an important drug for malaria and several studies have indicated that it also exhibits anti-T. gondii activity. However, its specific effect and mechanisms are still not clear. To elucidate its specific role and potential mechanism, we first evaluated its cytotoxicity and anti-Toxoplasma effect on human foreskin fibroblast cells, and then analyzed its inhibitory activity during T. gondii invasion and intracellular proliferation. Finally, we examined its effect on mitochondrial membrane potential and reactive oxygen species (ROS) in T. gondii. The CC50 value of artemether was found to be 866.4 μM, and IC50 was 9.035 μM. It exhibited anti-T. gondii activity and inhibited the growth of T. gondii in a dose-dependent manner. We also found that the inhibition occurred primarily in intracellular proliferation, achieved by reducing the mitochondrial membrane integrity of T. gondii and stimulating ROS production. These findings suggest that the mechanism of artemether against T. gondii is related to a change in the mitochondrial membrane and the increase in ROS production, which may provide a theoretical basis for optimizing artemether derivatives and further improving their anti-Toxoplasma efficacy.

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Charron, Audra J., and L. David Sibley. "Host cells: mobilizable lipid resources for the intracellular parasite Toxoplasma gondii." Journal of Cell Science 115, no. 15 (August 1, 2002): 3049–59. http://dx.doi.org/10.1242/jcs.115.15.3049.

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Successful replication of the intracellular parasite Toxoplasma gondii within its parasitophorous vacuole necessitates a substantial increase in membrane mass. The possible diversion and metabolism of host cell lipids and lipid precursors by Toxoplasma was therefore investigated using radioisotopic and fluorophore-conjugated compounds. Confocal microscopic analyses demonstrated that Toxoplasma is selective with regards to both the acquisition and compartmentalization of host cell lipids. Lipids were compartmentalized into parasite endomembranes and, in some cases, were apparently integrated into the surrounding vacuolar membrane. Additionally,some labels became concentrated in discrete lipid bodies that were biochemically and morphologically distinct from the parasite apical secretory organelles. Thin layer chromatography established that parasites readily scavenged long-chain fatty acids as well as cholesterol, and in certain cases modified the host-derived lipids. When provided with radiolabeled phospholipid precursors, including polar head groups, phosphatidic acid and small fatty acids, intracellular parasites preferentially accrued phosphatidylcholine(PtdCho) over other phospholipids. Moreover, Toxoplasma was found to be competent to synthesize PtdCho from radiolabeled precursors obtained from its environment. Together, these studies underscore the ability of Toxoplasma gondii to divert and use lipid resources from its host, a process that may contribute to the biogenesis of parasite membranes.

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Nie, Lan-Bi, Qin-Li Liang, Meng Wang, Rui Du, Meng-Yuan Zhang, Hany M. Elsheikha, and Xing-Quan Zhu. "Global profiling of protein lysine malonylation in Toxoplasma gondii strains of different virulence and genetic backgrounds." PLOS Neglected Tropical Diseases 16, no. 5 (May 16, 2022): e0010431. http://dx.doi.org/10.1371/journal.pntd.0010431.

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Lysine malonylation is a post-translational modification (PTM), which regulates many cellular processes. Limited information is available about the level of lysine malonylation variations between Toxoplasma gondii strains of distinct genetic lineages. Yet, insights in such variations are needed to understand the extent to which lysine malonylation contributes to the differences in the virulence and repertoire of virulence factors between T. gondii genotypes. In this study, we profiled lysine malonylation in T. gondii using quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immuno-affinity purification. This analysis was performed on three T. gondii strains with distinctive pathogenicity in mice, including RH strain (type I), PRU strain (type II), and VEG strain (type III). In total, 111 differentially malonylated proteins and 152 sites were upregulated, and 17 proteins and 17 sites were downregulated in RH strain versus PRU strain; 50 proteins and 59 sites were upregulated, 50 proteins and 53 sites were downregulated in RH strain versus VEG strain; and 72 proteins and 90 sites were upregulated, and 7 proteins and 8 sites were downregulated in VEG strain versus PRU strain. Differentially malonylated proteins were involved in key processes, such as those mediating the regulation of protein metabolism, stress response, glycolysis, and actin cytoskeleton. These results reveal an association between lysine malonylation and intra-species virulence differences in T. gondii and offer a new resource for elucidating the contribution of lysine malonylation to energy metabolism and virulence in T. gondii.

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Sullivan, William J., Stacy E. Dixon, Catherine Li, Boris Striepen, and Sherry F. Queener. "IMP Dehydrogenase from the Protozoan Parasite Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 49, no. 6 (June 2005): 2172–79. http://dx.doi.org/10.1128/aac.49.6.2172-2179.2005.

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ABSTRACT The opportunistic apicomplexan parasite Toxoplasma gondii damages fetuses in utero and threatens immunocompromised individuals. The toxicity associated with standard antitoxoplasmal therapies, which target the folate pathway, underscores the importance of examining alternative pharmacological strategies. Parasitic protozoa cannot synthesize purines de novo; consequently, targeting purine salvage enzymes is a plausible pharmacological strategy. Several enzymes critical to purine metabolism have been studied in T. gondii, but IMP dehydrogenase (IMPDH), which catalyzes the conversion of IMP to XMP, has yet to be characterized. Thus, we have cloned the gene encoding this enzyme in T. gondii. Northern blot analysis shows that two IMPDH transcripts are present in T. gondii tachyzoites. The larger transcript contains an open reading frame of 1,656 nucleotides whose deduced protein sequence consists of 551 amino acids (TgIMPDH). The shorter transcript is an alternative splice product that generates a 371-amino-acid protein lacking the active-site flap (TgIMPDH-S). When TgIMPDH is expressed as a recombinant protein fused to a FLAG tag, the fusion protein localizes to the parasite cytoplasm. Immunoprecipitation with anti-FLAG was employed to purify recombinant TgIMPDH, which converts IMP to XMP as expected. Mycophenolic acid is an uncompetitive inhibitor relative to NAD+, with a intercept inhibition constant (Kii ) of 0.03 ± 0.004 μM. Tiazofurin and its seleno analog were not inhibitory to the purified enzyme, but adenine dinucleotide analogs such as TAD and the nonhydrolyzable β-methylene derivatives of TAD or SAD were inhibitory, with Kii values 13- to 60-fold higher than that of mycophenolic acid.

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Milovanović, Ivan, Marija Vujanić, Ivana Klun, Branko Bobić, Aleksandra Nikolić, Vladimir Ivović, Alexander M. Trbovich, and Olgica Djurković-Djaković. "Toxoplasma gondii infection induces lipid metabolism alterations in the murine host." Memórias do Instituto Oswaldo Cruz 104, no. 2 (March 2009): 175–78. http://dx.doi.org/10.1590/s0074-02762009000200008.

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Milovanovic, I., A. M. Trbovich, M. Vujanic, I. Klun, B. Bobic, A. Nikolic, V. Ivovic, and O. Djurkovic-Djakovic. "Toxoplasma gondii Infection Induces Lipid Metabolism Alterations in the Murine Host." International Journal of Infectious Diseases 12 (December 2008): e172-e173. http://dx.doi.org/10.1016/j.ijid.2008.05.430.

