BK polyomavirus (BKPyV) is a risk factor for bladder cancer through induction of APOBEC3-mediated genomic damage

Abstract

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. BK polyomavirus (BKPyV) is a common childhood infection that can be reactivated in the adult kidney leading to viruria. Here we used a mitotically-quiescent, differentiated, normal human urothelial in vitro model to study BKPyV infection. BKPyV infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry into the cell cycle via inhibition of Retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, which combined to push urothelial cells from G0 into an arrested G2 cell cycle state. The single-stranded DNA displacement loops formed during BKPyV-infection, provide a substrate for APOBEC3 enzymes where they interacted with LT-Ag. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations, including transplant patients and the elderly.

The urothelial transcriptomic response to interferon gamma predicts T1 recurrence-free and basal/squamous muscle-invasive bladder cancer survival and better targeted strategies for immune checkpoint blocking

“…Of particular note, the CXCL9/10/11-CXCR3 axis is a critical regulator of leukocyte migration, differentiation and activation [4], including recruitment of effector T cells. We have shown elsewhere that CXCL10/11 are highly induced following exposure of normal urothelium to BK virus [5] and were the only genes to be further upregulated, rather than repressed, by treatment with exogenous IFNγ. We therefore suggest that attenuated BK virus could be used to generate a pro-inflammatory, IFNγ-rich local environment akin to that induced by BCG.…”