bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–06–22
fifteen papers selected by
Lakesh Kumar, BITS Pilani



  1. Infect Agent Cancer. 2025 Jun 18. 20(1): 39
      
    Keywords:   Toxoplasma gondii ; Antitumor immunity; Cytokine modulation; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13027-025-00673-z
  2. Parasite Epidemiol Control. 2025 Aug;30 e00433
      Toxoplasma gondii (T. gondii) is a ubiquitous protozoan parasite with a complex life cycle involving various intermediate hosts, including dogs. Dogs can act as intermediate hosts for T. gondii, allowing the parasite to undergo asexual reproduction within their tissues. This can lead to the formation of tissue cysts containing bradyzoites, which can be transmitted to other hosts. Therefore, the infectious strains of T. gondii in dogs could reflect the primary genotypes infecting the environment, humans, and animals. This comprehensive research aims to assess the genetic diversity of T. gondii isolates collected from dogs worldwide. A thorough search of four academic databases (PubMed, Scopus, ScienceDirect, and Web of Science) and Google Scholar was conducted for literature published from January 1990 to March 2024. In the present study, a total of 26 papers met the criteria for inclusion. The results revealed that atypical genotypes were the most prevalent, accounting for 78.2 % of the total isolates (151 out of 193). Clonal Types III, II, and I were less frequent, with prevalence rates of 9.8 % (19 out of 193), 7.8 % (15 out of 193), and 3.1 % (6 out of 193), respectively. Type I clonal isolates have been documented in regions including Asia, Europe, and North America. Type II isolates have been identified in Africa, Europe, Oceania, and North America. Furthermore, Type III isolates, along with atypical genotypes, have been reported across Africa, Asia, North America, and South America. According to an analysis of 159 ToxoDB genotypes found in dogs worldwide, ToxoDB #2 (Type III) was the most prevalent genotype (18/159), followed by ToxoDB #1 or #3 (Type II) (15/159), ToxoDB #9 (15/159), and ToxoDB #20 (15/159). Overall, our study revealed low genetic diversity of T. gondii in dogs from Europe, Oceania, and Africa, with circulating clonal strains. Conversely, despite the higher number of isolates in Asia, North America, and South America, non-clonal parasites with extensive genetic diversity were prevalent.
    Keywords:  Dogs; Genotype; Systematic review; Toxoplasma gondii; Toxoplasmosis
    DOI:  https://doi.org/10.1016/j.parepi.2025.e00433
  3. Nanomedicine (Lond). 2025 Jun 18. 1-15
      Vaccination is widely regarded as the most effective control measure for disease prevention, as demonstrated by its success against numerous infectious diseases. However, the development of vaccines to prevent parasitic diseases in humans remains a significant challenge. Despite decades of effort, malaria continues to remain as the leading cause of death among parasitic diseases in tropical regions, while chronic infections caused by Leishmania spp. Toxoplasma gondii, and Trypanosoma spp. persist in causing severe morbidity and economic loss. As climate change increasingly facilitates the spread of arthropod vectors that transmit these diseases into temperate regions, the need for effective vaccines against parasitic infections has never been greater. Virus-like particle (VLP) vaccines targeting infections caused by the protozoan parasites T. gondii, Plasmodium spp. and Leishmania spp. have the potential to make a significant contribution to public health. In this review, we summarize recent advances in VLP-based vaccines targeting these globally important protozoan parasites and discuss key challenges impeding their development.
