bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2023–10–22
nine papers selected by
Lakesh Kumar, BITS Pilani
  1. Contact sites between host organelles and pathogens: boon or bane?
  2. Toxoplasma gondii infection regulates apoptosis of host cells via miR-185/ARAF axis.
  3. Hydroxamate-based compounds are potent inhibitors of Toxoplasma gondii HDAC biological activity.
  4. Anti-Toxoplasma gondii screening of MMV Pandemic Response Box and evaluation of RWJ-67657 efficacy in chronically infected mice.
  5. Novel insights into the role of acetyl-CoA producing enzymes in epigenetic regulation.
  6. Immunomodulatory chitosan nanoparticles for Toxoplasma gondii infection: Novel application of chitosan in complex propranolol-hydrochloride as an adjuvant in vaccine delivery.
  7. Parasite-mediated manipulation? Toxoplasma gondii infection increases risk behaviour towards culling in red deer.
  8. Toltrazuril alkalizer-modifying solid dispersions againstToxoplasma gondii: a pharmacotechnical strategy to improve the efficacy of the drug.
  9. Distinct non-synonymous mutations in cytochrome b highly correlate with decoquinate resistance in apicomplexan parasite Eimeria tenella.
  1. mSphere. 2023 Oct 18. e0044823
    Contact sites between host organelles and pathogens: boon or bane?
    Chahat Mehra, Lena Pernas.
      A microbe and its host are in constant communication. An emerging platform for direct communication is the membrane contact sites that form between several pathogens and host organelles. Here, we review our progress on the molecular mechanisms underlying contact sites between host mitochondria and the human parasite Toxoplasma gondii. We discuss open questions regarding their function during infection as well as those formed between the host endoplasmic reticulum and Toxoplasma.
    Keywords:  Toxoplasma gondii; endoplasmic reticulum; membrane; membrane contact sites; mitochondria; pathogens
    DOI:  https://doi.org/10.1128/msphere.00448-23
  2. Parasit Vectors. 2023 Oct 19. 16(1): 371
    Toxoplasma gondii infection regulates apoptosis of host cells via miR-185/ARAF axis.
    Dingzeyang Su, Shifan Zhu, Zhaofeng Hou, Fuxing Hao, Kangzhi Xu, Fan Xu, Yuyang Zhu, Dandan Liu, Jinjun Xu, Jianping Tao.
       BACKGROUND: Toxoplasmosis is a zoonosis with a worldwide presence that is caused by the intracellular parasite Toxoplasma gondii. Active regulation of apoptosis is an important immune mechanism by which host cells resist the growth of T. gondii or avoid excessive pathological damage induced by this parasite. Previous studies found that upregulated expression of microRNA-185 (miR-185) during T. gondii infection has a potential role in regulating the expression of the ARAF gene, which is reported to be associated with cell proliferation and apoptosis.
    METHODS: The expression levels of miR-185 and the ARAF gene were evaluated by qPCR and Western blot, respectively, in mice tissues, porcine kidney epithelial cells (PK-15) and porcine alveolar macrophages (3D4/21) following infection with the T. gondii ToxoDB#9 and RH strains. The dual luciferase reporter assay was then used to verify the relationship between miR-185 and ARAF targets in PK-15 cells. PK-15 and 3D4/21 cell lines with stable knockout of the ARAF gene were established by CRISPR, and then the apoptosis rates of the cells following T. gondii infection were detected using cell flow cytometry assays. Simultaneously, the activities of cleaved caspase-3, as a key apoptosis executive protein, were detected by Western blot to evaluate the apoptosis levels of cells.
    RESULTS: Infection with both the T. gondii ToxoDB#9 and RH strains induced an increased expression of miR-185 and a decreased expression of ARAF in mice tissues, PK-15 and 3D4/21 cells. MiR-185 mimic transfections showed a significantly negative correlation in expression levels between miR-185 and the ARAF gene. The dual luciferase reporter assay confirmed that ARAF was a target of miR-185. Functional investigation revealed that T. gondii infection induced the apoptosis of PK-15 and 3D4/21 cells, which could be inhibited by ARAF knockout or overexpression of miR-185. The expression levels of cleaved caspase-3 protein were significantly lower in cells with ARAF knockout than in normal cells, which were consistent with the results of the cell flow cytometry assays.
