SUMMARY Interferons (IFNs) are critical products of the immune system that limit the replication of viruses in cells. However, during pregnancy-associated infections, IFNs can also produce placenta malformation resulting in fetal demise. While the toxicities of IFNs have been known for decades, the underlying toxic mechanisms are not known, particularly in the placenta. IFNs induce the production of hundreds of effector proteins, and the deleterious effects of these individual IFN-induced proteins have been largely unexplored. We have made significant progress in understanding the IFN-induced transmembrane proteins (IFITMs) and their ability to limit the severity of virus infections by altering cell membranes to broadly block virus fusion with host cells. Interestingly, placenta trophoblasts express co-opted retroviral fusion proteins (Syncytin-1 and Syncytin-2) that allow these cells to fuse with one another to form the syncytiotrophoblast, a placental structure critical for absorption of oxygen and nutrients at the maternal-fetal interface. Since the fusion of trophoblasts is akin to virus membrane fusion, we hypothesize that this cell-to-cell fusion reaction can be inhibited by IFNs and specifically by the anti-fusogenic IFITMs. Our preliminary results indicate that IFITM3 is capable of inhibiting Syncytin-mediated fusion of heterologous cells and that IFNβ inhibits fusion of a trophoblast cell line and primary trophoblasts. We will now systematically investigate the effects of IFN subtypes I, II, and III (Aim 1) and the antiviral IFITMs (IFITM1, 2, and 3) (Aim 2) on Syncytin-mediated fusion in heterologous cells and human trophoblasts. These studies will provide the missing mechanistic link between IFNs and placenta toxicity, thus identifying specific molecular targets for mitigating the negative effects of IFNs during pregnancy- associated infections.