bims-toxgon 2025-12-07 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2025–12–07
nine papers selected by
Lakesh Kumar, BITS Pilani

The role of parasite-produced dopamine in Toxoplasma gondii-altered host behaviour.
Evaluation of immune protection of a multi-antigenic DNA vaccine encoding TgROP6 and TgMIC12 against Toxoplasma gondii infection.
The HosA histone deacetylase regulates stress resistance, host cell interactions, and virulence in Aspergillus fumigatus.
Pathogenicity and virulence of Cryptosporidium.
Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.
Histone post-translational modifications of Leishmania braziliensis.
Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival.
Evaluation of Plasmodium falciparum PSSP17 essentiality in human-to-mosquito transmission and its prospective candidacy as a biomarker.
Neuromodulatory control of energy reserves in dopaminergic neurons.

Nat Commun. 2025 Dec 05. 16(1): 10906

The role of parasite-produced dopamine in Toxoplasma gondii-altered host behaviour.

Beatriz Calvo-Urbano, Maya Kaushik, An-Chi Cheng, Greg C Bristow, Emese Prandovszky, Martin Walker, Poppy H L Lamberton, Glenn A McConkey, Joanne P Webster.

Certain parasites can manipulate host behaviour for their own benefit, but the mechanisms remain largely unknown. Toxoplasma gondii, the agent of the toxoplasmosis, is a canonical example, altering behaviour in rodents and other hosts, including humans. Dopamine dysregulation has been suggested as a mechanism, with parasite-encoded tyrosine hydroxylases (TgTH) proposed as a direct source of dopamine, though their role is debated. Here, using Rattus norvegicus as a model, with subtle and specific behavioural and biostatistical assays and analyses, we examine the contribution of TgTH to behavioural change. Two engineered T. gondii Prugniaud lines with moderate and high TgTH overexpression (OE) are compared to wild-type and recombinant wild-type parasites, alongside uninfected controls. All genetically modified lines induce weaker behavioural changes than true wild-type, but changes correlate with TgTH expression levels. Our findings provide empirical support that TgTH contributes to T. gondii-associated behavioural alterations, highlighting both theoretical significance and applied implications.

DOI: https://doi.org/10.1038/s41467-025-66139-3
Front Vet Sci. 2025 ;12 1674435

Evaluation of immune protection of a multi-antigenic DNA vaccine encoding TgROP6 and TgMIC12 against Toxoplasma gondii infection.

Bohuai Xu, Yue Bi, Yaowen Wang, Jie Sun, Jia Chen, Jingqi Mu.

   Introduction: Toxoplasma gondii infection causes severe congenital disease and abortion in humans and animals. This study evaluated a novel multivalent DNA vaccine targeting ROP6, and MIC12 for protection against acute (RH strain) and chronic (PRU strain) toxoplasmosis in mouse models.
Methods: Eukaryotic plasmids encoding pVAX-ROP6 and pVAX-MIC12 were constructed, and mice were immunized with either single or combined formulations.
Results and discussion: Vaccination elicited a robust Th1-biased immune response, characterized by elevated IgG2a/IgG1 ratios, enhanced cytotoxic T lymphocyte activity, increased CD4+ and CD8+ T cell populations, and elevated production of IFN-γ, IL-12, and IL-2. The dual vaccine demonstrated superior efficacy, significantly prolonging survival following lethal RH challenge (compared to uniform mortality in controls by day 6) and reducing PRU brain cyst burden by 56.6%, outperforming single-gene formulations. Although these results establish pVAX-ROP6/MIC12 as promising vaccine candidates, protection remained partial, highlighting the need for further optimization. Overall, this study underscores the potential of bivalent DNA vaccines to induce broad protective immunity against toxoplasmosis, supporting their continued development for clinical and veterinary use.

Keywords:  DNA vaccine; TgMIC12; TgROP6; Toxoplasma gondii; toxoplasmosis

DOI:  https://doi.org/10.3389/fvets.2025.1674435
bioRxiv. 2025 Nov 19. pii: 2025.11.19.689210. [Epub ahead of print]

The HosA histone deacetylase regulates stress resistance, host cell interactions, and virulence in Aspergillus fumigatus.

Hong Liu, Pamela Lee, Alice Vo, Sanjoy Paul, Quynh T Phan, Jianfeng Lin, Vincent M Bruno, Mark A Stamnes, W Scott Moye-Rowley, Scott G Filler.

