Abstract
Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/β-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function.
Highlights
Human Cytomegalovirus (HCMV) is a betaherpesvirus that is ubiquitously present in the human population
The T cell-specific factor (TCF)/lymphoid enhancer-binding factor-1 (LEF-1)-luciferase reporter construct TOPflash was used to determine whether HCMV infection affects b-catenin activity
We report for the first time that HCMV inhibits the canonical Wnt signaling pathway in dermal fibroblasts and human extravillous cytotrophoblasts
Summary
Human Cytomegalovirus (HCMV) is a betaherpesvirus that is ubiquitously present in the human population. Infection with HCMV is usually subclinical in healthy adults, but can cause serious disease in populations with underdeveloped or compromised immune systems [1]. HCMV is the leading viral cause of congenital birth defects in the developed world [2,3]. The majority of congenitally infected infants are asymptomatic at birth, 5 to 20 percent of the infected neonates are born with symptoms. Opportunistic infections with HCMV increase morbidity in immunocompromised individuals, such as organ transplant recipients and AIDS patients [1]. Infection with HCMV compromises the success of bone marrow and solid organ transplantations, where it is associated with graft rejection [7]. Recent evidence implicates HCMV infection as a contributing factor in the development of atherosclerosis and cardiovascular disease [8]
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