bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–04–20
eleven papers selected by
Lakesh Kumar, BITS Pilani
  1. Tartrolon E rapidly blocks Toxoplasma gondii capacity to invade host cells.
  2. Role of Toxoplasma gondii p24δ in Regulating the Transition from Tachyzoite to Bradyzoite Development.
  3. GRA12 is a common virulence factor across Toxoplasma gondii strains and mouse subspecies.
  4. Cytoskeletal alterations in neuronal cells implicate Toxoplasma gondii secretory machinery and host microRNA-containing extracellular vesicles.
  5. ICAM-1/CD18-mediated sequestration of parasitized phagocytes in cortical capillaries promotes neuronal colonization by Toxoplasma gondii.
  6. Role of Toxoplasma surface proteins in host-parasite immune modulation.
  7. Anti-Toxoplasma and Antioxidant Activity of a Terpene and Methyl-Ester-Rich Subfraction from Pleopeltis crassinervata.
  8. P300 regulates Melanophilin expression by modulating TFAP2A binding through histone acetylation.
  9. Exposure of Eurasian blackbird (Turdus merula) to Toxoplasma gondii in an urban area in Thuringia, Germany.
  10. Microtubule acetylation is a biomarker of cytoplasmic health during cellular senescence.
  11. SIRT7 Is a Lysine Deacylase with a Preference for Depropionylation and Demyristoylation.
  1. Int J Parasitol Drugs Drug Resist. 2025 Apr 14. pii: S2211-3207(25)00014-4. [Epub ahead of print]28 100591
    Tartrolon E rapidly blocks Toxoplasma gondii capacity to invade host cells.
    Fernanda G Fumuso, Jason A Clement, Matthew J Todd, Roberta M O'Connor.
      Toxoplasmosis is a worldwide parasitic disease caused by the apicomplexan Toxoplasma gondii. Severe neurological illness occurs in immunosuppressed patients, and congenital disorders can follow transplacental primo infection during pregnancy. New effective antiparasitic drugs are needed since chronic cystic stages are resistant to current available treatments, and some of the congenital infections are unresponsive to available therapeutics. Tartrolon E (trtE) is a marine secondary metabolite that has high selectivity against human and animal apicomplexan parasites including T. gondii, Cryptosporidium parvum and Plasmodium falciparum. We evaluated the effect of the compound on extracellular tachyzoite viability, morphology, membrane permeability and its ability to block host cell attachment and/or invasion. While 80 % of T. gondii infective capacity is blocked after only 30 min of compound treatment, parasite viability, morphology, membrane integrity and host cell attachment were unaffected until after 4 h of treatment. These effects were irreversible when parasites were allowed to infect host cells after trtE treatment. Drug exposure for more than 4 h significantly affected tachyzoite survival and altered parasite morphology. The mechanism of action of trtE is still unknown but includes blocking parasite invasion processes. Further research is needed to determine the molecular target of trtE to further progress the compound as an antiparasitic candidate.
    Keywords:  Antiparasitic compounds; Drug candidates; Marine natural compounds; Toxoplasmosis
    DOI:  https://doi.org/10.1016/j.ijpddr.2025.100591
  2. Int J Mol Sci. 2025 Apr 03. pii: 3331. [Epub ahead of print]26(7):
    Role of Toxoplasma gondii p24δ in Regulating the Transition from Tachyzoite to Bradyzoite Development.
    Zifu Zhu, Zhu Ying, Yanqun Pei, Zhili Shan, Jing Peng, Ming Sun, Qun Liu, Jing Liu.
      Toxoplasma gondii is an obligate intracellular parasite capable of infecting warm-blooded vertebrates, including humans. In its intermediate hosts, T. gondii can transition between two life stages: the rapidly replicating tachyzoite and the quiescent bradyzoite. In Saccharomyces cerevisiae, the p24 protein acts as a cargo receptor, cycling between the ER and Golgi in the early secretory pathway to recruit cargo proteins into nascent vesicles. However, the function of p24 in T. gondii remains undefined. In this study, we identified four p24 proteins in T. gondii, with Tgp24δ specifically localizing to the ER-Golgi system. Loss of p24δ in a type Ι strain (RHΔku80) significantly reduced proliferation and virulence in mice. Transcriptome and proteomic analyses showed that TgΔp24δ tachyzoites expressed high levels of bradyzoite-specific genes, including bag1, ldh2, and bpk1, under standard culture conditions. Additional data indicate that TgΔp24δ tachyzoites can differentiate and form bradyzoites in vitro. This suggests that Tgp24δ is important for the parasite's growth.
