Epigenetic Inhibitors as Potential Anti-Viral Treatment against BK Polyoma Virus Associated Nephropathy
Notice bibliographique
Résumé
Introduction BK polyomavirus reactivation in immuno-compromised renal transplant patients may cause rapid graft loss within six months of transplant due to serious complication i.e. BK polyoma virus associated nephropathy (BKPVAN). Due to lack of an appropriate antiviral therapy against BKV it is important to study the underlying mechanism of pathogenesis causing BKPVAN. Objective To investigate BKV pathogenesis and to determine the potential anti-viral therapy against BKPVAN. Methods Human Proximal Tubular Epithelial Cells (HPTCs) and CCD1105 cell lines were infected with BKV. In order to elucidate the epigenetic mechanism another set of cells were treated with DNA methyl transferase enzyme 1 inhibitor RG108 and Histone acetyl transferase inhibitor CPTH2. Urine samples were collected from BKV viruria/viremia positive patients. RNA/DNA was isolated to perform Methylation Specific PCR (MSP) to assess DNA methylation. Further, Real-time PCR, RNA sequencing, western blot and Immunofluorscence staining were performed. Results The downregulation of epithelial cell marker E-cadherin (CDH1) and Collagen-IV (COLIVA1) gene expression was observed in BKV infected cells, whereas, increase in expression of fibrotic marker collagen I suggests that BKV infection induces epithelial mesenchymal transition (EMT). MSP confirmed silencing of those genes through a DNA methylation mechanism by demonstrating hypermethylation of the promoters of CDH1 and COLIVA1 genes in primary cells and patient’s samples. Imunofluorescence staining has shown an increase in Vimentin and disruption of actin filaments in BKV infected cells confirming EMT. RG108 treatment, a demethylating agent, has shown altered COLIVA expression and a decrease in methylation of the promoter, demonstrating that BKV uses DNA methylation for inducing EMT and eventually fibrosis. We observed that BKV hypermethylates the RB1 gene promoter to silence it and instigate host cell division for its own replication however, RG108 treatment had demonstrated significant decrease in BKV DNA (p-value<0.037). |RNA sequencing data has revealed that GCN5 (HAT family) expression is increased in BKV infected cells which is required for viral pathogenesis and during replication whereas HATi treatment has shown significant decrease in VP1 expression (the marker of BKV infection) conferring that histone modification also plays an important role in BKV pathogenesis. Conclusion Investigating BKV pathogenesis from an epigenetic point of view revealed that BKV orchestrates EMT and pathogenesis by using a DNA methylation and histone modification mechanisms. The use of DNMTi and HATi could reverse or prevent progression of disease and block BKV replication, therefore, these epigenetic inhibitors widely used in cancer treatment, may be potentially useful as an antiviral therapy for BKPVAN. Canadian National Transplant Research Program and Alberta Transplant Institute provided fund as Fellowship to Minal Borkar-Tripathi for pursuing postdoctoral research.
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 | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 ».