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Boothroyd, John C., Michael Black, Serge Bonnefoy, Adrian Hehl, Laura J. Knoll, Ian D. Manger, Eduardo Ortega–Barria, and Stanislas Tomavo. "Genetic and biochemical analysis of development in Toxoplasma gondii." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 352, no. 1359 (September 29, 1997): 1347–54. http://dx.doi.org/10.1098/rstb.1997.0119.

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Toxoplasma gondii has recently come under intense study as a model for intracellular parasitism because it has a number of properties that facilitate experimental manipulation. Attention is now being turned towards understanding the developmental biology of this complex parasite. The differentiation between the two asexual stages, the rapidly growing tachyzoites and the more slowly dividing, encysted bradyzoites, is of particular interest. Progression from the former to the latter is influenced by the host's immune response. This paper describes current progress on a number of research fronts, all aimed at understanding the triggers that push the tachyzoite–bradyzoite equilibrium in one or other direction and the changes that occur in gene expression (and ultimately metabolism and function). Chief among the techniques used for these studies are genetics and molecular genetics. Recent progress in these areas is described.

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Conseil, V., M. Soête, and J. F. Dubremetz. "Serine Protease Inhibitors Block Invasion of Host Cells by Toxoplasma gondii." Antimicrobial Agents and Chemotherapy 43, no. 6 (June 1, 1999): 1358–61. http://dx.doi.org/10.1128/aac.43.6.1358.

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ABSTRACT We investigated the effect of protease inhibitors on the asexual development of the protozoan parasite Toxoplasma gondii. Among the inhibitors tested only two irreversible serine protease inhibitors, 3,4-dichloroisocoumarin and 4-(2-aminoethyl)-benzenesulfonyl fluoride, clearly prevented invasion of the host cells by specifically affecting parasite targets in a dose-dependent manner, with 50% inhibitory concentrations between 1 and 5 and 50 and 100 μM, respectively. Neither compound significantly affected parasite morphology, basic metabolism, or gliding motility within the range of the experimental conditions in which inhibition of invasion was demonstrated. No partial invasion was observed, meaning that inhibition occurred at an early stage of the interaction. These results suggest that at least one serine protease of the parasite is involved in the invasive process of T. gondii.

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Rovira, Paula, Blanca Gutiérrez, Antonio Sorlózano-Puerto, José Gutiérrez-Fernández, Esther Molina, Margarita Rivera, Rafael Martínez-Leal, et al. "Toxoplasma gondii Seropositivity Interacts with Catechol-O-methyltransferase Val105/158Met Variation Increasing the Risk of Schizophrenia." Genes 13, no. 6 (June 18, 2022): 1088. http://dx.doi.org/10.3390/genes13061088.

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Schizophrenia is a heterogeneous and severe psychotic disorder. Epidemiological findings have suggested that the exposure to infectious agents such as Toxoplasma gondii (T. gondii) is associated with an increased risk for schizophrenia. On the other hand, there is evidence involving the catechol-O-methyltransferase (COMT) Val105/158Met polymorphism in the aetiology of schizophrenia since it alters the dopamine metabolism. A case–control study of 141 patients and 142 controls was conducted to analyse the polymorphism, the prevalence of anti-T. gondii IgG, and their interaction on the risk for schizophrenia. IgG were detected by ELISA, and genotyping was performed with TaqMan Real-Time PCR. Although no association was found between any COMT genotype and schizophrenia, we found a significant association between T. gondii seropositivity and the disorder (χ2 = 11.71; p-value < 0.001). Furthermore, the risk for schizophrenia conferred by T. gondii was modified by the COMT genotype, with those who had been exposed to the infection showing a different risk compared to that of nonexposed ones depending on the COMT genotype (χ2 for the interaction = 7.28, p-value = 0.007). This study provides evidence that the COMT genotype modifies the risk for schizophrenia conferred by T. gondii infection, with it being higher in those individuals with the Met/Met phenotype, intermediate in heterozygous, and lower in those with the Val/Val phenotype.

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Kloehn, Joachim, Matteo Lunghi, Emmanuel Varesio, David Dubois, and Dominique Soldati-Favre. "Untargeted Metabolomics Uncovers the Essential Lysine Transporter in Toxoplasma gondii." Metabolites 11, no. 8 (July 23, 2021): 476. http://dx.doi.org/10.3390/metabo11080476.

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Apicomplexan parasites are responsible for devastating diseases, including malaria, toxoplasmosis, and cryptosporidiosis. Current treatments are limited by emerging resistance to, as well as the high cost and toxicity of existing drugs. As obligate intracellular parasites, apicomplexans rely on the uptake of many essential metabolites from their host. Toxoplasma gondii, the causative agent of toxoplasmosis, is auxotrophic for several metabolites, including sugars (e.g., myo-inositol), amino acids (e.g., tyrosine), lipidic compounds and lipid precursors (cholesterol, choline), vitamins, cofactors (thiamine) and others. To date, only few apicomplexan metabolite transporters have been characterized and assigned a substrate. Here, we set out to investigate whether untargeted metabolomics can be used to identify the substrate of an uncharacterized transporter. Based on existing genome- and proteome-wide datasets, we have identified an essential plasma membrane transporter of the major facilitator superfamily in T. gondii—previously termed TgApiAT6-1. Using an inducible system based on RNA degradation, TgApiAT6-1 was depleted, and the mutant parasite’s metabolome was compared to that of non-depleted parasites. The most significantly reduced metabolite in parasites depleted in TgApiAT6-1 was identified as the amino acid lysine, for which T. gondii is predicted to be auxotrophic. Using stable isotope-labeled amino acids, we confirmed that TgApiAT6-1 is required for efficient lysine uptake. Our findings highlight untargeted metabolomics as a powerful tool to identify the substrate of orphan transporters.

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Wang, Ze-Xiang, Rui-Si Hu, Chun-Xue Zhou, Jun-Jun He, Hany M. Elsheikha, and Xing-Quan Zhu. "Label-Free Quantitative Acetylome Analysis Reveals Toxoplasma gondii Genotype-Specific Acetylomic Signatures." Microorganisms 7, no. 11 (October 30, 2019): 510. http://dx.doi.org/10.3390/microorganisms7110510.

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Distinct genotypic and pathogenic differences exist between Toxoplasma gondii genotypes. For example, genotype I is highly virulent, whereas genotype II and genotype III are less virulent. Moreover, Chinese 1 genotype (ToxoDB#9) is also virulent. Here, we compare the acetylomes of genotype 1 (RH strain) and Chinese 1 genotype (ToxoDB#9, PYS strain) of T. gondii. Using mass spectrometry enriched for acetylated peptides, we found a relationship between the levels of protein acetylation and parasite genotype-specific virulence. Notably, lysine acetylation was the largest (458 acetylated proteins) in RH strain, followed by PYS strain (188 acetylated proteins), whereas only 115 acetylated proteins were detected in PRU strain. Our analysis revealed four, three, and four motifs in RH strain, PRU strain and PYS strain, respectively. Three conserved sequences around acetylation sites, namely, xxxxxKAcHxxxx, xxxxxKAcFxxxx, and xxxxGKAcSxxxx, were detected in the acetylome of the three strains. However, xxxxxKAcNxxxx (asparagine) was found in RH and PYS strains but was absent in PRU strain. Our analysis also identified 15, 3, and 26 differentially expressed acetylated proteins in RH strain vs. PRU strain, PRU strain vs. PYS strain and PYS strain vs. RH strain, respectively. KEGG pathway analysis showed that a large proportion of the acetylated proteins are involved in metabolic processes. Pathways for the biosynthesis of secondary metabolites, biosynthesis of antibiotics and microbial metabolism in diverse environments were featured in the top five enriched pathways in all three strains. However, acetylated proteins from the virulent strains (RH and PYS) were more enriched in the pyruvate metabolism pathway compared to acetylated proteins from PRU strain. Increased levels of histone-acetyl-transferase and glycyl-tRNA synthase were detected in RH strain compared to PRU strain and PYS strain. Both enzymes play roles in stress tolerance and proliferation, key features in the parasite virulence. These findings reveal novel insight into the acetylomic profiles of major T. gondii genotypes and provide a new important resource for further investigations of the roles of the acetylated parasite proteins in the modulation of the host cell response to the infection of T. gondii.

