Human Cytomegalovirus Induces TGF-β1 Activation in Renal Tubular Epithelial Cells after Epithelial-to-Mesenchymal Transition

Human cytomegalovirus (HCMV) infection is associated epidemiologically with poor outcome of renal allografts due to mechanisms which remain largely undefined. Transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine, is more abundant in rejecting renal allografts that are infected with either HCMV or rat CMV as compared to uninfected, rejecting grafts. TGF-β1 induces renal fibrosis via epithelial-to-mesenchymal transition (EMT) of renal epithelial cells, a process by which epithelial cells acquire mesenchymal characteristics and a migratory phenotype, and secrete molecules associated with extracellular matrix deposition and remodeling. We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome

BMC Infect Dis

Background Cytomegalovirus infection is the most frequent viral congenital infection, with possible consequences such as deafness, or psychomotor retardation. In 2016, the French High Council of Public Health was mandated to update recommendations regarding prevention of cytomegalovirus infection in pregnant women. We summarize a critical appraisal of knowledge and deterministic decision analysis comparing the current no-screening situation to serological screening during pregnancy, and to hygiene promotion. Methods Screening was defined as systematic serological testing, during the first trimester, with repeated tests as needed, to all pregnant women. Outcomes were: 1) severe sequela: intellectual deficiency with IQ ≤ 50 or hearing impairment < 70 dB or sight impairment (≤ 3/10 at best eye); 2) moderate sequela: any level of intellectual, hearing or sight deficiency; and 3) death or termination of pregnancy. We simulated the one-year course of cytomegalovirus infection in a cohort of 800,000 pregnant women. We developed a deterministic decision model, using best and min-max estimates, extracted from systematic reviews or original studies. Results Relevant data were scarce or imprecise. We estimated that 4352 maternal primary infections would result in 1741 foetal infections, and an unknown number of maternal reinfections would result in 1699 foetal infections. There would be 788 cytomegalovirus-related consequences, including 316 foetal deaths or terminations of pregnancy, and 424 moderate and 48 severe sequelae. Screening would result in a 1.66-fold increase of poor outcomes, mostly related to a 2.93-fold increase in deaths and terminations of pregnancy, not compensated by the decrease in severe symptomatic newborns. The promotion of hygiene would result in a 0.75-fold decrease of poor outcomes, related to both a decrease in severe sequelae among symptomatic newborns (RR = 0.75; min-max: 1.00–0.68), and in deaths and terminations of pregnancy (RR = 0.75; min-max: 0.97–0.68). Conclusions Prevention of cytomegalovirus infection during pregnancy should promote hygiene; serological screening should not be recommended