    CONCLUSIONS: Toxoplasma gondii infection could lead to the upregulation of miR-185 and the downregulation of ARAF, which was not related to the strain of T. gondii and the host cells. Toxoplasma gondii infection could regulate the apoptosis of host cells via the miR-185/ARAF axis, which represents an additional strategy used by T. gondii to counteract host-cell apoptosis in order to maintain survival and reproduce in the host cells.
    Keywords:  ARAF; Apoptosis; Host cell; Regulation; Toxoplasma gondii; miR-185
    DOI:  https://doi.org/10.1186/s13071-023-05991-y
  3. Antimicrob Agents Chemother. 2023 Oct 18. e0066123
    Hydroxamate-based compounds are potent inhibitors of Toxoplasma gondii HDAC biological activity.
    Tom Boissavy, Dante Rotili, Thomas Mouveaux, Emmanuel Roger, El Moukthar Aliouat, Christine Pierrot, Sergio Valente, Antonello Mai, Mathieu Gissot.
      Toxoplasmosis is a critical health issue for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii that is found worldwide. Although efficient drugs are commonly used to treat toxoplasmosis, serious adverse events are common. Therefore, new compounds with potent anti-T. gondii activity are needed to provide better suited treatments. We have tested compounds designed to target specifically histone deacetylase enzymes. Among the 55 compounds tested, we identified three compounds showing a concentration of drug required for 50% inhibition (IC50) in the low 100 nM range with a selectivity index of more than 100. These compounds are not only active at inhibiting the growth of the parasite in vitro but also at preventing some of the consequences of the acute disease in vivo. Two of these hydroxamate based compound also induce a hyper-acetylation of the parasite histones while the parasitic acetylated tubulin level remains unchanged. These findings suggest that the enzymes regulating histone acetylation are potent therapeutic targets for the treatment of acute toxoplasmosis.
    Keywords:  HDAC; apicomplexa; histone deacetylase inhibitors; toxoplasma; toxoplasmosis
    DOI:  https://doi.org/10.1128/aac.00661-23
  4. Parasitology. 2023 Oct 20. 1-29
    Anti-Toxoplasma gondii screening of MMV Pandemic Response Box and evaluation of RWJ-67657 efficacy in chronically infected mice.
    Bruna Ramos Dos Santos, Amanda Bruno da Silva Bellini Ramos, Renata Priscila Barros de Menezes, Marcus Tullius Scotti, Fábio Antônio Colombo, Marcos José Marques, Juliana Quero Reimão.
      
    DOI:  https://doi.org/10.1017/S0031182023000999
  5. Front Endocrinol (Lausanne). 2023 ;14 1272646
    Novel insights into the role of acetyl-CoA producing enzymes in epigenetic regulation.
    Marta Russo, Francesco Pileri, Serena Ghisletti.
      Inflammation-dependent changes in gene expression programs in innate immune cells, such as macrophages, involve extensive reprogramming of metabolism. This reprogramming is essential for the production of metabolites required for chromatin modifications, such as acetyl-CoA, and regulate their usage and availability impacting the macrophage epigenome. One of the most transcriptionally induced proinflammatory mediator is nitric oxide (NO), which has been shown to inhibit key metabolic enzymes involved in the production of these metabolites. Recent evidence indicates that NO inhibits mitochondrial enzymes such as pyruvate dehydrogenase (PDH) in macrophages induced by inflammatory stimulus. PDH is involved in the production of acetyl-CoA, which is essential for chromatin modifications in the nucleus, such as histone acetylation. In addition, acetyl-CoA levels in inflamed macrophages are regulated by ATP citrate lyase (ACLY) and citrate transporter SLC25A1. Interestingly, acetyl-CoA producing enzymes, such as PDH and ACLY, have also been reported to be present in the nucleus and to support the local generation of cofactors such as acetyl-CoA. Here, we will discuss the mechanisms involved in the regulation of acetyl-CoA production by metabolic enzymes, their inhibition by prolonged exposure to inflammation stimuli, their involvement in dynamic inflammatory expression changes and how these emerging findings could have significant implications for the design of novel therapeutic approaches.
    Keywords:  acetyl-CoA; chromatin; inflammation; macrophages; mitochondrial enzymes; nitric oxide; transcription
    DOI:  https://doi.org/10.3389/fendo.2023.1272646
  6. Int J Biol Macromol. 2023 Oct 13. pii: S0141-8130(23)04125-9. [Epub ahead of print] 127228
    Immunomodulatory chitosan nanoparticles for Toxoplasma gondii infection: Novel application of chitosan in complex propranolol-hydrochloride as an adjuvant in vaccine delivery.