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Okomo-Adhiambo, Margaret, Craig Beattie, and Anette Rink. "cDNA Microarray Analysis of Host-Pathogen Interactions in a Porcine In Vitro Model for Toxoplasma gondii Infection." Infection and Immunity 74, no. 7 (July 2006): 4254–65. http://dx.doi.org/10.1128/iai.00386-05.

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ABSTRACT Toxoplasma gondii induces the expression of proinflammatory cytokines, reorganizes organelles, scavenges nutrients, and inhibits apoptosis in infected host cells. We used a cDNA microarray of 420 annotated porcine expressed sequence tags to analyze the molecular basis of these changes at eight time points over a 72-hour period in porcine kidney epithelial (PK13) cells infected with T. gondii. A total of 401 genes with Cy3 and Cy5 spot intensities of ≥500 were selected for analysis, of which 263 (65.6%) were induced ≥2-fold (expression ratio, ≥2.0; P ≤ 0.05 [t test]) over at least one time point and 48 (12%) were significantly down-regulated. At least 12 functional categories of genes were modulated (up- or down-regulated) by T. gondii. The majority of induced genes were clustered as transcription, signal transduction, host immune response, nutrient metabolism, and apoptosis related. The expression of selected genes altered by T. gondii was validated by quantitative real-time reverse transcription-PCR. These results suggest that significant changes in gene expression occur in response to T. gondii infection in PK13 cells, facilitating further analysis of host-pathogen interactions in toxoplasmosis in a secondary host.

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Contreras, Susana M., Romina T. Zambrano Siri, Elías M. Rivera, Constanza Cristaldi, Laura Kamenetzky, Kami Kim, Marina Clemente, Josefina Ocampo, Laura Vanagas, and Sergio O. Angel. "Architecture, Chromatin and Gene Organization of Toxoplasma gondii Subtelomeres." Epigenomes 6, no. 3 (September 15, 2022): 29. http://dx.doi.org/10.3390/epigenomes6030029.

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Subtelomeres (ST) are chromosome regions that separate telomeres from euchromatin and play relevant roles in various biological processes of the cell. While their functions are conserved, ST structure and genetic compositions are unique to each species. This study aims to identify and characterize the subtelomeric regions of the 13 Toxoplasma gondii chromosomes of the Me49 strain. Here, STs were defined at chromosome ends based on poor gene density. The length of STs ranges from 8.1 to 232.4 kbp, with a gene density of 0.049 genes/kbp, lower than the Me49 genome (0.15 kbp). Chromatin organization showed that H3K9me3, H2A.X, and H3.3 are highly enriched near telomeres and the 5′ end of silenced genes, decaying in intensity towards euchromatin. H3K4me3 and H2A.Z/H2B.Z are shown to be enriched in the 5′ end of the ST genes. Satellite DNA was detected in almost all STs, mainly the sat350 family and a novel satellite named sat240. Beyond the STs, only short dispersed fragments of sat240 and sat350 were found. Within STs, there were 12 functional annotated genes, 59 with unknown functions (Hypothetical proteins), 15 from multigene FamB, and 13 from multigene family FamC. Some genes presented low interstrain synteny associated with the presence of satellite DNA. Orthologues of FamB and FamC were also detected in Neospora caninum and Hammondia hammondi. A re-analysis of previous transcriptomic data indicated that ST gene expression is strongly linked to the adaptation to different situations such as extracellular passage (evolve and resequencing study) and changes in metabolism (lack of acetyl-CoA cofactor). In conclusion, the ST region of the T. gondii chromosomes was defined, the STs genes were determined, and it was possible to associate them with high interstrain plasticity and a role in the adaptability of T. gondii to environmental changes.

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Astegno, Alessandra, Elena Maresi, Mariarita Bertoldi, Valentina La Verde, Alessandro Paiardini, and Paola Dominici. "Unique substrate specificity of ornithine aminotransferase from Toxoplasma gondii." Biochemical Journal 474, no. 6 (March 7, 2017): 939–55. http://dx.doi.org/10.1042/bcj20161021.

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Toxoplasma gondii is a protozoan parasite of medical and veterinary relevance responsible for toxoplasmosis in humans. As an efficacious vaccine remains a challenge, chemotherapy is still the most effective way to combat the disease. In search of novel druggable targets, we performed a thorough characterization of the putative pyridoxal 5′-phosphate (PLP)-dependent enzyme ornithine aminotransferase from T. gondii ME49 (TgOAT). We overexpressed the protein in Escherichia coli and analysed its molecular and kinetic properties by UV-visible absorbance, fluorescence and CD spectroscopy, in addition to kinetic studies of both the steady state and pre-steady state. TgOAT is largely similar to OATs from other species regarding its general transamination mechanism and spectral properties of PLP; however, it does not show a specific ornithine aminotransferase activity like its human homologue, but exhibits both N-acetylornithine and γ-aminobutyric acid (GABA) transaminase activity in vitro, suggesting a role in both arginine and GABA metabolism in vivo. The presence of Val79 in the active site of TgOAT in place of Tyr, as in its human counterpart, provides the necessary room to accommodate N-acetylornithine and GABA, resembling the active site arrangement of GABA transaminases. Moreover, mutation of Val79 to Tyr results in a change of substrate preference between GABA, N-acetylornithine and L-ornithine, suggesting a key role of Val79 in defining substrate specificity. The findings that TgOAT possesses parasite-specific structural features as well as differing substrate specificity from its human homologue make it an attractive target for anti-toxoplasmosis inhibitor design that can be exploited for chemotherapeutic intervention.

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Yong, E. C., E. Y. Chi, and W. R. Henderson. "Toxoplasma gondii alters eicosanoid release by human mononuclear phagocytes: role of leukotrienes in interferon gamma-induced antitoxoplasma activity." Journal of Experimental Medicine 180, no. 5 (November 1, 1994): 1637–48. http://dx.doi.org/10.1084/jem.180.5.1637.

