Innate immune signaling in trophoblast and decidua organoids defines differential antiviral defenses at the maternal-fetal interface

Abstract Infections at the maternal-fetal interface can directly harm the fetus and induce additional complications that adversely impact pregnancy outcomes. Innate immune signaling by both fetal-derived placental trophoblasts and the maternal decidua must provide antimicrobial defenses at this critical interface without compromising its integrity. Here, we developed matched trophoblast and decidua organoids from human placentas to define their relative contributions to innate immune antiviral defenses at the maternal-fetal interface. We show that trophoblast and decidua organoids recapitulate some, but not all, of the basal cytokine release observed in matched tissue explants. We further show that trophoblast organoids constitutively release antiviral type III interferons (IFNs) and that fetal and maternal organoids differentially respond to viral infections through the induction of organoid-specific cytokines. These findings define key differences in innate immune signaling generated by fetal-derived trophoblasts and the maternal decidua, which together must protect the fetus from viral infections.