Infections at the maternal-fetal interface can directly harm the developing fetus and compromise the health of the pregnant woman. 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 trophoblast and decidua organoids from matched human placentas to define their relative contributions to innate immune 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, but not decidua, 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.

SummaryViruses circulating in wild and domestic animals pose a constant threat to human health1. Identifying human genetic factors that protect against zoonotic infections is a health priority. The RD-114 and Type-D retrovirus (RDR) interference group includes infectious viruses that circulate in domestic cats and various Old World monkeys (OWM), and utilize ASCT2 as a common target cell receptor2. While human ASCT2 can mediate RDR infection in cell culture, it is unknown whether humans and other hominoids encode factors that restrict RDR infection in nature2,3. Here we test the hypothesis that Suppressyn, a truncated envelope protein that binds ASCT2 and is derived from a human endogenous retrovirus4,5, restricts RDR infection. Transcriptomics and regulatory genomics reveal that Suppressyn expression initiates in the preimplantation embryo. Loss and gain of function experiments in cell culture show Suppressyn expression is necessary and sufficient to restrict RDR infection. Evolutionary analyses show Suppressyn was acquired in the genome of a common ancestor of hominoids and OWMs, but preserved by natural selection only in hominoids. Restriction assays using modern primate orthologs and reconstructed ancestral genes indicate that Suppressyn antiviral activity has been conserved in hominoids, but lost in most OWM. Thus in humans and other hominoids, Suppressyn acts as a restriction factor against retroviruses with zoonotic capacity. Transcriptomics data predict that other virus-derived proteins with potential antiviral activity lay hidden in the human genome.

14Rift Valley fever virus (RVFV) infections in pregnant livestock are associated with high 15 rates of fetal demise and have been linked to miscarriage in pregnant women. To address how 16 acute RVFV infection during pregnancy causes detrimental effects on the fetus, we developed an 17 immunocompetent pregnant rodent model of RVFV infection. We found that pregnant rats were 18 more susceptible to RVFV-induced death than their non-pregnant counterparts and that RVFV 19 infection resulted in intrauterine fetal death and severe congenital abnormalities, even in pups from 20 infected asymptomatic pregnant rats. Virus distribution in infected dams was widespread, with a 21 previously unrecognized preference for infection, replication, and tissue damage in the placenta. 22In human mid-gestation placental tissue, RVFV directly infected placental chorionic villi, with 23 replication detected in the outermost syncytial layer. Our work identifies direct placental infection 24 by RVFV as a mechanism for vertical transmission and points to the teratogenic potential of this 25 virus in humans. This is the first time vertical transmission of RVFV has been shown in species 26