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Toxoplasma gondii tachyzoites markedly alter the profile of eicosanoids released by human mononuclear phagocytes. Freshly isolated, 2-h adherent human monocytes release both cyclooxygenase (e.g., thromboxane [TX] B2, prostaglandin [PG] E2) and 5-lipoxygenase (e.g., leukotriene [LT] B4, LTC4) products of arachidonic acid metabolism after stimulation by the calcium ionophore A23187 or ingestion of opsonized zymosan particles or heat-killed T. gondii. However, after incubation with viable T. gondii, normal and chronic granulomatous disease monocytes release only the cyclooxygenase products TXB2 and PGE2 and fail to form LTB4, LTC4, or other 5-lipoxygenase products. Monocytes maintained in culture for 5 d lose this capacity to release TXB2 and PGE2 after incubation with T. gondii. T. gondii significantly inhibit calcium ionophore A23187-induced LTB4 release by monocyte-derived macrophages; heat-killed organisms do not affect this calcium ionophore A23187-induced release of LTB4. T. gondii-induced inhibition of LTB4 release by calcium ionophore A23187-stimulated monocyte-derived macrophage is reversed by interferon (IFN)-gamma treatment of the monolayers. LTB4 induced extensive damage to the cellular membranes and cytoplasmic contents of the organisms as observed by transmission electron microscopy. Exogenous LTB4 (10(-6) M) induced intracellular killing of ingested T. gondii by non-IFN-gamma-treated monocyte-derived macrophages. IFN-gamma-induced antitoxoplasma activity in monocyte-derived macrophages was inhibited by the selective 5-lipoxygenase inhibitor zileuton but not by the cyclooxygenase inhibitor indomethacin. These findings suggest a novel role for 5-lipoxygenase arachidonic acid products in human macrophage IFN-gamma-induced antitoxoplasma activity.

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Acharjee, Rajib, Keith Talaam, Endah Hartuti, Yuichi Matsuo, Takaya Sakura, Bundutidi Gloria, Shinya Hidano, et al. "Biochemical Studies of Mitochondrial Malate: Quinone Oxidoreductase from Toxoplasma gondii." International Journal of Molecular Sciences 22, no. 15 (July 22, 2021): 7830. http://dx.doi.org/10.3390/ijms22157830.

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Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malate:quinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 μM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.

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Notarangelo, F. M., E. H. Wilson, K. J. Horning, M. A. R. Thomas, T. H. Harris, Q. Fang, C. A. Hunter, and R. Schwarcz. "Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: Implications for schizophrenia." Schizophrenia Research 152, no. 1 (January 2014): 261–67. http://dx.doi.org/10.1016/j.schres.2013.11.011.

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Tjhin, Edwin T., Jenni A. Hayward, Geoffrey I. McFadden, and Giel G. van Dooren. "Characterization of the apicoplast-localized enzyme TgUroD in Toxoplasma gondii reveals a key role of the apicoplast in heme biosynthesis." Journal of Biological Chemistry 295, no. 6 (December 30, 2019): 1539–50. http://dx.doi.org/10.1074/jbc.ra119.011605.

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Apicomplexan parasites such as Toxoplasma gondii possess an unusual heme biosynthesis pathway whose enzymes localize to the mitochondrion, cytosol, or apicoplast, a nonphotosynthetic plastid present in most apicomplexans. To characterize the involvement of the apicoplast in the T. gondii heme biosynthesis pathway, we investigated the role of the apicoplast-localized enzyme uroporphyrinogen III decarboxylase (TgUroD). We found that TgUroD knockdown impaired parasite proliferation, decreased free heme levels in the parasite, and decreased the abundance of heme-containing c-type cytochrome proteins in the parasite mitochondrion. We validated the effects of heme loss on mitochondrial cytochromes by knocking down cytochrome c/c1 heme lyase 1 (TgCCHL1), a mitochondrial enzyme that catalyzes the covalent attachment of heme to c-type cytochromes. TgCCHL1 depletion reduced parasite proliferation and decreased the abundance of c-type cytochromes. We further sought to characterize the overall importance of TgUroD and TgCCHL1 for both mitochondrial and general parasite metabolism. TgUroD depletion decreased cellular ATP levels, mitochondrial oxygen consumption, and extracellular acidification rates. By contrast, depletion of TgCCHL1 neither diminished ATP levels in the parasite nor impaired extracellular acidification rate, but resulted in specific defects in mitochondrial oxygen consumption. Together, our results indicate that the apicoplast has a key role in heme biology in T. gondii and is important for both mitochondrial and general parasite metabolism. Our study highlights the importance of heme and its synthesis in these parasites.

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Nelson, M. M., A. R. Jones, J. C. Carmen, A. P. Sinai, R. Burchmore, and J. M. Wastling. "Modulation of the Host Cell Proteome by the Intracellular Apicomplexan Parasite Toxoplasma gondii." Infection and Immunity 76, no. 2 (October 29, 2007): 828–44. http://dx.doi.org/10.1128/iai.01115-07.

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ABSTRACT To investigate how intracellular parasites manipulate their host cell environment at the molecular level, we undertook a quantitative proteomic study of cells following infection with the apicomplexan parasite Toxoplasma gondii. Using conventional two-dimensional electrophoresis, difference gel electrophoresis (DIGE), and mass spectrometry, we identified host proteins that were consistently modulated in expression following infection. We detected modification of protein expression in key metabolic pathways, including glycolysis, lipid and sterol metabolism, mitosis, apoptosis, and structural-protein expression, suggestive of global reprogramming of cell metabolism by the parasite. Many of the differentially expressed proteins had not been previously implicated in the response to the parasite, while others provide important corroborative protein evidence for previously proposed hypotheses of pathogen-cell interactions. Significantly, over one-third of all modulated proteins were mitochondrial, and this was further investigated by DIGE analysis of a mitochondrion-enriched preparation from infected cells. Comparison of our proteomic data with previous transcriptional studies suggested that a complex relationship exits between transcription and protein expression that may be partly explained by posttranslational modifications of proteins and revealed the importance of investigating protein changes when interpreting transcriptional data. To investigate this further, we used phosphatase treatment and DIGE to demonstrate changes in the phosphorylation states of several key proteins following infection. Overall, our findings indicate that the host cell proteome responds in a dramatic way to T. gondii invasion, in terms of both protein expression changes and protein modifications, and reveal a complex and intimate molecular relationship between host and parasite.

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Arbune, Anca-Adriana, Manuela Arbune, and Victorita Stefanescu. "Parkinsonian Syndrome and Toxoplasmic Encephalitis." Journal of Critical Care Medicine 2, no. 2 (April 1, 2016): 89–92. http://dx.doi.org/10.1515/jccm-2016-0009.

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Abstract Toxoplasmosis encephalitis in patients with human immunodeficiency virus may progress rapidly with a potentially fatal outcome. Less common neurological symptoms associated with this are Parkinsonism, focal dystonia, rubral tremor and hemichorea–hemiballismus syndrome. A 58 year old woman suddenly lost consciousness and was admitted to the emergency service. Her medical history was unremarkable, except for frequent headaches in the last year, recurrent herpes simplex skin lesions and an episode of urticaria. A computer tomography scan showed supra and infra-tentorial lesions on suggestive of cerebral toxoplasmosis. Both Toxoplasma gondii and HIV tests were positive. In the intensive care unit, antiparasitic and antiretroviral drugs were administered, and she recovered from the coma after six weeks but presented with tetraparesis, diplopia, and depression. The LCD4 count increased from 7 to 128/mm3. The neurological lesions slowly resolved over the next two months, although postural instability, rigidity, bradykinesia and predominantly left side tremor persisted. Mild improvement was achieved after the administration of levodopa. Associated Parkinsonian syndrome in HIV patients is a rare condition, explained by the location of the brain and basal ganglia lesions, and by the observed effect of Toxoplasma gondii which increases dopamine metabolism in neural cells. Early HIV diagnostic and treatment are necessary to prevent neurological disability.