    Keywords:  Leishmaniasis; malaria; protozoan parasites; toxoplasmosis; vaccine; virus-like particle
    DOI:  https://doi.org/10.1080/17435889.2025.2518915
  4. PLoS Pathog. 2025 Jun 16. 21(6): e1012733
      Toxoplasma gondii (T. gondii), a prolific protozoan parasite, forms cysts within neurons of the central nervous system that maintain infection for the lifetime of the host. Astrocytes are fundamental to neuronal health by providing nutrients and structural support and help regulate neurotransmitters by continuous communication with neurons. It is not yet known how infection and the presence of intracellular cysts, disrupts the crucial relationship between these cells. Extracellular vesicles (EVs) function in intracellular communication and can contain proteins, lipids, DNA, miRNA, and other RNA subtypes. EVs are produced by all cells and play an important role in neuronal-astrocyte interactions, including the regulation of glutamate receptors on astrocytes. Previous work has demonstrated that Toxoplasma infection reduces astrocytic expression of the primary glutamate transporter, GLT-1. Here we tested if cyst infection of neurons alters the production and content of EVs. EVs were isolated from uninfected and infected primary murine cortical neurons and their size, concentration, and characterization were confirmed with nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), ELISA, western blot, liquid chromatography (LC)-mass spectrometry (MS)/MS, and microRNA sequencing. Analysis reveals that infection of neurons reduced neuronal production of EVs and altered their protein and miRNA content. In addition to changes in host protein content, EVs from infected neurons contained the Toxoplasma proteins GRA1, GRA2, GRA7, MAG1 and MAG2. Following incubation of neuronal EVs with primary astrocytes, GRA7 protein could be observed within intracellular EVs and the nuclei of GRA7 + EV-containing cells. EVs from infected neurons altered gene expression of astrocytes resulting in an increase in pro-inflammatory transcriptional signatures, along with a downregulation of GLT-1 protein expression with similar transcriptional changes found in astrocytes in vivo. These results demonstrate the ability of a parasitic infection in the brain to alter EV production and the fundamental communication between neurons and astrocytes.
    DOI:  https://doi.org/10.1371/journal.ppat.1012733
  5. Mol Biol Rep. 2025 Jun 16. 52(1): 603
       BACKGROUND: The pathophysiology of renal tubular injury in diabetic kidney disease involves complex interactions between metabolic dysregulation, inflammation, and oxidative stress. Dysregulation of FAO leads to the accumulation of toxic metabolites, which may exacerbate mitochondrial dysfunction and contribute to cellular injury. CPT1a is a pivotal enzyme in FAO. Dysfunction of CPT1a impairs the translocation of long-chain fatty acyl-CoA into the mitochondria, which ultimately leads to tubular injury. Acetylation is a critical post-translational modification of proteins in essential cellular processes. In this study, we aimed to investigate the regulatory role of SIRT3 in CPT1a and its protective role against tubular injury in mice with diabetic kidney disease.
    METHODS AND RESULTS: We found that decreased SIRT3 expression was accompanied by elevated acetylation in the renal tubules of diabetic mice. Acetylome analysis using LC-MS/MS showed that mitochondrial proteins were hyper-acetylated in the tubules of diabetic mice. Specifically, CPT1a was hyperacetylated at lysines 86 and 639 in tubular epithelial cells of diabetic mice and was regulated by SIRT3. Furthermore, proximal tubular epithelial cells-specific Sirt3 knockout diabetic mice showed more pronounced lipid accumulation in the renal tubules and more significant urinary protein. The integrated optical density per area for SIRT3 was positively correlated with glomerular filtration rate and negatively correlated with urinary protein levels in humans.
    CONCLUSIONS: The study findings revealed that SIRT3 is downregulated in renal tubules during diabetes and interferes with the activity of CPT1a through deacetylation, disrupting fatty acid metabolism in the tubules and ultimately leading to tubular injury.
    Keywords:  Acetylation; CPT1a; Diabetes; SIRT3; Tubular epithelial cells
    DOI:  https://doi.org/10.1007/s11033-025-10712-y
  6. Yi Chuan. 2025 Jun;47(6): 625-635
      Protein-protein interactions are essential to almost all biological processes within cells. In recent years, proximity labeling technology has emerged as a cutting-edge approach for studying protein interactions and subcellular compartment proteomics. This technique enables labeling and capture of neighboring proteins by introducing chemical tags in the vicinity of a target protein. When combined with mass spectrometry, proximity labeling facilitates the effective identification of protein-protein interactions and proteomic landscapes of subcellular compartments with high spatiotemporal resolution. Compared to traditional methods, proximity labeling offers superior resolution, sensitivity, and real-time tracking capabilities,making it a powerful tool for investigating protein functions, interactions, and spatial proteomics within cells. In this review, we provide a comprehensive overview of the principles, classifications, and applications of proximity labeling technology, aiming to offer researchers valuable insights into this innovative methodology and to promote its broader application in cell biology, proteomics, and the study of disease mechanisms.
