Human cytomegalovirus (CMV) is the leading cause of congenital infection in developed countries. CMV infection during pregnancy may result in fetal and neonatal death or the development of serious clinical sequelae. Fetal injury results from direct viral cytopathic damage to the CMV-infected fetus. However, increasing evidence indicates placental infection may adversely affect pregnancy via immune modulation leading to placental dysfunction and subsequent fetal injury.
This study investigated the effects of CMV infection on expression of the pro-inflammatory chemokine MCP-1 (CCL2) and cytokine TNF-α in placentae from stillborn babies, ex vivo placental explant histocultures and in vitro cell culture models. Tissue cytokine mRNA levels were measured using real time PCR and protein levels assessed using quantitative immunohistochemistry and dual immunofluorescence.
CMV-infected placentae from stillborn babies showed an elevated trend for MCP-1 and TNF-α mRNA expression and had significantly elevated MCP-1 and TNF-α protein levels compared to uninfected placentae (p=0.001 and p=0.007) and to placentae infected with other microorganisms (p=0.01 and p=0.038) (n=7 per group). Modelling acute clinical infection using ex vivo placental explant histocultures showed CMV infection caused elevated expression of MCP-1 and TNF-α mRNA (p=0.015 and p=0.004) and protein (p=0.0003 and p<0.0001) compared with uninfected explants (n=25 per group). CMV infection of fibroblast (MRC-5) and trophoblast (TEV-1) cell cultures demonstrated elevated expression of MCP-1 and TNF-α was a direct response to CMV replication within infected cells.
Cytokine dysregulation has been associated with adverse outcomes of pregnancy and can negatively affect many aspects of placental development and function. These novel findings demonstrate CMV infection modulates the placental immune environment in vivo and in a multicellular ex vivo model, suggesting CMV-induced cytokine modulation as a potential initiator and/or exacerbator of placental and fetal injury.