    Keywords:  T. gondii; Tgp24δ protein; bradyzoite; bradyzoite-specific genes; differentiation
    DOI:  https://doi.org/10.3390/ijms26073331
  3. Nat Commun. 2025 Apr 16. 16(1): 3570
    GRA12 is a common virulence factor across Toxoplasma gondii strains and mouse subspecies.
    Francesca Torelli, Simon Butterworth, Eloise Lockyer, Ana N Matias, Franziska Hildebrandt, Ok-Ryul Song, Jennifer Pearson-Farr, Moritz Treeck.
      Toxoplasma gondii parasites exhibit extraordinary host promiscuity owing to over 250 putative secreted proteins that disrupt host cell functions, enabling parasite persistence. However, most of the known effector proteins are specific to Toxoplasma genotypes or hosts. To identify virulence factors that function across different parasite isolates and mouse strains that differ in susceptibility to infection, we performed systematic pooled in vivo CRISPR-Cas9 screens targeting the Toxoplasma secretome. We identified several proteins required for infection across parasite strains and mouse species, of which the dense granule protein 12 (GRA12) emerged as the most important effector protein during acute infection. GRA12 deletion in IFNγ-activated macrophages results in collapsed parasitophorous vacuoles and increased host cell necrosis, which is partially rescued by inhibiting early parasite egress. GRA12 orthologues from related coccidian parasites, including Neospora caninum and Hammondia hammondi, complement TgΔGRA12 in vitro, suggesting a common mechanism of protection from immune clearance by their hosts.
    DOI:  https://doi.org/10.1038/s41467-025-58876-2
  4. Sci Rep. 2025 Apr 12. 15(1): 12606
    Cytoskeletal alterations in neuronal cells implicate Toxoplasma gondii secretory machinery and host microRNA-containing extracellular vesicles.
    Thomas Mazza, Morteza Aslanzadeh, Lïse Berentsen, Franziska Bonath, Marc R Friedländer, Antonio Barragan.
      The widespread protozoan Toxoplasma gondii chronically infects neural tissue in vertebrates and is linked to various neurological and neuropsychiatric disorders in humans. However, its effects on sparsely infected neurons and on broader neural circuits remain elusive. Our study reveals that T. gondii infection disrupts cytoskeletal dynamics in SH-SY5Y neuronal cells and primary cortical neurons. Infected neuronal cells undergo significant cytomorphological changes, including retraction of dendritic extensions and alterations in microtubule and F-actin networks, across both parasite genotypes I and II. These cytoskeletal alterations were notably diminished in cells exposed to T. gondii mutants with impaired secretion via the MYR translocon, and were independent of intraneuronal parasite replication. Moreover, a bystander effect was observed, with supernatants from T. gondii-challenged cells inducing similar cytoskeletal changes in uninfected cells. Analyses of extracellular vesicles (EVs) in supernatants revealed differential expression of host microRNAs in response to infection, most notably the upregulation of miR-221-3p, a microRNA not previously associated with T. gondii. The data indicate that unidentified parasite-derived effector(s) secreted via the MYR translocon, in conjunction with MYR-independently induced EV-associated host microRNAs, mediate cytoskeletal alterations in both infected and bystander neuronal cells. The findings provide new insights into molecular mechanisms by which T. gondii infection may disrupt neural networks, shedding light on its potential role in neuronal dysregulation.
    Keywords:  Apicomplexan parasites; Cytoskeleton; Extracellular vesicle; Host–pathogen interaction; Neuron; microRNA
    DOI:  https://doi.org/10.1038/s41598-025-96298-8
  5. Nat Commun. 2025 Apr 14. 16(1): 3529
    ICAM-1/CD18-mediated sequestration of parasitized phagocytes in cortical capillaries promotes neuronal colonization by Toxoplasma gondii.
