Human cytomegalovirus infection triggers a paracrine senescence loop in renal epithelial cells

Human cytomegalovirus (HCMV) is an opportunistic pathogen that can cause severe diseases in immunosuppressed individuals. To enable replication of its long double-stranded DNA genome, HCMV induces profound changes in cellular homeostasis that may resemble senescence. However, it remains to be determined whether HCMV-induced senescence contributes to organ-specific disease pathogenesis in immunosuppressed individuals, such as kidney transplant recipients (KTRs). Here, we show a direct cytopathic effect of HCMV on primary renal proximal tubular epithelial cells (RPTECs), a natural setting of HCMV infection and disease. Specifically, we find that RPTECs are fully permissive for HCMV replication, which endows them with an inflammatory gene signature resembling the senescence-associated secretory phenotype (SASP). Although HCMV-induced senescence is not cell-type specific as it can be observed in both RPTECs and human fibroblasts (HFFs), only infected RPTECs show downregulation of LAMINB1 and KI67 mRNAs, two well regarded markers of senescence, alongside enhanced secretion of IL-6 and IL-8, two senescence associated inflammatory cytokines. Finally, HCMV-infected RPTECs but not HFFs are capable of triggering a senescence/inflammatory loop that leads bystander non-infected cells to develop a similar senescent/inflammatory phenotype. Overall, our findings raise the intriguing possibility that HCMV mediated paracrine senescence of epithelial cells may contribute to HCMV-related pathogenesis in the kidney.