Mining bulk transcriptomic datasets identifies inflammasome activation and antigen presentation as key novel mechanisms of BK polyomavirus‐associated nephropathy

Abstract BK polyomavirus (BKPyV) is a viral infection experienced by kidney transplant recipients that can lead to the development of BKPyV‐associated nephropathy (BKPyVAN), graft dysfunction, and loss. There are no BKPyV‐specific treatments available to prevent this significant cause of transplant failure. This bioinformatic study aims to characterise the cellular networks and pathways involved in BKPyVAN to identify novel therapeutic targets. Four publicly available bulk transcriptomic datasets containing BKPyVAN post‐transplant biopsy tissue were identified in the National Centre for Biotechnology Information Gene Expression Omnibus (NCBI GEO). Differentially expressed genes (DEGs) (adjusted p < 0.05, fold change ≥ 1.5) were identified and dataset comparisons made between BKPyVAN versus stable grafts and acute rejection versus stable grafts. Canonical pathways were investigated using QIAGEN Ingenuity Pathway Analyses and protein interaction networks using STRING v12.0. There were 226 genes identified as differentially expressed in BKPyVAN compared with stable graft function that were conserved across all four datasets. This gene signature was associated with three cellular networks and 201 significantly enriched pathways. The cellular networks identified included 67 immune‐related proteins; eight proteins associated with the absent in melanoma 2 (AIM2) inflammasome; and four HLA class II proteins. The most notable pathways significantly increased in BKPyVAN included HLA class II antigen presentation ( p < 0.001), inflammasome ( p < 0.001), and interleukin 6 signalling ( p < 0.01). There were seven DEGs that were observed as common to all BKPyVAN versus acute rejection comparisons. The TUBB3 gene was the only gene that was consistently upregulated in all datasets. Several pathways and potential treatment targets were identified using a bulk RNA mining strategy, including HLA class II antigen presentation, AIM2 inflammasome, and IL‐6 signalling in BKPyVAN pathology. Such tools provide an important first step in identifying novel mediators of disease pathogenesis and likely hold the key for the discovery of potential treatment targets for BKPyVAN in the future. © 2026 The Pathological Society of Great Britain and Ireland.