    Matias E Rodriguez, Ali Hassan, Nikolaos Linaroudis, Felix Harryson-Oliveberg, Arne L Ten Hoeve, Antonio Barragan.
      Microbial translocation across the blood-brain barrier (BBB) is a prerequisite for colonization of the central nervous system. The obligate intracellular parasite Toxoplasma gondii chronically infects the brain parenchyma of humans and animals, in a remarkably stealthy fashion. We investigated the mechanisms of BBB traversal by T. gondii (genotypes I, II, III) and T. gondii-infected leukocytes, using intracarotid arterial delivery into the cerebral circulation of mice. Unexpectedly, parasitized dendritic cells (DCs) and other peripheral blood mononuclear cells were found to persistently sequester within cortical capillaries. Post-replicative egress of T. gondii from sequestered DCs was followed by rapid parasite localization within cortical neurons. Infection-induced microvascular inflammation dramatically elevated the sequestration of parasitized DCs, while treatments targeting the ICAM-1/CD18 leukocyte adhesion axis with blocking antibodies strongly reverted sequestration. The parasite effectors TgWIP and GRA15, known to promote leukocyte hypermigration and inflammatory activation, further increased both the capillary sequestration of infected DCs and cerebral parasite loads in a strain-dependent manner. These findings reveal that the sequestration of parasitized leukocytes in cortical capillaries, with subsequent BBB traversal following parasite egress, provides a mechanism for T. gondii's rapid access to cortical neurons during primary infection.
    DOI:  https://doi.org/10.1038/s41467-025-58655-z
  6. Cell Mol Biol (Noisy-le-grand). 2025 Apr 15. 71(3): 146-150
    Role of Toxoplasma surface proteins in host-parasite immune modulation.
    Hawri Mustafa Bakr.
      Toxoplasma gondii is an intracellular parasite that evades the host immune system using its surface proteins. These proteins, including SAGs, MICs, and GRA, regulate host immune responses by interacting with immune receptors, modifying immune signaling pathways, and suppressing inflammatory responses. This modulation allows the parasite to survive and replicate within host cells. The study employed various biochemical and immunological methods, such as ELISA, flow cytometry, RT-PCR, Surface Plasmon Resonance (SPR), and co-immunoprecipitation (Co-IP), to assess the effects of these surface proteins on immune responses. Results showed that Toxoplasma surface proteins reduced the production of inflammatory cytokines (e.g., TNF-α) and increased anti-inflammatory cytokines (e.g., IL-10). SPR analyses confirmed direct interactions between parasite proteins and host immune receptors, altering immune-related signaling pathways. These findings emphasize the significant role of Toxoplasma surface proteins in suppressing the immune system and promoting parasite survival and replication. A deeper understanding of these mechanisms could aid in developing new therapeutic strategies and vaccines against toxoplasmosis. Future research could focus on identifying additional signaling pathways and creating targeted interventions.
    DOI:  https://doi.org/10.14715/cmb/2025.71.3.17
  7. Antioxidants (Basel). 2025 Mar 14. pii: 342. [Epub ahead of print]14(3):
    Anti-Toxoplasma and Antioxidant Activity of a Terpene and Methyl-Ester-Rich Subfraction from Pleopeltis crassinervata.
    Jhony Anacleto-Santos, Ricardo Mondragón-Flores, Perla Yolanda López-Camacho, María Isabel Rivera-Vivanco, Teresa de Jesús López-Pérez, Brenda Casarrubias-Tabares, Mónica Mondragón-Castelán, Sirenia González-Pozos, Fernando Calzada, Elisa Vega-Ávila, Norma Rivera-Fernández.