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Müller, Joachim, Ghalia Boubaker, Dennis Imhof, Kai Hänggeli, Noé Haudenschild, Anne-Christine Uldry, Sophie Braga-Lagache, Manfred Heller, Luis-Miguel Ortega-Mora, and Andrew Hemphill. "Differential Affinity Chromatography Coupled to Mass Spectrometry: A Suitable Tool to Identify Common Binding Proteins of a Broad-Range Antimicrobial Peptide Derived from Leucinostatin." Biomedicines 10, no. 11 (October 23, 2022): 2675. http://dx.doi.org/10.3390/biomedicines10112675.

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Leucinostatins are antimicrobial peptides with a broad range of activities against infectious agents as well as mammalian cells. The leucinostatin-derivative peptide ZHAWOC_6027 (peptide 6027) was tested in vitro and in vivo for activity against the intracellular apicomplexan parasite Toxoplasma gondii. While highly efficacious in vitro (EC50 = 2 nM), subcutaneous application of peptide 6027 (3 mg/kg/day for 5 days) in mice experimentally infected with T. gondii oocysts exacerbated the infection, caused mild clinical signs and elevated cerebral parasite load. Peptide 6027 also impaired the proliferation and viability of mouse splenocytes, most notably LPS-stimulated B cells, in vitro. To identify common potential targets in Toxoplasma and murine splenocytes, we performed differential affinity chromatography (DAC) with cell-free extracts from T. gondii tachyzoites and mouse spleens using peptide 6027 or an ineffective analogue (peptide 21,358) coupled to N-hydroxy-succinimide sepharose, followed by mass spectrometry. Proteins specifically binding to peptide 6027 were identified in eluates from the peptide 6027 column but not in peptide 21,358 nor the mock column eluates. In T. gondii eluates, 269 proteins binding specifically to peptide 6027 were identified, while in eluates from mouse spleen extracts 645 proteins specifically binding to this peptide were detected. Both datasets contained proteins involved in mitochondrial energy metabolism and in protein processing and secretion. These results suggest that peptide 6027 interacts with common targets in eukaryotes involved in essential pathways. Since this methodology can be applied to various compounds as well as target cell lines or organs, DAC combined with mass spectrometry and proteomic analysis should be considered a smart and 3R-relevant way to identify drug targets in pathogens and hosts, thereby eliminating compounds with potential side effects before performing tedious and costly safety and efficacy assessments in animals or humans.

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MacRae, James I., Lilach Sheiner, Amsha Nahid, Christopher Tonkin, Boris Striepen, and Malcolm J. McConville. "Mitochondrial Metabolism of Glucose and Glutamine Is Required for Intracellular Growth of Toxoplasma gondii." Cell Host & Microbe 12, no. 5 (November 2012): 682–92. http://dx.doi.org/10.1016/j.chom.2012.09.013.

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Munera López, Jonathan, Andrés Mariano Alonso, Maria Julia Figueras, Ana María Saldarriaga Cartagena, Miryam A. Hortua Triana, Luis Diambra, Laura Vanagas, Bin Deng, Silvia N. J. Moreno, and Sergio Oscar Angel. "Analysis of the Interactome of the Toxoplasma gondii Tgj1 HSP40 Chaperone." Proteomes 11, no. 1 (March 1, 2023): 9. http://dx.doi.org/10.3390/proteomes11010009.

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Toxoplasma gondii is an obligate intracellular apicomplexan that causes toxoplasmosis in humans and animals. Central to its dissemination and pathogenicity is the ability to rapidly divide in the tachyzoite stage and infect any type of nucleated cell. Adaptation to different cell contexts requires high plasticity in which heat shock proteins (Hsps) could play a fundamental role. Tgj1 is a type I Hsp40 of T. gondii, an ortholog of the DNAJA1 group, which is essential during the tachyzoite lytic cycle. Tgj1 consists of a J-domain, ZFD, and DNAJ_C domains with a CRQQ C-terminal motif, which is usually prone to lipidation. Tgj1 presented a mostly cytosolic subcellular localization overlapping partially with endoplasmic reticulum. Protein–protein Interaction (PPI) analysis showed that Tgj1 could be implicated in various biological pathways, mainly translation, protein folding, energy metabolism, membrane transport and protein translocation, invasion/pathogenesis, cell signaling, chromatin and transcription regulation, and cell redox homeostasis among others. The combination of Tgj1 and Hsp90 PPIs retrieved only 70 interactors linked to the Tgj1-Hsp90 axis, suggesting that Tgj1 would present specific functions in addition to those of the Hsp70/Hsp90 cycle, standing out invasion/pathogenesis, cell shape motility, and energy pathway. Within the Hsp70/Hsp90 cycle, translation-associated pathways, cell redox homeostasis, and protein folding were highly enriched in the Tgj1-Hsp90 axis. In conclusion, Tgj1 would interact with a wide range of proteins from different biological pathways, which could suggest a relevant role in them.

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Fleige, Tobias, Karsten Fischer, David J. P. Ferguson, Uwe Gross, and Wolfgang Bohne. "Carbohydrate Metabolism in the Toxoplasma gondii Apicoplast: Localization of Three Glycolytic Isoenzymes, the Single Pyruvate Dehydrogenase Complex, and a Plastid Phosphate Translocator." Eukaryotic Cell 6, no. 6 (April 20, 2007): 984–96. http://dx.doi.org/10.1128/ec.00061-07.

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ABSTRACT Many apicomplexan parasites, such as Toxoplasma gondii and Plasmodium species, possess a nonphotosynthetic plastid, referred to as the apicoplast, which is essential for the parasites’ viability and displays characteristics similar to those of nongreen plastids in plants. In this study, we localized several key enzymes of the carbohydrate metabolism of T. gondii to either the apicoplast or the cytosol by engineering parasites which express epitope-tagged fusion proteins. The cytosol contains a complete set of enzymes for glycolysis, which should enable the parasite to metabolize imported glucose into pyruvate. All the glycolytic enzymes, from phosphofructokinase up to pyruvate kinase, are present in the T. gondii genome, as duplicates and isoforms of triose phosphate isomerase, phosphoglycerate kinase, and pyruvate kinase were found to localize to the apicoplast. The mRNA expression levels of all genes with glycolytic products were compared between tachyzoites and bradyzoites; however, a strict bradyzoite-specific expression pattern was observed only for enolase I. The T. gondii genome encodes a single pyruvate dehydrogenase complex, which was located in the apicoplast and absent in the mitochondrion, as shown by targeting of epitope-tagged fusion proteins and by immunolocalization of the native pyruvate dehydrogenase complex. The exchange of metabolites between the cytosol and the apicoplast is likely to be mediated by a phosphate translocator which was localized to the apicoplast. Based on these localization studies, a model is proposed that explains the supply of the apicoplast with ATP and the reduction power, as well as the exchange of metabolites between the cytosol and the apicoplast.

