Wnt/β-catenin signalling underpins juvenile <i>Fasciola hepatica</i> growth and development
Notice bibliographique
Résumé
ABSTRACT Infection by the liver fluke, Fasciola hepatica , places a substantial burden on the global agri-food industry and poses a significant threat to human health in endemic regions. Widespread resistance to a limited arsenal of chemotherapeutics, including the frontline flukicide triclabendazole (TCBZ), renders F. hepatica control unsustainable and accentuates the need for novel therapeutic target discovery. A key facet of F. hepatica biology is a population of specialised stem cells which drive growth and development - their dysregulation is hypothesised to represent an appealing avenue for control. The exploitation of this system as a therapeutic target is impeded by a lack of understanding of the molecular mechanisms underpinning F. hepatica growth and development. Wnt signalling pathways govern a myriad of stem cell processes during embryogenesis and drive tumorigenesis in adult tissues. Here, we identify five putative Wnt ligands and five Frizzled receptors in liver fluke transcriptomic datasets and find that Wnt/β-catenin signalling is most active in juveniles, the most pathogenic life stage. FISH-mediated transcript localisation revealed partitioning of the five Wnt ligands, with each displaying a distinct expression pattern, consistent with each Wnt regulating the development of different cell/tissue types. The silencing of each individual Wnt or Frizzled gene yielded significant reductions in juvenile worm growth and, in select cases, blunted the proliferation of neoblast-like cells. Notably, silencing Fh CTNNB1, the key effector of the Wnt/β-catenin signal cascade led to aberrant development of the neuromuscular system which ultimately proved fatal - the first report of a lethal RNAi-induced phenotype in F. hepatica . The absence of any discernible phenotypes following the silencing of the inhibitory Wnt/β-catenin destruction complex components is consistent with low destruction complex activity in rapidly developing juvenile worms, corroborates transcriptomic expression profiles and underscores the importance of Wnt signalling as a key molecular driver of growth and development in early stage juvenile fluke. The pharmacological inhibition of Wnt/β-catenin signalling using commercially available inhibitors phenocopied RNAi results and provides impetus for drug repurposing. Taken together, these data functionally and chemically validate the targeting of Wnt signalling as a novel strategy to undermine the pathogenicity of juvenile F. hepatica . AUTHOR SUMMARY The liver fluke, Fasciola hepatica significantly undermines the health and welfare of livestock worldwide and causes fascioliasis, a neglected tropical disease of humans. The most damaging stage of liver fluke infection is caused by the migration of juvenile worms within the liver tissue. Of all drugs approved for liver fluke treatment, just one, triclabendazole (TCBZ), is active on this pathogenic juvenile stage. TCBZ resistance is now widespread rendering liver fluke control unsustainable. This highlights the need for novel drug target identification and validation. A key aspect of juvenile worm biology is their ability to rapidly grow and develop, processes driven by a population of specialised stem cells. As such, the dysregulation of stem cells represents an attractive avenue for liver fluke control. One molecular pathway known to regulate stem cell dynamics in higher organisms is the Wnt signalling pathway. Bioinformatic searches of gene sequence datasets identified all major signalling components of both canonical and non-canonical Wnt pathways in F. hepatica . The localisation of Fh Wnt pathway components revealed remarkably distinct and widespread expression patterns throughout the F. hepatica body. Gene silencing of putative Fh Wnt pathway components revealed that those involved in the Wnt/β-catenin signal cascade are fundamental to juvenile growth and, in some cases, stem-like cell proliferation. The silencing of liver fluke β-catenin led to aberrant neuromuscular development and proved lethal to juvenile fluke. Biweekly exposures to commercially available Wnt pathway inhibitory compounds phenocopied the delayed development observed in the gene silencing experiments. These data suggest that Fh Wnt pathway components represent attractive targets for the development of novel flukicides or indeed, the repurposing of existing Wnt antagonists for parasite control.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».