    Keywords:  protein-protein interactions; proximity labeling technology; spatial proteome
    DOI:  https://doi.org/10.16288/j.yczz.24-307
  7. Pharmacol Res. 2025 Jun 13. pii: S1043-6618(25)00238-5. [Epub ahead of print] 107813
      Histone acetylation is currently one of the epigenetic mechanisms that have been extensively and profoundly studied, and is associated with the occurrence and development of various diseases such as cancer and neurodegenerative disorders.Histone acetylation/deacetylation refers to the addition/removal of acetyl groups on histone lysine residues under the action of histone acetyltransferase (HAT)/histone deacetylase (HDAC), and is read by BET proteins, influencing gene transcription. In recent years, an increasing amount of evidence has indicated that histone acetylation plays a vital role in neuropathic pain. Neuropathic pain is an unresolved medical issue for which no effective treatment measures are available.Therefore, This article, from a novel perspective of HAT, HDAC, and BET proteins, deeply exploresthe mechanism of histone acetylation in various neuropathic pain models. The study found that HAT, HDAC, and BET proteins,at multiple levels, affect the expression of proteins such as ion channels, chemokines.and inflammatory factors through gene regulatory mechanisms. Based on this, future research can focus on the drug development targeting HAT, HDAC, and BET proteins, with the expectation of achieving more precise and effective regulation of neuropathic pain at the genetic level.
    Keywords:  Neuropathic pain Histone acetylation HAT HDAC BET proteins
    DOI:  https://doi.org/10.1016/j.phrs.2025.107813
  8. Anim Microbiome. 2025 Jun 13. 7(1): 63
       BACKGROUND: Sirtuins are deacetylases that are highly conserved throughout the animal kingdom. They act as metabolic sensors that coordinate cellular responses, allowing an adapted response to various stressors. Epithelial cells, especially those of the intestine, are directly exposed to a wide range of stressors. Together with the microbiota, they form a complex ecosystem with mutual influences. The significance of sirtuins in this complex system is still waiting to be clarified.
    RESULTS: Here, we show that a protein-restricted diet strongly increases the intestinal expression of sirtuin 4 (dSirt4), the only mitochondrial sirtuin in Drosophila. To elucidate the effects of deregulated dSirt4 expression in the intestine, we analyzed dSirt4 knockout flies. These flies showed substantial changes in their intestinal proteome and physiological properties. One of the most striking effects was the strong induction of lysozymes in the intestine, with a corresponding increase in lysozyme activity. This effect was organ-autonomous, as it was also observed in flies with dSirt4 knocked out only in intestinal enterocytes. The significant increase in lysozyme abundance in response to tissue-specific dSirt4 knockdown did not reduce the total number of bacteria in the intestine. However, it did affect the microbiota composition by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to dSirt4-dependent lysozyme expression, which is absent in a lysozyme-deficient background. dSirt4 knockout in the enterocytes shortened the lifespan of the flies, as did ectopic lysozyme overexpression in the enterocytes.
    CONCLUSIONS: The only mitochondrial sirtuin in Drosophila, dSirt4, is induced by dietary stress in intestinal epithelial cells, which directly regulates the lysozyme activity of these cells. We could associate this altered lysozyme activity with a shift in the microbiota composition, demonstrating a direct link between stress, nutrition, and the host's microbiota regulation.
    DOI:  https://doi.org/10.1186/s42523-025-00431-x
  9. Methods Mol Biol. 2025 ;2921 73-91
      The nuclear proteome encompasses diverse proteins that regulate critical cellular functions, including histone modifications, chromatin structure, and transcription. Mutations to many of these nuclear proteins correlate with the onset of diseases such as cancer. Due to the disease relevance of nuclear proteins, drug development efforts have focused on identifying small-molecule modulators of nuclear protein function. Covalent ligands provide a promising strategy to therapeutically target nuclear proteins that lack distinct substrate binding pockets. In particular, chemoproteomic strategies have enabled the identification of ligandable sites within the proteome, with a particular emphasis on covalent targeting of cysteine residues. Nuclear proteins are typically poorly represented in chemoproteomic workflows that utilize whole-cell lysates due to the low abundance of these proteins and the localization of nuclear proteins in multiple cellular compartments. To specifically focus on the nuclear proteome, we coupled proximity labeling using a histone-TurboID construct with chemoproteomics. Notably, this platform can be utilized to identify ligandable sites within the nuclear proteome, and monitor changes in nuclear localization and chromatin association upon exposure to covalent ligands. Here, we describe the steps required to generate histone-TurboID expressing cell lines, and apply tandem mass tag (TMT)-based quantitative proteomics to monitor protein localization changes induced by covalent ligands. Together, this methodology provides a streamlined approach toward identifying covalent ligands that regulate nuclear protein function.