    Zohreh Khorshidvand, Sadegh Shirian, Hanieh Amiri, Alireza Zamani, Amir Hossein Maghsood.
      The study aimed to investigate the immunomodulatory effects of propranolol hydrochloride (PRO) in combination with chitosan nanoparticles (CS NPs) as an adjuvant to develop an effective vaccine against T. gondii. A total of 105 BALB/c mice were randomly divided into seven equal groups including PBS alone, CS NPs, SAG1 (Surface antigen 1), CS-SAG1 NPs, CS-PRO NPs, SAG1-PRO, and CS-SAG1-PRO NPs. The immunostimulatory effect of each adjuvant used for vaccine delivery was evaluated in a mice immunization model. The results showed that the mice immunized with CS-SAG1-PRO NPs exhibited the highest lymphocyte proliferation rate, along with increased secretion of IFN-γ, TNF-α, IL-6, IL-12, IL-17, and IL-23, as well as elevated levels of protective cytokines such as TGF-β, IL-27, and IL-10. Although, the CS-SAG1-PRO NPs immunized mice showed the highest level of T. gondii specific IgG compared to the other groups, a significant production of IgG2a and IgG1 was observed in the sera of mice immunized with the CS-SAG1-PRO NPs compared to the other group (p < 0.001). The higher IgG2a/IgG1 ratio observed in the CS-SAG1-PRO NPs group indicates a bias towards Th1 cell polarization, suggesting the promotion of Th1 cell-mediated immune responses. Considering the combination of the highest lymphocyte proliferation and survival rates, IgG2a/IgG1 ratio, and cytokine levels in the mice immunized with CS-SAG1-PRO NPs, this approach holds promise for immunostimulation and vaccine delivery against T. gondii infection.
    Keywords:  Adjuvant; Chitosan; Nanoparticles; Propranolol-hydrochloride; Toxoplasma gondii; Vaccine
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.127228
  7. Biol Lett. 2023 Oct;19(10): 20230292
    Parasite-mediated manipulation? Toxoplasma gondii infection increases risk behaviour towards culling in red deer.
    Matteo Nava, Luca Corlatti, Nicoletta Formenti, Tiziana Trogu, Luca Pedrotti, Alessandro Gugiatti, Paolo Lanfranchi, Camilla Luzzago, Nicola Ferrari.
      Parasites can modify host behaviour to increase their chances of survival and transmission. Toxoplasma gondii is a globally distributed protozoan whose ability to modify host behaviour is well known in taxa such as rats and humans. Less well known are the effects on the behaviour of wild species, with the exception of a few studies on primates and carnivores. Taking advantage of a culling activity conducted in Stelvio National Park (Italy), the serological status of T. gondii was studied in 260 individuals of red deer Cervus elaphus with respect to the risk of being culled. A temporal culling rank index was fitted as a response variable, and T. gondii serological status as the main explanatory variable in linear models, accounting for covariates such as sex, age, jaw length, bone marrow fat and culling location. The overall seroprevalence of T. gondii was 31.5%, and the selected models suggested that seropositive deer were culled earlier than seronegative ones, but this effect was only evident in females, in individuals with medium-good body condition, and in areas with greater human presence. Our results suggest that T. gondii may be involved in risk behaviour in large herbivores, supporting its role as a facilitator of predation risk.
    Keywords:  behavioural changes; culling; host manipulation; parasites; pathogens; wild ungulates
    DOI:  https://doi.org/10.1098/rsbl.2023.0292
  8. Eur J Pharm Sci. 2023 Oct 18. pii: S0928-0987(23)00243-9. [Epub ahead of print] 106613
    Toltrazuril alkalizer-modifying solid dispersions againstToxoplasma gondii: a pharmacotechnical strategy to improve the efficacy of the drug.
    Weiwei Sun, Bohan Wang, Penglong Wang, Boxing Liu, An Yan, Baoliang Pan.
