title: Human cytomegalovirus-induces cytokine changes in the placenta with implications for adverse pregnancy outcomes.
abstract: 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.
authors.affiliation: Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia.
authors.forename: Stuart T
authors.initials: ST
authors.lastname: Hamilton
authors.forename: Gillian
authors.initials: G
authors.lastname: Scott
authors.forename: Zin
authors.initials: Z
authors.lastname: Naing
authors.forename: Jenna
authors.initials: J
authors.lastname: Iwasenko
authors.forename: Beverley
authors.initials: B
authors.lastname: Hall
authors.forename: Nicole
authors.initials: N
authors.lastname: Graf
authors.forename: Susan
authors.initials: S
authors.lastname: Arbuckle
authors.forename: Maria E
authors.initials: ME
authors.lastname: Craig
authors.forename: William D
authors.initials: WD
authors.lastname: Rawlinson
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D005260:Female; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006801:Humans; D010920:Placenta / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D012189:Retrospective Studies; D050497:Stillbirth; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014779:Virus Replication
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha