Human Cytomegalovirus-Induces Cytokine Changes in the Placenta with Implications for Adverse Pregnancy Outcomes

• DOI: 10.1371/journal.pone.0052899
• Publication Date: 2012-12-31T22:25:39Z
• Authors: Stuart T. Hamilton; Gillian Scott; Zin Naing; Jenna Iwasenko; Beverley Hall; Nicole Graf; Susan Arbuckle; Maria E. Craig; William D. Rawlinson
• Keywords: 0301 basic medicine; Science; Placenta; Cytomegalovirus; Gene Expression; Virus Replication; Tissue Culture Techniques; 03 medical and health sciences; Pregnancy; Humans; Pregnancy Complications, Infectious; Cells, Cultured; Chemokine CCL2; Retrospective Studies; Tumor Necrosis Factor-alpha; Q; R; Stillbirth; Trophoblasts; Up-Regulation; 3. Good health; Cytomegalovirus Infections; Host-Pathogen Interactions; Medicine; Cytokines; Female; Research Article

Human cytomegalovirus (CMV) infection of the developing fetus can result in adverse pregnancy outcomes including death in utero. Fetal injury results from direct viral cytopathic damage to the CMV-infected fetus, although evidence suggests CMV placental infection may indirectly cause injury to the fetus, possibly via immune dysregulation with placental dysfunction. This study investigated the effects of CMV infection on expression of the chemokine MCP-1 (CCL2) and cytokine TNF-α in placentae from naturally infected stillborn babies, and compared these changes with those found in placental villous explant histocultures acutely infected with CMV ex vivo. Tissue cytokine protein levels were assessed using quantitative immunohistochemistry. CMV-infected placentae from stillborn babies had significantly elevated MCP-1 and TNF-α levels compared with uninfected placentae (p = 0.001 and p = 0.007), which was not observed in placentae infected with other microorganisms (p = 0.62 and p = 0.71) (n = 7 per group). Modelling acute clinical infection using ex vivo placental explant histocultures showed infection with CMV laboratory strain AD169 (0.2 pfu/ml) caused significantly elevated expression of MCP-1 and TNF-α compared with uninfected explants (p = 0.0003 and p<0.0001) (n = 25 per group). Explant infection with wild-type Merlin at a tenfold lower multiplicity of infection (0.02 pfu/ml), caused a significant positive correlation between increased explant infection and upregulation of MCP-1 and TNF-α expression (p = 0.0001 and p = 0.017). Cytokine dysregulation has been associated with adverse outcomes of pregnancy, and can negatively affect 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.