The uterine immune response during early pregnancy has consequences for embryo implantation, placental and fetal development, and offspring health. In this study, we investigated the cellular and molecular mechanisms underpinning adverse pregnancy outcomes following induction of a mild anti-viral inflammatory response during the peri-implantation window.
Female C57Bl/6 mice mated to C57Bl/6 males were administered a low dose of synthetic viral mimetic poly I:C (10 mg/kg) on gestational days (gd)0.5 and 2.5 and evaluated for effects on endometrial gene expression (gd3.5), uterine leukocytes (gd3.5), placental development and decidual spiral arteries (gd10.5), and placental structure and fetal growth (gd17.5). Flow cytometry of uterine leukocytes on gd3.5 revealed a 6.4-fold increase in conventional T cells, a 9.0-fold increase in regulatory T cells, and a 77% reduction in uterine natural killer (uNK) cells (n=7-9/group, P<0.01). RNA sequencing of the endometrium on gd3.5 identified 223 differentially expressed genes (n=3-5/group, FDR<0.05, logFC=0.485), including many associated with viral inflammatory signalling pathways and NK cell activity. Several genes encoding factors that support implantation and trophoblast invasion, angiogenesis, and vascular function were downregulated. qPCR showed a >3-fold increase in endometrial expression of pro-inflammatory cytokines Ifng, Il6 and Tnf. On gd10.5, constrained placental development and impaired decidual artery remodelling was evident, with a 41% reduction in vessel lumen cross-sectional area (n=8-9/group, P<0.001). By late pregnancy (gd17.5) fetuses were growth restricted (~19% reduction in mean weight) and placental weights were increased (n=13-15/group, P<0.001), indicative of placental insufficiency.
These findings provide compelling evidence that even mild viral-associated inflammation during the peri-implantation period disrupts the uterine immune response and dysregulates endometrial gene expression pathways and T cell-uNK cell networks critical for decidual vascular adaptation and trophoblast invasion. These perturbations are implicated as causal mechanisms underpinning compromised placental development and fetal growth, with potential consequences for long-term offspring health and disease susceptibility.