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Integrating Single-Cell RNA-Seq and Bulk RNA-Seq Reveals Ischemic Injury Promoting Polyomavirus Replication by DNA
Feng Yang1,2, Hui Zhang1, Xutao Chen1,3
1Organ Transplant Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Abstract:
BK polyomavirus (BKPyV) can establish persistent infections in 90% of the healthy adult population, and its reactivation is associated with graft failure in kidney transplant patients. Ischemic injury (IS) increases the risk of viral reactivation, making BKPyV a primary cause of allograft failure. However, the detailed molecular mechanisms of IS that promote BKPyV replication are not well characterized. The aim of the study was to identify the critical pathways and hub genes involved in IS's promotion of polyomavirus replication based on single-cell RNA-seq and bulk RNA-seq data. We found that IS could activate the DNA damage response pathway to promote polyomavirus replication. Additionally, we identified CDK1 as a hub gene according to the conservation of gene expression pattern and key pathways in mice and humans. Subsequently, using siRNA experiments, we demonstrated that CDK1 knockdown inhibits BKPyV replication. Together, the present study found that IS could regulate the expression of CDK1 via the "DNA damage response" pathway to promote polyomavirus replication.
Insights
Ischemic injury activates the DNA damage response pathway, increasing BK polyomavirus (BKPyV) replication. This study identifies CDK1 as a key gene, showing that inhibiting CDK1 can reduce BKPyV replication in kidney transplants.
Area of Science:
- Virology
- Molecular Biology
- Transplantation Immunology
Background:
- BK polyomavirus (BKPyV) establishes persistent infections in most adults.
- BKPyV reactivation is a significant cause of kidney allograft failure, particularly after ischemic injury (IS).
- The molecular mechanisms linking IS to enhanced BKPyV replication remain unclear.
Purpose of the Study:
- To identify key molecular pathways and genes involved in IS-induced BKPyV replication.
- To elucidate the role of the DNA damage response in viral reactivation.
- To validate potential therapeutic targets for preventing BKPyV allograft nephropathy.
Main Methods:
- Analysis of single-cell and bulk RNA-sequencing data from kidney injury models.
- Bioinformatic identification of conserved pathways and hub genes in human and mouse models.
- siRNA-mediated knockdown of candidate genes (CDK1) to assess BKPyV replication.
Main Results:
- Ischemic injury was found to activate the DNA damage response pathway.
- The cell cycle kinase CDK1 was identified as a conserved hub gene linking IS and viral replication.
- CDK1 knockdown significantly inhibited BKPyV replication in experimental models.
Conclusions:
- Ischemic injury promotes BKPyV replication by activating the DNA damage response pathway.
- CDK1 plays a critical role in IS-mediated BKPyV replication.
- Targeting CDK1 may offer a novel strategy to prevent BKPyV-associated allograft failure.
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