      Pleopeltis crassinervata has demonstrated antimicrobial effects, including anti-Toxoplasma activity, which has been attributed to the presence of compounds such as terpenes and fatty acid methyl esters. In this study, the effects of P. crassinervata hexane subfraction one (Hsf1) on the Toxoplasma gondii tachyzoite ultrastructure were evaluated using TEM and SEM, and lytic cycle processes such as adhesion, invasion, and proliferation were evaluated using phase-contrast microscopy. Additionally, the antioxidant capacity of the subfraction and its main compounds (phytol and hexadecenoic acid methyl ester) were determined as well as their effects on parasite viability. Hsf1 exhibited a dose-dependent inhibitory effect on the lytic process at a concentration of 47.2 µg/mL. Among the eighteen compounds identified in this subfraction, six were evaluated, of which two (phytol and hexadecanoic acid methyl ester) significantly reduced the viability of T. gondii to 0.11% and 16.6%, respectively, at a concentration of 100 µg/mL. Additionally, Hsf1 demonstrated an antioxidant capacity of 30% as assessed using the ORAC method. The two active compounds also exhibited antioxidant properties, with antioxidant capacities of 13.33% and 33% for hexadecanoic acid methyl ester and phytol, respectively, at concentrations up to 15.4 mg/mL. Hsf1 showed membrane damage and conoid extrusion in T. gondii tachyzoites, suggesting direct interference with the lytic cycle of the parasite. These findings underscore the therapeutic potential of Hsf1 as a promising tool for controlling infections caused by T. gondii, thereby providing an alternative in the search for new antiparasitic agents. However, further research is required to determine the in vivo pharmacological effects and properties of these compounds with potential anti-Toxoplasma activity.
    Keywords:  FAME; ORAC method; Toxoplasma gondii; antioxidant; phytol
    DOI:  https://doi.org/10.3390/antiox14030342
  8. J Dermatol Sci. 2025 Apr 03. pii: S0923-1811(25)00042-8. [Epub ahead of print]
    P300 regulates Melanophilin expression by modulating TFAP2A binding through histone acetylation.
    Chan Song Jo, Zhao Hairu, Gyu Cheol Baek, Eun Jeong Lee, Chang Mo You, Jae Sung Hwang.
       BACKGROUND: Melanophilin is an effector protein that interacts with Rab27a and Myosin Va and regulates melanosome transport in melanocytes. Type 3 Griscelli syndrome, a mutation in Mlph gene, is characterized by partial pigment dilution, without any associated systemic problems. P300 plays roles in histone acetylation and changes chromatin state. There has been considerable interest in epigenetic regulation of melanocytes. However, epigenetic control of Mlph expression is still poorly understood.
    OBJECTIVES: We investigated the underlying mechanisms by which P300 controls Mlph expression by histone acetylation.
    METHODS: siRNA transfection was performed to knock down gene expression. We used numerous methods, including western blotting, quantitative PCR (qPCR), co-immunoprecipitation (co-IP), and chromatin immunoprecipitation (ChIP), to identify the mechanisms of epigenetic regulation via P300.
    RESULTS: Perinuclear aggregation of melanosome is induced and Mlph expression is decreased by knockdown of P300. In this process, TFAP2A acts as a transcription factor and regulates Mlph transcription. Knockdown of P300 decreased TFAP2A binding to intron region of Mlph and H3K27ac level and then finally reduced Mlph expression. Our study revealed that P300 facilitates an open chromatin state through acetylation of H3K27 and TFAP2A could regulate Mlph expression by binding to the intron 1 region of Mlph.
    CONCLUSION: Mlph expression is regulated by epigenetic regulation via P300 in melanocytes. These findings provide new insights into the epigenetic mechanism of melanosome transport.
    Keywords:  Epigenetics; Melanosome transport; Mlph; P300; TFAP2A
    DOI:  https://doi.org/10.1016/j.jdermsci.2025.04.002
  9. Int J Parasitol Parasites Wildl. 2025 Aug;27 101060
    Exposure of Eurasian blackbird (Turdus merula) to Toxoplasma gondii in an urban area in Thuringia, Germany.
    Mike Heddergott, Rainer Hunold, Natalia Osten-Sacken.