The capacity of Aspergillus fumigatus to cause invasive pulmonary aspergillosis depends on its ability to adapt to dynamic and stressful microenvironments within the host. Epigenetic regulation, including histone deacetylation, plays a critical role in fungal adaptation to stress. Here, we investigated the role of the class I histone deacetylase (HDAC) HosA in A. fumigatus stress resistance, host cell interactions, and virulence. A Δ hosA mutant had increased susceptibility to intracellular oxidant stress induced by menadione. It also had impaired capacity to invade and damage two pulmonary epithelial cell lines in vitro . In a corticosteroid-immunosuppressed mouse model of invasive aspergillosis, mice infected with the Δ hosA mutant survived significantly longer than those infected with the wild-type strain, despite having similar pulmonary fungal burden. The Δ hosA mutant also induced a weaker inflammatory response than the wild-type strain. Transcriptomic analysis revealed that HosA regulates genes involved in secondary metabolite biosynthesis and energy metabolism, functioning as both an activator and repressor of distinct gene sets. Collectively, these results indicate that HosA is a key epigenetic regulator that governs A. fumigatus interactions with host cells and virulence during invasive pulmonary aspergillosis.
Importance: Epigenetic modifications in A. fumigatus can be induced by environmental changes and stresses such as those induced by interaction with host cells. HosA, a class I histone deacetylase, has been shown to play a key role in regulating secondary metabolism in several Aspergillus species, but its function in A. fumigatus was previously unknown. We found that deletion of hosA increased susceptibility to intracellular, but not extracellular, oxidative stress. The Δ hosA mutant also exhibited significantly reduced pulmonary epithelial cell invasion and host cell damage, as well as attenuated virulence in immunosuppressed mice. Together, these findings indicate that HosA functions as a key epigenetic regulator that governs stress resistance, secondary metabolism, and fungal-host interactions. Defining the functions of HosA could provide critical insight into the epigenetic mechanisms that control fungal pathogenicity and may reveal a potential therapeutic target for invasive aspergillosis.

DOI: https://doi.org/10.1101/2025.11.19.689210
Virulence. 2025 Dec;16(1): 2597642

Pathogenicity and virulence of Cryptosporidium.

Ying Zhang, Peng Jiang, Jigang Yin, Guan Zhu.

  Cryptosporidium is a genus of apicomplexan parasites that causes diarrheal disease in humans and animals worldwide. The primary species affecting humans are C. parvum and C. hominis, while other species may also infect humans, specially immunocompromised individuals. Infections are particularly severe in people with weakened immune systems and malnourished children in developing countries. In livestock, especially young ruminants, C. parvum leads to significant economic losses. The parasite occupies a unique epicellular niche and undergoes a complex life cycle involving both asexual and sexual stages. While the mechanisms of parasite invasion, replication, immune evasion, and tissue damage have been challenging to unravel due to earlier technical limitations and lack of genetic tools, recent advances have transformed our understanding. Innovations in genomics, transcriptomics, and molecular genetics have identified key virulence factors and clarified intricate host-parasite interactions. The parasite's secretory organelles (micronemes, rhoptries, dense granules, and small granules) play central roles by releasing molecules that facilitate host cell attachment, invasion, and modulation of host defenses. This review provides an up-to-date overview of the biology and pathogenic mechanisms of Cryptosporidium, highlighting structural features, invasion strategies, and host immune responses. It also covers recent progress in experimental models, vaccine development, and identification of new molecular targets for treatment and prevention. By synthesizing recent discoveries with previous research, this review offers a current perspective linking fundamental biology to disease outcomes and potential control strategies.

Keywords:  Cryptosporidium; apicomplexan parasites; host–pathogen interactions; microneme proteins; secretory organelles; virulence mechanisms

DOI:  https://doi.org/10.1080/21505594.2025.2597642
Am J Physiol Cell Physiol. 2025 Dec 05.

Glutamine deficiency enhances nuclear localization of TCA cycle enzymes and epigenetic modifications, impairing myogenesis.

Angad Yadav, Susan Schmitt, Wenxia Ma, James A Mobley, Anna Elizabeth Thalacker-Mercer.

  Extracellular glutamine (Gln) is essential for muscle progenitor cell (MPC) function and skeletal muscle regeneration / development, especially under physiological stress like aging or catabolic conditions. Gln availability regulates MPC proliferation by modulating intracellular metabolic and epigenetic states. Gln deficiency reduces cell viability, induces G0/G1 cell cycle arrest, and downregulates MyoD expression, collectively inhibiting myogenesis in human primary myoblasts (HSMM) and mouse C2C12 cells. Mechanistically, Gln deficiency enhances nuclear localization of TCA cycle enzyme, KGDHC, components (i.e., DLST and OGDH), elevates histone succinylation, and reduces chromatin accessibility at the myogenic regulatory regions (MyoD1 locus). These changes establish a direct link between Gln availability and an epigenetic-metabolic axis crucial for myogenic gene regulation. Thus, extracellular Gln acts as a key regulator of MPC proliferation through metabolic mediated control of chromatin state.

Keywords:  Chromatin accessibility; Glutamine metabolism; Succinylation; TCA cycle compartmentalization; myogenesis

DOI:  https://doi.org/10.1152/ajpcell.00568.2025
Sci Data. 2025 Dec 03. 12(1): 1899

Histone post-translational modifications of Leishmania braziliensis.

Rafael Fogaça de Almeida, Matheus Fernandes, Fabiano Borges Figueiredo, Lyris Martins Franco de Godoy.

