Preimplantation exposure to viral dsRNA impairs decidualization leading to altered placental development and fetal...

Viral infections are associated with early pregnancy loss and later gestational complications, including preeclampsia and fetal growth restriction. While viral components, including viral double-stranded RNA (dsRNA), have been shown to affect placental trophoblast function, how these components may affect maternal endometrial function is less understood. Endometrial stromal cells make up the bulk of the human endometrium, and they undergo a specialized hormone-driven differentiation process termed decidualization, monthly in preparation for pregnancy. We have previously shown that these stromal cells exhibit robust inflammatory responses to bacterial LPS and viral dsRNA. The goals of this study are to determine the effects of prior viral dsRNA exposure on endometrial decidualization and whether this affects subsequent placentation and pregnancy outcomes. Using a combination of 2D endometrial stromal cell cultures, 3D human endometrial assembloids, and mouse models of decidualization and pregnancy, we demonstrated that exposure to viral dsRNA (Poly(I:C)) 48 h prior to hormonal stimulation impaired decidualization in vitro and in vivo. Similarly, preimplantation exposure to Poly(I:C) on GD0.5 in timed-mated dams inhibited decidualization, reduced implantation success, and induced fetal growth restriction. This was associated with altered placentation, in particular, formation of the Syn-TII cells in the labyrinth zone, and dysregulated expression of glucose and amino acid transporters in the placenta. This work emphasizes the importance of preconception endometrial health for successful pregnancy and identifies a novel mechanism by which prior viral infection can lead to implantation failure and later pregnancy complications.

Viral infections increase the risk of early pregnancy loss and later complications, such as poor fetal growth. While viruses are known to affect the placenta, less is understood about their impact on the uterine lining, which must be healthy for pregnancy to begin. The uterine lining is made up of cells that undergo changes each month called decidualization, which is driven by hormones to help with implantation. In this study, we examined how early exposure to viral infection affects decidualization and pregnancy outcomes. Using cell cultures, 3D uterine models, and mouse studies, we found that exposure to viral factors impaired decidualization, reduced embryo implantation, and disrupted fetal growth. These effects were linked to abnormal placental development and altered nutrient transport to the fetus. Overall, our findings show that uterine health before conception is critical for successful pregnancy and identify a mechanism by which early maternal viral infections may lead to pregnancy complications. This provides exciting opportunities to screen and prevent complications much earlier on in pregnancy.