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Fujigaki, Suwako, Kuniaki Saito, Masao Takemura, Naoya Maekawa, Yasuhiro Yamada, Hisayasu Wada, and Mitsuru Seishima. "l-Tryptophan-l-Kynurenine Pathway Metabolism Accelerated by Toxoplasmagondii Infection Is Abolished in Gamma Interferon-Gene-Deficient Mice: Cross-Regulation between Inducible Nitric Oxide Synthase and Indoleamine-2,3-Dioxygenase." Infection and Immunity 70, no. 2 (February 2002): 779–86. http://dx.doi.org/10.1128/iai.70.2.779-786.2002.

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ABSTRACT l-Tryptophan degradation by indoleamine 2,3-dioxygenase (IDO) might have an important role in gamma interferon (IFN-γ)-induced antimicrobial effects. In the present study, the effects of Toxoplasma gondii infection on IDO were investigated by using wild-type and IFN-γ-gene-deficient (knockout) (IFN-γ KO) mice. In wild-type C57BL/6J mice, enzyme activities and mRNA levels for IDO in both lungs and brain were markedly increased and lung l-tryptophan concentrations were dramatically decreased following T. gondii infection. In contrast, these metabolic changes did not occur in T. gondii-infected IFN-γ KO mice or in uninfected IFN-γ KO mice. The levels of inducible nitric oxide synthase (iNOS) induction in infected IFN-γ KO mice were high in lungs and low in brain compared to those in infected wild-type mice. The extent of increased mRNA expression of T. gondii surface antigen gene 2 (SAG2) induced in lungs and brain by T. gondii infection was significantly enhanced in IFN-γ KO mice compared to wild-type mice on day 7 postinfection. Treatment with N-nitro-l-arginine methyl ester, an iNOS inhibitor, increased the levels of SAG2 mRNA in brain but not in lungs and of plasma l-kynurenine after T. gondii infection. This in vivo study provides evidence that l-tryptophan depletion caused by T. gondii is directly mediated by IFN-γ in the lungs, where iNOS is not induced by IFN-γ. This study suggests that there is an antitoxoplasma mechanism of cross-regulation between iNOS and IDO and that the expression of the main antiparasite effector mechanisms for iNOS and/or IDO may vary among tissues.

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Niu, Zhipeng, Shu Ye, Jiaojiao Liu, Mengyu Lyu, Lilan Xue, Muxiao Li, Congcong Lyu, Junlong Zhao, and Bang Shen. "Two apicoplast dwelling glycolytic enzymes provide key substrates for metabolic pathways in the apicoplast and are critical for Toxoplasma growth." PLOS Pathogens 18, no. 11 (November 30, 2022): e1011009. http://dx.doi.org/10.1371/journal.ppat.1011009.

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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.

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Pereira Filho, Adalberto Alves, Mariana Maciel Cunha, Mariana Alves Stanton, Lydia Fumiko Yamaguchi, Massuo Jorge Kato, and Érica S. Martins-Duarte. "In Vitro Activity of Essential Oils from Piper Species (Piperaceae) against Tachyzoites of Toxoplasma gondii." Metabolites 13, no. 1 (January 6, 2023): 95. http://dx.doi.org/10.3390/metabo13010095.

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Toxoplasmosis is a tropical and neglected disease caused by the parasitic protozoa Toxplasma gondii. Conventional treatment with sulfadiazine and pyrimethamine plus folinic acid, has some drawbacks, such as inefficacy in the chronic phase, toxic side effects, and potential cases of resistance have been observed. In this study, the activity of essential oils (EOs) from three Piper species and their main constituents, including α-Pinene (Piper lindbergii and P. cernuum), β-Pinene (P. cernuum), and dillapiole (P. aduncum), were evaluated against tachyzoites of T. gondii. α-Pinene was more active [(IC50 0.3265 (0.2958 to 0.3604) μg/mL)] against tachyzoites than P. lindbergii EO [0.8387 (0.6492 to 1.084) μg/mL]. Both α-Pinene and P. lindbergii EO exhibited low cytotoxicity against NHDF cells, with CC50 41.37 (37.64 to 45.09) µg/mL and 83.80 (75.42 to 91.34) µg/mL, respectively, suggesting they could be of potential use against toxoplasmosis.

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Liu, Cheng-Hu, Fabiana S. Machado, Rishu Guo, Kim E. Nichols, A. Wesley Burks, Julio C. Aliberti, and Xiao-Ping Zhong. "Diacylglycerol kinase ζ regulates microbial recognition and host resistance to Toxoplasma gondii." Journal of Experimental Medicine 204, no. 4 (March 19, 2007): 781–92. http://dx.doi.org/10.1084/jem.20061856.

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Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the ζ isoform of the DGK family (DGKζ) is expressed in macrophages (Mφ) and dendritic cells. DGKζ deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor α production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKζ negatively controls the phosphatidylinositol 3–kinase (PI3K)–Akt pathway and that inhibition of PI3K activity or treatment with PA can restore lipopolysaccharide-induced IL-12 production by DGKζ-deficient Mφ. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKζ promotes TLR responses via a pathway involving inhibition of PI3K.

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Romano, Julia D., Sabrina Sonda, Emily Bergbower, Maria Elisa Smith, and Isabelle Coppens. "Toxoplasma gondiisalvages sphingolipids from the host Golgi through the rerouting of selected Rab vesicles to the parasitophorous vacuole." Molecular Biology of the Cell 24, no. 12 (June 15, 2013): 1974–95. http://dx.doi.org/10.1091/mbc.e12-11-0827.

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The obligate intracellular protozoan Toxoplasma gondii actively invades mammalian cells and, upon entry, forms its own membrane-bound compartment, named the parasitophorous vacuole (PV). Within the PV, the parasite replicates and scavenges nutrients, including lipids, from host organelles. Although T. gondii can synthesize sphingolipids de novo, it also scavenges these lipids from the host Golgi. How the parasite obtains sphingolipids from the Golgi remains unclear, as the PV avoids fusion with host organelles. In this study, we explore the host Golgi–PV interaction and evaluate the importance of host-derived sphingolipids for parasite growth. We demonstrate that the PV preferentially localizes near the host Golgi early during infection and remains closely associated with this organelle throughout infection. The parasite subverts the structure of the host Golgi, resulting in its fragmentation into numerous ministacks, which surround the PV, and hijacks host Golgi–derived vesicles within the PV. These vesicles, marked with Rab14, Rab30, or Rab43, colocalize with host-derived sphingolipids in the vacuolar space. Scavenged sphingolipids contribute to parasite replication since alterations in host sphingolipid metabolism are detrimental for the parasite's growth. Thus our results reveal that T. gondii relies on host-derived sphingolipids for its development and scavenges these lipids via Golgi-derived vesicles.

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Maclean, Andrew E., Hannah R. Bridges, Mariana F. Silva, Shujing Ding, Jana Ovciarikova, Judy Hirst, and Lilach Sheiner. "Complexome profile of Toxoplasma gondii mitochondria identifies divergent subunits of respiratory chain complexes including new subunits of cytochrome bc1 complex." PLOS Pathogens 17, no. 3 (March 2, 2021): e1009301. http://dx.doi.org/10.1371/journal.ppat.1009301.

