Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophob last apoptosis in a Toll-like receptor-2 and tumour necrosis factor-α dependent manner

Placentae obtained from newborns with congenital human cytomegalovirus (HCMV) infection often display chronic villitis and disruptions of the syncytiotrophoblast (ST). Little is known about how HCMV infection induces inflammation in the villous placenta and loss of the trophoblast. We propose that the inflammation is initiated with innate defence responses of the ST to maternal blood-borne virus. In this paper we show with a culture model (ST derived from primary cytotrophoblasts) that UV-inactivated HCMV (UV-HCMV) doubled the frequency of ST apoptosis. ST cultures challenged with UV-HCMV increased transcription and secretion of the inflammatory cytokines tumour necrosis factor alpha (TNF alpha) and interleukin-8, and antibody to TNF alpha inhibited UV-HCMV-induced apoptosis. Treatment with cycloheximide, an inhibitor of protein translation, did not reduce UV-HCMV-induced TNFa gene transcription, indicating that upregulation was independent of de novo protein synthesis. Neutralizing antibody to Toll-like receptor (TLR)2 inhibited UV-HCMV-induced transcription and translation of TNFa, and consequently inhibited the increase in ST apoptosis. Our results show that even transcriptionally inactive HCMV binding to TLR2 on ST can initiate inflammation, including secretion of TNFa, which leads to trophoblast death. Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.