    Keywords:  Chemoproteomics; Chromatin association; Nuclear cysteine ligandability; Nuclear localization; Proximity labeling; TurboID
    DOI:  https://doi.org/10.1007/978-1-0716-4502-4_4
  10. Metab Eng. 2025 Jun 16. pii: S1096-7176(25)00093-X. [Epub ahead of print]
      Genetic regulation tools have been examined for their ability to enable sophisticated dynamic control of biosynthesis in microbial cell factories, enhancing the production performance of valuable compounds. However, most genetic tools are pathway- or intermediate-specific, hindering their broad applicability in synthetic biology. Moreover, their potential to balance metabolic fluxes in central metabolism between cell growth and product formation remains under-explored, raising the question of whether they can facilitate efficient biosynthesis. To answer this, we established the PdhR biosensor system that responds to pyruvate to dynamically regulate metabolic flux distribution in central metabolism. In this study, we first characterized the dose response of PdhR biosensor system by screening multiple PdhR homologs derived from various microorganisms. Computational analysis further guided the identification of key factors contributing to their functional differences, enabling the optimization of biosensor properties through site-directed mutagenesis. As proof of concept, we employed our biosensor system to improve the biosynthesis of trehalose and 4-hydroxycoumarin (4HC), respectively. Specifically, trehalose titer increased to 3.72 g/L, which is 2.33-fold higher than the control group. In addition, we improved the 4HC titer to 491.5 mg/L, which possessed a 1.63-fold increase over the static strategy. In summary, the established central metabolism-responsive biosensor system underlined the necessity of metabolic flux distribution and validated its broad applicability in the biosynthesis of central metabolism-derived compounds.
    Keywords:  4-Hydroxycoumarin; Central Metabolism; Dynamic Control; Genetic Biosensors; Trehalose
    DOI:  https://doi.org/10.1016/j.ymben.2025.06.007
  11. Dis Model Mech. 2025 Jun 01. pii: dmm052313. [Epub ahead of print]18(6):
      Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors and found that human tumors with metabolic signatures similar to those of fly tumors have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis.
    Keywords:   Drosophila melanogaster ; Acetyl-CoA; Epigenetics; Invertebrate tumor model; Metabolism; S-Adenosyl methionine
    DOI:  https://doi.org/10.1242/dmm.052313
  12. J Med Chem. 2025 Jun 18.
      Proteolysis-targeting chimeras (PROTACs) are emerging new therapeutic modalities that facilitate the targeted degradation of disease-relevant proteins via an event-driven mode of action. In this work, we report the design, synthesis, and biological evaluation of the first-in-class selective degraders of the class IIb histone deacetylases (HDACs) 6 and 10. To this end, the dual HDAC6/10 inhibitor tubastatin A and a ring-opened analog were connected via well-established PROTAC linkers to pomalidomide and phenylglutarimides as cereblon recruiters. This approach led to the discovery of AP1 (HDAC6 DC50 = 13 nM; HDAC10 DC50 = 29 nM) as a potent degrader of class IIb HDACs. Importantly, AP1 neither degraded HDAC1/8 (class I) and HDAC4/7 (class IIa), nor induced histone H3 hyperacetylation, thereby confirming its selectivity for class IIb HDACs. Due to its low cytotoxicity against hematological and solid cancer cell lines, AP1 represents a valuable tool compound for the chemical knockdown of class IIb HDACs.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c00674
