The placental cytokine network plays an integral role in immunological functions and associated with implantation, placental growth, and maintenance of healthy pregnancy. Human cytomegalovirus (CMV) infection during gestation can cause intrauterine infection associated with pregnancy complications and fetal abnormalities. Our recent in vivo studies have demonstrated CMV induces a pro-inflammatory shift in cytokine expression following infection of the placenta. In this study, we investigated the role of CMV UL130 gene on infection of placental trophoblast cells and subsequent expression of pro-inflammatory cytokines, MCP-1 and TNF-α, during the course of infection.
CMV UL130 mutants demonstrated reduced infection efficiencies in trophoblast cell lines, TEV-1 and JEG-3, compared to wild-type strain (P<0.001), indicating the importance of UL130 gene in trophoblast tropism. Particularly, UL130 C-terminal mutant demonstrated reduced replication efficiencies in trophoblast cells, with significantly less viral replication proteins detected at all time points investigated. MCP-1 mRNA and protein were marginally elevated at early stages, but significantly down-regulated during late time points of infection (P<0.01). In contrast, sustained and marked up-regulation of TNF-α was detected in response to CMV infection (P<0.01). These alterations in cytokine expression were not observed during infection with replication deficient UL130 mutant, demonstrating pro-inflammatory cytokine dysregulation is dependent on active infection and replication within these cells.
We concluded that CMV UL130 gene plays an important role in infection of placental trophoblasts and subsequent cytokine dysregulation in the placenta that can have negative impact on normal functioning of the placenta and can potentially lead to placental damage and fetal abnormalities.