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The mitochondrial electron transport chain (mETC) and F1Fo-ATP synthase are of central importance for energy and metabolism in eukaryotic cells. The Apicomplexa, important pathogens of humans causing diseases such as toxoplasmosis and malaria, depend on their mETC in every known stage of their complicated life cycles. Here, using a complexome profiling proteomic approach, we have characterised the Toxoplasma mETC complexes and F1Fo-ATP synthase. We identified and assigned 60 proteins to complexes II, IV and F1Fo-ATP synthase of Toxoplasma, of which 16 have not been identified previously. Notably, our complexome profile elucidates the composition of the Toxoplasma complex III, the target of clinically used drugs such as atovaquone. We identified two new homologous subunits and two new parasite-specific subunits, one of which is broadly conserved in myzozoans. We demonstrate all four proteins are essential for complex III stability and parasite growth, and show their depletion leads to decreased mitochondrial potential, supporting their assignment as complex III subunits. Our study highlights the divergent subunit composition of the apicomplexan mETC and F1Fo-ATP synthase complexes and sets the stage for future structural and drug discovery studies.

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Bottova, Iveta, Ursula Sauder, Vesna Olivieri, Adrian B. Hehl, and Sabrina Sonda. "The P-glycoprotein Inhibitor GF120918 Modulates Ca2+-Dependent Processes and Lipid Metabolism in Toxoplasma Gondii." PLoS ONE 5, no. 4 (April 8, 2010): e10062. http://dx.doi.org/10.1371/journal.pone.0010062.

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Blader, Ira J., and Anita A. Koshy. "Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond." Eukaryotic Cell 13, no. 8 (June 20, 2014): 965–76. http://dx.doi.org/10.1128/ec.00081-14.

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ABSTRACTIntracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections.Toxoplasma gondiiis an obligate intracellular protozoan that infects ∼30% of the world's population and causes severe and life-threatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence ofToxoplasmain humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by whichToxoplasmainteracts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.

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Larrazabal, Camilo, Liliana M. R. Silva, Learta Pervizaj-Oruqaj, Susanne Herold, Carlos Hermosilla, and Anja Taubert. "P-Glycoprotein Inhibitors Differently Affect Toxoplasma gondii, Neospora caninum and Besnoitia besnoiti Proliferation in Bovine Primary Endothelial Cells." Pathogens 10, no. 4 (March 25, 2021): 395. http://dx.doi.org/10.3390/pathogens10040395.

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Apicomplexan parasites are obligatory intracellular protozoa. In the case of Toxoplasma gondii, Neospora caninum or Besnoitia besnoiti, to ensure proper tachyzoite production, they need nutrients and cell building blocks. However, apicomplexans are auxotrophic for cholesterol, which is required for membrane biosynthesis. P-glycoprotein (P-gp) is a transmembrane transporter involved in xenobiotic efflux. However, the physiological role of P-gp in cholesterol metabolism is unclear. Here, we analyzed its impact on parasite proliferation in T. gondii-, N. caninum- and B. besnoiti-infected primary endothelial cells by applying different generations of P-gp inhibitors. Host cell treatment with verapamil and valspodar significantly diminished tachyzoite production in all three parasite species, whereas tariquidar treatment affected proliferation only in B. besnoiti. 3D-holotomographic analyses illustrated impaired meront development driven by valspodar treatment being accompanied by swollen parasitophorous vacuoles in the case of T. gondii. Tachyzoite and host cell pre-treatment with valspodar affected infection rates in all parasites. Flow cytometric analyses revealed verapamil treatment to induce neutral lipid accumulation. The absence of a pronounced anti-parasitic impact of tariquidar, which represents here the most selective P-gp inhibitor, suggests that the observed effects of verapamil and valspodar are associated with mechanisms independent of P-gp. Out of the three species tested here, this compound affected only B. besnoiti proliferation and its effect was much milder as compared to verapamil and valspodar.

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Liu, Cheng-hu, Fabiana S. Machado, Rishu Guo, Kim E. Nichols, A. Wesley Burks, Julio C. Aliberti, and Xiao-Ping Zhong. "Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii (51.16)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S99. http://dx.doi.org/10.4049/jimmunol.178.supp.51.16.

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Abstract Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting diacylglycerol (DAG) to phosphatidic acid (PA). Here, we demonstrate that the ζ isoform of the DGK family (DGKζ) is expressed in macrophages (Mϕ) and dendritic cells (DC). DGKζ deficiency results in impaired IL-12 and TNFα production following TLR stimulation in vitro and in vivo, increased resistance to endotoxin shock, and enhanced susceptibility to Toxoplasma gondii infection. We further show that DGKζ negatively controls the PI3K-Akt pathway and that inhibition of PI3K activity can restore LPS-induced IL-12 production by DGKζ deficient macrophages. Collectively, our data provide the first genetic evidence that an enzyme involved in DAG/PA metabolism plays an important role in innate immunity and indicate that DGKζ promotes TLR responses via a pathway involving inhibition of PI3K.

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Mbekeani, Alison, Will Stanley, Vishal Kalel, Noa Dahan, Einat Zalckvar, Lilach Sheiner, Wolfgang Schliebs, Ralf Erdmann, Ehmke Pohl, and Paul Denny. "Functional Analyses of a Putative, Membrane-Bound, Peroxisomal Protein Import Mechanism from the Apicomplexan Protozoan Toxoplasma gondii." Genes 9, no. 9 (August 29, 2018): 434. http://dx.doi.org/10.3390/genes9090434.

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Peroxisomes are central to eukaryotic metabolism, including the oxidation of fatty acids—which subsequently provide an important source of metabolic energy—and in the biosynthesis of cholesterol and plasmalogens. However, the presence and nature of peroxisomes in the parasitic apicomplexan protozoa remains controversial. A survey of the available genomes revealed that genes encoding peroxisome biogenesis factors, so-called peroxins (Pex), are only present in a subset of these parasites, the coccidia. The basic principle of peroxisomal protein import is evolutionarily conserved, proteins harbouring a peroxisomal-targeting signal 1 (PTS1) interact in the cytosol with the shuttling receptor Pex5 and are then imported into the peroxisome via the membrane-bound protein complex formed by Pex13 and Pex14. Surprisingly, whilst Pex5 is clearly identifiable, Pex13 and, perhaps, Pex14 are apparently absent from the coccidian genomes. To investigate the functionality of the PTS1 import mechanism in these parasites, expression of Pex5 from the model coccidian Toxoplasma gondii was shown to rescue the import defect of Pex5-deleted Saccharomyces cerevisiae. In support of these data, green fluorescent protein (GFP) bearing the enhanced (e)PTS1 known to efficiently localise to peroxisomes in yeast, localised to peroxisome-like bodies when expressed in Toxoplasma. Furthermore, the PTS1-binding domain of Pex5 and a PTS1 ligand from the putatively peroxisome-localised Toxoplasma sterol carrier protein (SCP2) were shown to interact in vitro. Taken together, these data demonstrate that the Pex5–PTS1 interaction is functional in the coccidia and indicate that a nonconventional peroxisomal import mechanism may operate in the absence of Pex13 and Pex14.

