Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophoblast apoptosis in a Toll-like receptor-2 and tumour necrosis factor-alpha 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 (TNFalpha) and interleukin-8, and antibody to TNFalpha inhibited UV-HCMV-induced apoptosis. Treatment with cycloheximide, an inhibitor of protein translation, did not reduce UV-HCMV-induced TNFalpha 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 TNFalpha, 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 TNFalpha, which leads to trophoblast death.
Chan
G
G
Department of Medical Microbiology and Immunology and Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada.
Guilbert
L J
LJ
D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D051195:Toll-Like Receptor 2 / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D014327:Trophoblasts / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*; D014466:Ultraviolet Rays; D038301:Virus Inactivation / Q000528:radiation effects
D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha