title: Viral single stranded RNA induces a trophoblast pro-inflammatory and antiviral response in a TLR8-dependent and -independent manner.
abstract: Interest is growing in the role of viral infections and their association with adverse pregnancy outcomes. The trophoblast is permissive to viruses, but little is known about their impact on the placenta. We previously established that viral single stranded RNA (ssRNA), a Toll-like receptor 8 (TLR8) agonist, induces a restricted trophoblast pro-inflammatory cytokine/chemokine response by upregulating the secretion of interleukin (IL)-6 and IL-8. In parallel, the type I interferon, IFNbeta, is produced and acts back on the cell in an autocrine/paracrine manner to trigger caspase-3-dependent apoptosis. In this study, we sought to extend these findings by determining the mechanisms involved, examining whether viral ssRNA could induce a trophoblast antiviral response, and evaluating the influence of viral ssRNA on pregnancy outcome using a mouse model. Viral ssRNA induced human first-trimester trophoblast inflammation, type I interferon production, an antiviral response, and apoptosis in both a TLR8/MyD88-dependent and -independent manner. Furthermore, administration of viral ssRNA to pregnant mice induced placental caspase-3 activation, a pro-inflammatory cytokine/chemokine, type I interferon, and antiviral response as well as immune cell infiltration. Thus, ssRNA viral infections may compromise pregnancy by altering placental trophoblast survival and function through both TLR8 and non-TLR8 signaling pathways, leading to immune changes at the maternal-fetal interface.
authors.affiliation: Department of Obstetrics, Gynecology, & Reproductive Sciences, Divisions of Reproductive Sciences and Maternal-Fetal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Potter
authors.affiliation: Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Manish
authors.initials: M
authors.lastname: Garg
authors.affiliation: Department of Obstetrics, Gynecology, & Reproductive Sciences, Divisions of Reproductive Sciences and Maternal-Fetal Medicine, Yale School of Medicine, New Haven, Connecticut Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Girard
authors.affiliation: Department of Obstetrics, Gynecology, & Reproductive Sciences, Divisions of Reproductive Sciences and Maternal-Fetal Medicine, Yale School of Medicine, New Haven, Connecticut vikki.abrahams@yale.edu.
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D051379:Mice; D008813:Mice, Inbred ICR; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology; D012367:RNA, Viral / Q000502:physiology*; D051200:Toll-Like Receptor 8 / Q000502:physiology*; D014327:Trophoblasts / Q000276:immunology* / Q000821:virology
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012367:RNA, Viral; C552579:TLR8 protein, mouse; D051200:Toll-Like Receptor 8; D053148:Caspase 3
keywords: Toll-like receptors; antiviral; apoptosis; cytokines; inflammation; pregnancy; reproductive immunology; trophoblast; viral ssRNA