      Toxoplasma gondii is a zoonotic protozoan that can parasitize nucleated cells of all warm-blooded animals, and seriously harm human and livestock. Toltrazuril (TOL) has insecticidal activity against parasites of the phylum Apicomplexan at multiple development stages, but the clinical application is limited by its poor water solubility. To improve the dissolution of TOL, nine ternary solid dispersions (SD) were prepared with PEG6000 as the carrier and various alkalizers as the pH modifier. Compared with the binary SD, all ternary SDs had improved TOL dissolution although dissolution rates differed. The complete dissolution was achieved for the Ca(OH)2-SD, associated with a gradual release of the alkalizer and adequate pH regulation of the microenvironment. DSC, PXRD and FTIR analyses indicated that TOL in the Ca(OH)2-SD was present in an amorphous form and had a strong hydrogen bond with Ca(OH)2. Within the drug concentration of 100 μg/mL, Ca(OH)2-SD was proved to have no damage to host cells by in vitro cytotoxicity analysis, and its anti-T. gondii efficacy was significantly higher than that of TOL and binary SD. The in vivo efficacy of Ca(OH)2-SD against T. gondii in mice further confirmed that Ca(OH)2-SD could be used as a new strategy to prevent T. gondii from killing mice and treat toxoplasmosis. In conclusion, Ca(OH)2-SD is expected to eventually turn into a clinical candidate for toxoplasmosis treatment in the future.
    Keywords:  Characterization; Efficacy; Solid dispersion; Toltrazuril; Toxoplasma gondii
    DOI:  https://doi.org/10.1016/j.ejps.2023.106613
  9. Parasit Vectors. 2023 Oct 17. 16(1): 365
    Distinct non-synonymous mutations in cytochrome b highly correlate with decoquinate resistance in apicomplexan parasite Eimeria tenella.
    Zhenkai Hao, Junmin Chen, Pei Sun, Linlin Chen, Yuanyuan Zhang, Wenxuan Chen, Dandan Hu, Feifei Bi, Zhenyan Han, Xinming Tang, Jingxia Suo, Xun Suo, Xianyong Liu.
       BACKGROUND: Protozoan parasites of the genus Eimeria are the causative agents of chicken coccidiosis. Parasite resistance to most anticoccidial drugs is one of the major challenges to controlling this disease. There is an urgent need for a molecular marker to monitor the emergence of resistance against anticoccidial drugs, such as decoquinate.
    METHODS: We developed decoquinate-resistant strains by successively exposing the Houghton (H) and Xinjiang (XJ) strains of E. tenella to incremental concentrations of this drug in chickens. Additionally, we isolated a decoquinate-resistant strain from the field. The resistance of these three strains was tested using the criteria of weight gain, relative oocyst production and reduction of lesion scores. Whole-genome sequencing was used to identify the non-synonymous mutations in coding genes that were highly associated with the decoquinate-resistant phenotype in the two laboratory-induced strains. Subsequently, we scrutinized the missense mutation in a field-resistant strain for verification. We also employed the AlphaFold and PyMOL systems to model the alterations in the binding affinity of the mutants toward the drug molecule.
    RESULTS: We obtained two decoquinate-resistant (DecR) strains, DecR_H and XJ, originating from the original H and XJ strains, respectively, as well as a decoquinate-resistant E. tenella strain from the field (DecR_SC). These three strains displayed resistance to 120 mg/kg decoquinate administered through feed. Through whole-genome sequencing analysis, we identified the cytochrome b gene (cyt b; ETH2_MIT00100) as the sole mutated gene shared between the DecR_H and XJ strains and also detected this gene in the DecR_SC strain. Distinct non-synonymous mutations, namely Gln131Lys in DecR_H, Phe263Leu in DecR_XJ, and Phe283Leu in DecR_SC were observed in the three resistant strains. Notably, these mutations were located in the extracellular segments of cyt b, in close proximity to the ubiquinol oxidation site Qo. Drug molecular docking studies revealed that cyt b harboring these mutants exhibited varying degrees of reduced binding ability to decoquinate.
    CONCLUSIONS: Our findings emphasize the critical role of cyt b mutations in the development of decoquinate resistance in E. tenella. The strong correlation observed between cyt b mutant alleles and resistance indicates their potential as valuable molecular markers for the rapid detection of decoquinate resistance.
    Keywords:  Cytochrome b; Decoquinate; Drug resistance; Eimeria tenella; Non-synonymous mutation; Whole-genome sequencing
    DOI:  https://doi.org/10.1186/s13071-023-05988-7
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