  13. J Pathol. 2025 Jun 20.
      Peritoneal fibrosis (PF) is a serious complication contributing to ultrafiltration failure in patients undergoing peritoneal dialysis that currently lacks effective treatment strategies. Our recent studies highlighted the key role of histone deacetylase 6 (HDAC6) in the development of PF. To better understand the mechanisms underlying the involvement of HDAC6 in PF, we conducted in vivo experiments using Hdac6 KO mice and in vitro studies using human peritoneal mesothelial cells (HPMCs). Our results demonstrated that HDAC6 gene silencing improved PF and angiogenesis in vivo and altered pathological phenotypes in vitro. In Hdac6 KO mice, the key pathways regulating extracellular matrix accumulation, angiogenesis, and secretion of inflammatory cytokines (including TGFB1/SMAD3, HIF-1α/VEGFR-2/MAPK3/MAPK1, and TLR4/NF-κB pathways) were inhibited. We also identified heat shock protein 90 (HSP90) as the substrate of HDAC6 in both PF mice and HPMCs and demonstrated that HDAC6 exerted its regulatory function in PF through the deacetylation of HSP90. Overall, our study provides novel insights into the critical role of the HDAC6-HSP90 interplay in PF using Hdac6 KO mice. We identify HSP90 as an essential substrate through which HDAC6 exerts its function in PF, providing an experimental basis for the development of novel therapeutic strategies. © 2025 The Pathological Society of Great Britain and Ireland.
    Keywords:  heat shock protein 90; histone deacetylase 6; peritoneal angiogenesis; peritoneal fibrosis; peritoneal inflammation; peritoneal phenotype transition
    DOI:  https://doi.org/10.1002/path.6436
  14. Biochim Biophys Acta Proteins Proteom. 2025 Jun 11. pii: S1570-9639(25)00021-4. [Epub ahead of print] 141083
      HDAC7 (histone deacetylase 7) is involved in many diseases, including breast cancer. HDAC7 regulates gene expression epigenetically by assisting in the deacetylation of nucleosomal histones to remodel chromatin. However, HDAC7 is a pseudodeacetylase that displays weak enzymatic activity and cannot directly deacetylate histones. Instead, HDAC7 scaffolds histones to active HDAC3 (histone deacetylase 3) via NCoR (nuclear receptor corepressor) to regulation transcription. Recent evidence documented that the inactive pseudo-active site of HDAC7 binds an acetyllysine on the AR (androgen receptor) transcription factor to disrupt HDAC3-NCoR scaffolding and activate transcription. To expand on the acetylation-dependent reversible scaffolding observed with AR, here HDAC7 binding was tested with additional nuclear receptors, including GR (glucocorticoid receptor), PR (progesterone receptor), TR (thyroid receptor), and RXR (retinoid x receptor), with particular focus on ER-⍺ (estrogen receptor alpha). Acetyllysine-dependent HDAC7-NCoR-HDAC3 binding and gene expression was established with ER-⍺ in a physiologically relevant breast cancer cell line, which substantiates acetyllysine-mediated reversible scaffolding by HDAC7 in the epigenetic regulation of nuclear receptor transcriptional activation.
    Keywords:  Estrogen receptor; HDAC7; Histone deacetylase; Nuclear receptors; Pseudodeacetylase
    DOI:  https://doi.org/10.1016/j.bbapap.2025.141083
  15. RSC Med Chem. 2025 May 27.
      Malaria continues to devastate tropical regions of the world, with resistance to frontline drugs on the rise. Kinase inhibition has emerged as a promising novel mechanism of action in the fight against malaria. We previously reported the development of TCMDC-135051 (1), a highly potent, multi-stage inhibitor of Plasmodium falciparum CLK3 (PfCLK3). Building on this work, we subsequently developed the first covalent kinase inhibitor for malaria, selectively targeting a unique cysteine residue. Despite their high potency and selectivity, covalent inhibitors that target cysteine residues are particularly vulnerable to resistance arising from single point mutations of the nucleophilic residue. This work presents a novel strategy targeting the essential kinase catalytic lysine residue which has the potential to evade this resistance mechanism. Using structure based drug design, analogues of TCMDC-135051 (1) targeting Lys394 of PfCLK3 were developed. Four compounds, all harbouring benzaldehyde-based warheads, covalently engaged Lys394 as determined by protein mass spectrometry. These analogues were highly potent against recombinant protein, with good parasiticidal potency and cytotoxicity profiles. These molecules 4, 5, 8, 9 are the first lysine-targeting covalent inhibitors reported for malaria and offer a promising general strategy for future antimalarial drug discovery.
    DOI:  https://doi.org/10.1039/d5md00335k