Prognostic Biomarkers and Potential Treatment for BK Polyomavirus Associated Nephropathy
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".