      Toxoplasma gondii is a zoonotic, globally distributed, obligate intracellular protozoan. Within the context of the 'One Health' approach, studies on toxoplasmosis are essential as it affects humans as well as domestic and wild animals, including birds. The Eurasian blackbird (Turdus merula) is one of the most common songbird species in Germany and previous studies have shown that they can be infected with T. gondii. The aim of the present study was to analyze T. gondii exposure in an urban blackbird population in Germany. Between 2018 and 2022, we collected fresh blackbird carcasses from an urban population in Heilbad Heiligenstadt, a small town in the German state of Thuringia. Altogether 112 blackbirds were analyzed for the presence of antibodies using a commercial indirect modified agglutination test (MAT) and parasite DNA (qPCR; brain and heart). The present study reports a high T. gondii seroprevalence as antibodies were detected in 50.9 % (57/112; 95 % CI: 41.6-60.2 %) of the urban blackbirds. However, T. gondii DNA was not detected in any of the samples analyzed. Body weight was identified as a risk factor, with heavier birds, both juveniles and adults, being more likely to test positive. Additionally, there was a significant interaction between body weight and sex. Our results suggest that T. gondii infection is widespread in the urban blackbird population, indicating a high parasite circulation in the environment.
    Keywords:  Eurasian blackbild; Toxoplasma gondii; Turdus merula; Urban; Wildlife; Zoonotic
    DOI:  https://doi.org/10.1016/j.ijppaw.2025.101060
  10. bioRxiv. 2025 Apr 01. pii: 2025.03.31.646469. [Epub ahead of print]
    Microtubule acetylation is a biomarker of cytoplasmic health during cellular senescence.
    Yusheng Shen, Roilea Maxson, Richard J McKenney, Kassandra M Ori-McKenney.
      Cellular senescence is marked by cytoskeletal dysfunction, yet the role of microtubule post-translational modifications (PTMs) remains unclear. We demonstrate that microtubule acetylation increases during drug-induced senescence in human cells and during natural aging in Drosophila . Elevating acetylation via HDAC6 inhibition or α TAT1 overexpression in BEAS-2B cells disrupts anterograde Rab6A vesicle transport, but spares retrograde transport of Rab5 endosomes. Hyperacetylation results in slowed microtubule polymerization and decreased cytoplasmic fluidity, impeding diffusion of micron-sized condensates. These effects are distinct from enhanced detyrosination, and correlate with altered viscoelasticity and resistance to osmotic stress. Modulating cytoplasmic viscosity reciprocally perturbs microtubule dynamics, revealing bidirectional mechanical regulation. Senescent cells phenocopy hyperacetylated cells, exhibiting analogous effects on transport and microtubule polymerization. Our findings establish acetylation as a biomarker for cytoplasmic health and a potential driver of age-related cytoplasmic densification and organelle transport decline, linking microtubule PTMs to biomechanical feedback loops that exacerbate senescence. This work highlights the role of acetylation in bridging cytoskeletal changes to broader aging hallmarks.
    DOI:  https://doi.org/10.1101/2025.03.31.646469
  11. Int J Mol Sci. 2025 Mar 28. pii: 3153. [Epub ahead of print]26(7):
    SIRT7 Is a Lysine Deacylase with a Preference for Depropionylation and Demyristoylation.
    Mohammad Golam Kibria, Tatsuya Yoshizawa, Tianli Zhang, Katsuhiko Ono, Tomoya Mizumoto, Yoshifumi Sato, Tomohiro Sawa, Kazuya Yamagata.
      Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent deacylases that remove acyl groups from lysine residues on target proteins, releasing nicotinamide. SIRT7 is associated with aging and a number of age-related diseases, but the enzymatic properties of SIRT7 are largely unknown. In the present study, we investigated the biochemical activity of SIRT7 by performing a series of in vitro kinetic studies in the presence of different acyl substrates. The binding affinity of SIRT7 for NAD+ was dependent on the acyl substrate, and SIRT7 showed a preference for depropionylation and demyristoylation. Nicotinamide, the end-product of the sirtuin reaction, inhibits the activity of SIRT1-6. We also found that the sensitivity of SIRT7 to nicotinamide inhibition also depended on the chain length of the acylated peptides and that nicotinamide was a poor inhibitor of SIRT7 with non-acetylated substrates. These findings may provide insights into the development of novel SIRT7 modulators for the treatment of age-related diseases.
    Keywords:  NAD+; SIRT7; deacetylation; deacylation; nicotinamide; sirtuin
    DOI:  https://doi.org/10.3390/ijms26073153
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