Single-cell RNA sequencing highlights the role of epithelial-immune dual features of proximal tubule cells in BK polyomavirus nephropathy.

Up to 10% of renal allograft failures are caused by BK polyomavirus nephropathy (BKPyVN). However, there is no specific antiviral agent for BKPyVN. The only treatment is to reduce the levels of immunosuppression, which is not always practical and increases the risk of rejection. Since targeting the microenvironment is a promising approach, we performed single-cell RNA sequencing (scRNA-seq) on BKPyVN samples and stable allografts to obtain BKPyVN microenvironmental atlases. Interestingly, we identified a novel subpopulation of proximal tubule cells (annotated as IGKC+ PT) with epithelial-immune dual features that may contribute to the progression of BKPyVN through T-cell exhaustion. Additionally, we determined that the IGKC+ PT subpopulation might serve as a non-invasive diagnostic marker through scRNA-seq of urine samples and co-immunofluorescence staining. These results improve our understanding of the BKPyVN microenvironment and may guide the development of new therapeutic and diagnostic approaches for a wide range of patients.IMPORTANCEBKPyVN severely threatens kidney transplant recipients. Due to the lack of effective drugs against BK polyomavirus (BKPyV), reducing immunosuppressant therapy is the only treatment. Unfortunately, this approach is not always effective and increases the acute rejection risk. A growing body of research suggests that potential therapeutic targets may be identified by studying the disease microenvironment. However, traditional methods have not explained why the large number of infiltrating T cells in the BKPyVN microenvironment does not effectively clear BKPyV. Newly available large-scale scRNA-seq technology can be used to study gene expression at a single-cell resolution, offering a new way to investigate the BKPyVN microenvironment. By combining scRNA-seq with experimental analysis, we found a novel subpopulation of proximal tubule cells (annotated as IGKC+ PT) with epithelial-immune dual features that may contribute to the progression of BKPyVN through T-cell exhaustion.