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dos Santos, Bruna Ramos, Amanda Bruno da Silva Bellini Ramos, Renata Priscila Barros de Menezes, Marcus Tullius Scotti, Fábio Antônio Colombo, Marcos José Marques, and Juliana Quero Reimão. "Repurposing the Medicines for Malaria Venture’s COVID Box to discover potent inhibitors of Toxoplasma gondii, and in vivo efficacy evaluation of almitrine bismesylate (MMV1804175) in chronically infected mice." PLOS ONE 18, no. 7 (July 7, 2023): e0288335. http://dx.doi.org/10.1371/journal.pone.0288335.

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Toxoplasmosis, caused by the obligate intracellular parasite Toxoplasma gondii, affects about one-third of the world’s population and can cause severe congenital, neurological and ocular issues. Current treatment options are limited, and there are no human vaccines available to prevent transmission. Drug repurposing has been effective in identifying anti-T. gondii drugs. In this study, the screening of the COVID Box, a compilation of 160 compounds provided by the "Medicines for Malaria Venture" organization, was conducted to explore its potential for repurposing drugs to combat toxoplasmosis. The objective of the present work was to evaluate the compounds’ ability to inhibit T. gondii tachyzoite growth, assess their cytotoxicity against human cells, examine their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and investigate the potential of one candidate drug through an experimental chronic model of toxoplasmosis. Early screening identified 29 compounds that could inhibit T. gondii survival by over 80% while keeping human cell survival up to 50% at a concentration of 1 μM. The Half Effective Concentrations (EC50) of these compounds ranged from 0.04 to 0.92 μM, while the Half Cytotoxic Concentrations (CC50) ranged from 2.48 to over 50 μM. Almitrine was chosen for further evaluation due to its favorable characteristics, including anti-T. gondii activity at nanomolar concentrations, low cytotoxicity, and ADMET properties. Administering almitrine bismesylate (Vectarion®) orally at dose of 25 mg/kg/day for ten consecutive days resulted in a statistically significant (p < 0.001) reduction in parasite burden in the brains of mice chronically infected with T. gondii (ME49 strain). This was determined by quantifying the RNA of living parasites using real-time PCR. The presented results suggest that almitrine may be a promising drug candidate for additional experimental studies on toxoplasmosis and provide further evidence of the potential of the MMV collections as a valuable source of drugs to be repositioned for infectious diseases.

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Yang, Xuke, Xiaoyan Yin, Jiaojiao Liu, Zhipeng Niu, Jichao Yang, and Bang Shen. "Essential role of pyrophosphate homeostasis mediated by the pyrophosphate-dependent phosphofructokinase in Toxoplasma gondii." PLOS Pathogens 18, no. 2 (February 1, 2022): e1010293. http://dx.doi.org/10.1371/journal.ppat.1010293.

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Many biosynthetic pathways produce pyrophosphate (PPi) as a by-product, which is cytotoxic if accumulated at high levels. Pyrophosphatases play pivotal roles in PPi detoxification by converting PPi to inorganic phosphate. A number of apicomplexan parasites, including Toxoplasma gondii and Cryptosporidium parvum, express a PPi-dependent phosphofructokinase (PPi-PFK) that consumes PPi to power the phosphorylation of fructose-6-phosphate. However, the physiological roles of PPi-PFKs in these organisms are not known. Here, we report that Toxoplasma expresses both ATP- and PPi-dependent phosphofructokinases in the cytoplasm. Nonetheless, only PPi-PFK was indispensable for parasite growth, whereas the deletion of ATP-PFK did not affect parasite proliferation or virulence. The conditional depletion of PPi-PFK completely arrested parasite growth, but it did not affect the ATP level and only modestly reduced the flux of central carbon metabolism. However, PPi-PFK depletion caused a significant increase in cellular PPi and decreased the rates of nascent protein synthesis. The expression of a cytosolic pyrophosphatase in the PPi-PFK depletion mutant reduced its PPi level and increased the protein synthesis rate, therefore partially rescuing its growth. These results suggest that PPi-PFK has a major role in maintaining pyrophosphate homeostasis in T. gondii. This role may allow PPi-PFK to fine-tune the balance of catabolism and anabolism and maximize the utilization efficiency for carbon nutrients derived from host cells, increasing the success of parasitism. Moreover, PPi-PFK is essential for parasite propagation and virulence in vivo but it is not present in human hosts, making it a potential drug target to combat toxoplasmosis.

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Pace, Douglas A., Jianmin Fang, Roxana Cintron, Melissa D. Docampo, and Silvia N. J. Moreno. "Overexpression of a cytosolic pyrophosphatase (TgPPase) reveals a regulatory role of PPi in glycolysis for Toxoplasma gondii." Biochemical Journal 440, no. 2 (November 14, 2011): 229–40. http://dx.doi.org/10.1042/bj20110641.

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PPi is a critical element of cellular metabolism as both an energy donor and as an allosteric regulator of several metabolic pathways. The apicomplexan parasite Toxoplasma gondii uses PPi in place of ATP as an energy donor in at least two reactions: the glycolytic PPi-dependent PFK (phosphofructokinase) and V-H+-PPase [vacuolar H+-translocating PPase (pyrophosphatase)]. In the present study, we report the cloning, expression and characterization of cytosolic TgPPase (T. gondii soluble PPase). Amino acid sequence alignment and phylogenetic analysis indicates that the gene encodes a family I soluble PPase. Overexpression of the enzyme in extracellular tachyzoites led to a 6-fold decrease in the cytosolic concentration of PPi relative to wild-type strain RH tachyzoites. Unexpectedly, this subsequent reduction in PPi was associated with a higher glycolytic flux in the overexpressing mutants, as evidenced by higher rates of proton and lactate extrusion. In addition to elevated glycolytic flux, TgPPase-overexpressing tachyzoites also possessed higher ATP concentrations relative to wild-type RH parasites. These results implicate PPi as having a significant regulatory role in glycolysis and, potentially, other downstream processes that regulate growth and cell division.

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Krishnan, Aarti, and Dominique Soldati-Favre. "Amino Acid Metabolism in Apicomplexan Parasites." Metabolites 11, no. 2 (January 20, 2021): 61. http://dx.doi.org/10.3390/metabo11020061.

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Obligate intracellular pathogens have coevolved with their host, leading to clever strategies to access nutrients, to combat the host’s immune response, and to establish a safe niche for intracellular replication. The host, on the other hand, has also developed ways to restrict the replication of invaders by limiting access to nutrients required for pathogen survival. In this review, we describe the recent advancements in both computational methods and high-throughput –omics techniques that have been used to study and interrogate metabolic functions in the context of intracellular parasitism. Specifically, we cover the current knowledge on the presence of amino acid biosynthesis and uptake within the Apicomplexa phylum, focusing on human-infecting pathogens: Toxoplasma gondii and Plasmodium falciparum. Given the complex multi-host lifecycle of these pathogens, we hypothesize that amino acids are made, rather than acquired, depending on the host niche. We summarize the stage specificities of enzymes revealed through transcriptomics data, the relevance of amino acids for parasite pathogenesis in vivo, and the role of their transporters. Targeting one or more of these pathways may lead to a deeper understanding of the specific contributions of biosynthesis versus acquisition of amino acids and to design better intervention strategies against the apicomplexan parasites.

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Journal articles on the topic 'Metabolism in Toxoplasma Gondii'

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