Prognostic Biomarkers and Potential Treatment for BK Polyomavirus Associated Nephropathy
Notice bibliographique
Résumé
Introduction BK polyomavirus reactivation in kidney causes acute kidney disease in immuno-compromised renal transplant patients. Due to lack of an appropriate antiviral therapy against BKV it is important to study the underlying mechanism of pathogenesis causing BK polyoma virus associated nephropathy (BKPVAN). Objective To investigate BKV pathogenesis from an epigenetic point of view 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. Another set of cells were treated with DNMT1 inhibitor RG108. Urine samples were collected from BKV viruria/viremia positive patients. RNA/DNA was isolated to perform Methylation Specific PCR (MSP) to assess DNA methylation. Expression study was done by using Real-time PCR and western blot assays. Immunofluorscence staining experiment and flow cytometry were performed to demonstrate fibrosis and necroptosis respectively. Results The downregulation of 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 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. The protein study confirmed that BKV induced necroptosis by inducing the expression of Receptor-interacting serine/threonine-protein kinase 3, and phospho-Mixed Lineage Kinase Like-pseudokinase and High Mobility Group Protein B1. Regulation by RG108 indicated that BKV may induce necroptosis epigenetically. 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). Conclusion We have investigated BKV pathogenesis from an epigenetic point of view and we are the first to report that BKV orchestrates EMT and necroptosis by using a DNA methylation mechanism. The hypermethylated promoters of genes could serve as prospective biomarkers for prognosis of fibrosis. The use of DNMT inhibitors could reverse or prevent progression of fibrosis and block BKV replication, therefore, may be potentially useful as an antiviral therapy. However, further studies exploiting DNA methylation mechanism are needed to prevent graft loss due to BKPVAN.
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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 ».