Viral double-stranded RNA sensors induce antiviral, pro-inflammatory, and pro-apoptotic responses in human renal tubular epithelial cells

Abstract

Viral infection in the kidney is characterized by tubular injury induced directly by the virus and/or by cytotoxic lymphocytes. Previously, we found that human tubular epithelial cells express Toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and retinoic acid-inducible gene-I (RIG-I), all sensors of double-stranded RNA (dsRNA) and potent inducers of antiviral activity. Here, we demonstrate increased expression of these three dsRNA sensors in kidney transplant biopsies during cytomegalovirus or BK virus infection. In primary tubular epithelial cells, dsRNA sensor activation induced the production of pro-inflammatory TNF-α and antiviral IFN-β. Notably, dsRNA also enhanced the expression of pro-apoptotic proteins; however, dsRNA alone did not cause cell death due to the expression of anti-apoptotic proteins. The dsRNA sensitized tubular epithelial cells to apoptosis induced by an agonistic antibody against the Fas receptor (CD95), an apoptotic pathway that eliminates infected cells. These findings indicate that tubular epithelial cells require at least two signals to undergo apoptosis, which can help preserve tubular integrity even under inflammatory conditions. Thus, sensors of viral dsRNA promote antiviral, pro-inflammatory, and pro-apoptotic responses in tubular epithelial cells, which may orchestrate the control of viral infection in the kidney.