Histone post-translational modifications (hPTMs) constitute an epigenetic mechanism that plays a fundamental role in the regulation of gene expression in eukaryotic cells. In trypanosomatid parasites, such as Trypanosoma brucei, T. cruzi and Leishmania spp., gene regulation occurs mainly at the post-transcriptional level. Nevertheless, recent studies have demonstrated that hPTMs are abundant and diverse in T. brucei and T. cruzi, the causative agents of sleeping sickness and Chagas disease, respectively, suggesting a potential regulatory role for histone modifications in these organisms. However, data on hPTMs in Leishmania parasites, the etiological agents of leishmaniasis, remain scarce. Here, applying an optimized mass spectrometry-based proteomic workflow, we present the first large-scale, high-confidence map of hPTMs in Leishmania braziliensis, revealing a broad distribution of distinct histone modifications, like what is observed in T. cruzi and other eukaryotes. This dataset provides a valuable resource for future functional studies on chromatin regulation in Leishmania and other trypanosomatids of medical interest.

DOI: https://doi.org/10.1038/s41597-025-06187-y
PLoS Biol. 2025 Dec;23(12): e3003075

Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival.

Athena L Munden, Arjamand Mushtaq, Dominique S Lui, Katherine M Edwards, Daniel P Higgins, Kasturi Biswas, Rachel M Walker, Leah H Crowley, Matthew J Fanelli, Thien-Kim Ngyuen, Maria Ericsson, Adwait A Godbole, John A Haley, Caroline A Lewis, Jessica B Spinelli, Benjamin Harrison, Daniel Raftery, Danijel Djukovic, Daniel E L Promislow, Dana L Miller, Amy K Walker.

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.

DOI: https://doi.org/10.1371/journal.pbio.3003075
iScience. 2025 Dec 19. 28(12): 113919

Evaluation of Plasmodium falciparum PSSP17 essentiality in human-to-mosquito transmission and its prospective candidacy as a biomarker.

B López-Gutiérrez, N Hathaway, L Alonso-Palomares, V O Nyasembe, M Kato, T Hamerly, J B Parr, J J Juliano, M Harbers, R R Dinglasan.

  Reliance on detecting the Plasmodium falciparum histidine-rich protein 2 (PfHRP2) biomarker by current rapid diagnostic tests (RDTs) is compromised by the emergence of pfhrp2/3 deletion strains that evade detection and treatment. Additional biomarkers can arguably expand the diagnostic toolbox, but these new biomarkers must be essential for parasite development to avoid similar outcomes to PfHRP2. Recently, Plasmodium sexual stage protein 17 (PSSP17; PF3D7_1218800) was identified in saliva from children with subclinical infections, offering a non-invasive modality for malaria diagnosis. However, the essentiality of PSSP17 has not been determined. We show that pssp17 is dispensable in P. falciparum asexual stages but is important for onward transmission by mosquitoes. Importantly, the 19,280 publicly available P. falciparum genomes did not reveal naturally occurring deletions. Thus, should Δpssp17 mutants arise, mosquitoes cannot effectively transmit them. These data suggest that the further consideration of PSSP17 as an RDT biomarker for non-invasive, saliva-based sensitive RDTs is warranted.

Keywords:  Diagnostics; Genetics; Parasitology

DOI:  https://doi.org/10.1016/j.isci.2025.113919
Proc Natl Acad Sci U S A. 2025 Dec 16. 122(50): e2523019122

Neuromodulatory control of energy reserves in dopaminergic neurons.

Camila Pulido, Matthew S Gentry, Timothy A Ryan.

  The brain is a metabolically vulnerable organ as neurons have both high resting metabolic rates and the need for local rapid conversion of carbon sources to ATP during activity. Midbrain dopamine neurons are thought to be particularly vulnerable to metabolic perturbations, as a subset of these are the first to undergo degeneration in Parkinson's disease, a neurodegenerative disorder long suspected to be in part driven by deficits in mid-brain bioenergetics. In skeletal muscle, energy homeostasis under varying demands is achieved in part by its ability to rely on glycogen as a fuel store, whose conversion to ATP is under hormonal regulatory control. In neurons, however, the absence of easily observable glycogen granules has cast doubt on whether this fuel store is operational, even though brain neurons express the key regulatory enzymes associated with building or burning glycogen. We show here that in primary mid-brain dopaminergic neurons, glycogen availability is under the control of dopamine autoreceptors, such that dopamine itself provides a signal to store glycogen. We find that when glycogen stores are present, they provide remarkable resilience to dopamine nerve terminal function under extreme hypometabolic conditions, but loss of this dopamine-derived signal, or impairment of access to glycogen, makes them hypersensitive to fuel deprivation. These data show that neurons can use an extracellular cue to regulate local metabolism and suggest that loss of dopamine secretion might make dopamine neurons particularly subject to neurodegeneration driven by metabolic stress.

Keywords:  ATP; dopamine; glycogen; synapse

DOI:  https://doi.org/10.1073/pnas.2523019122