Viral ssRNA Induces First Trimester Trophoblast Apoptosis through an Inflammatory Mechanism

Abstract

Problem-Infection during pregnancy represents a significant cause of mobility and mortality. While viruses pose a major threat, little is known about their effect on early pregnancy, or the mechanisms involved. The objective of this study was to characterize the trophoblast response following exposure to viral ssRNA.Method of study-First trimester trophoblast cells were treated with or without viral ssRNA. Cytokine production was measured by multiplex analysis and ELISA. Apoptosis was determined using Hoescht staining, cell viability, and caspase activity assays.Results-Treatment of trophoblasts with viral ssRNA increased their secretion of IL-8, IL-6 and IFNβ. However, the ssRNA also induced trophoblast apoptosis. To test whether the viral ssRNAinduced inflammatory response was responsible for this induction of apoptosis, conditioned media (CM) from trophoblasts was added to a fresh culture of cells. The CM from viral ssRNA-treated induced higher levels of trophoblast apoptosis than the control CM. Moreover, recombinant IFNβ induced trophoblast apoptosis.Conclusion-We demonstrate that viral ssRNA induces a pro-inflammatory and type I interferon response in the trophoblast, and that this inflammatory process may indirectly induce trophoblast apoptosis. These results provide a novel mechanism by which certain viral infections might compromise placental integrity and function, and therefore, pregnancy outcome.

Functional Toll-like receptors in primary first trimester trophoblasts

“…Data from trophoblast cell lines, including BeWo cells, dominate previous reports on TLR function in early gestational trophoblasts (Komine-Aizawa et al, 2008, Klaffenbach et al, 2005, Aldo et al, 2010, Nakada et al, 2009. Our findings show substantial discrepancy between primary first trimester trophoblasts and the trophoblast cell line BeWo, with regards to both TLR gene expression and function, and this unresponsiveness of BeWo cells to TLR activation is supported by others (Fujisawa et al, 2000, Komine-Aizawa et al, 2008.…”

“…and TLR10 expression have been demonstrated in primary first trimester trophoblasts (Abrahams et al, 2004, Mulla et al, 2013 and of the endosomal TLRs, only TLR3 and TLR8 transcripts have been detected in early gestational placentas (Abrahams et al, 2005, Aldo et al, 2010.…”

Toll-like receptor profiling of seven trophoblast cell lines warrants caution for translation to primary trophoblasts

“…Ten different human TLRs, each responding to a specific set of ligands, have been identified [4]. TLR expression and activation in primary trophoblasts [5][6][7][8][9][10] may contribute substantially to development of inflammatory pregnancy complications such as preeclampsia [11][12][13]. In Tangerås/Stødle et al [7] we demonstrated a broad functional TLR profile in primary first trimester trophoblasts, while the trophoblast cell line BeWo showed no TLR mediated cytokine response.…”

Induction of an Embryonic Mouse Innate Immune Response following Inoculation In Utero with Minute Virus of Mice

“…Nonetheless, given the extensive communication between mother and embryo, we did expect to see some maternal response to the infected embryo. We tried to search for this response in the placenta, since the organ contains the maternal tissue that is in closest proximity to the infected embryo and is certainly capable of mounting an innate response (62,63). Surprisingly, the data indicated a minimal placental response.…”