ABSTRACT Antiviral immunity at the maternal-fetal interface involves a three-way interaction between the fetal-derived placenta, the maternal decidua, and viral infection. This immunological balance promotes tolerance of the semi- allogeneic fetus while protecting it from maternal pathogens. Zika virus (ZIKV), a mosquito-borne flavivirus, is among the few microbes (termed TORCH pathogens) able to surmount the physical and immunological barrier of the placenta to infect the developing fetus. However, the mechanisms by which ZIKV and other TORCH pathogens overcome the protective antiviral response at the maternal-fetal interface are poorly understood. Interferon lambda (IFN-λ) is a cytokine that contributes to antiviral immunity at anatomic barriers, including the placenta. Studies with primary human placental trophoblasts, human placental explants, and mouse models of congenital ZIKV infection have demonstrated a role for IFN-λ in antiviral immunity at the placental barrier. However, we have found that IFN-λ also can induce fetal and placental pathology during congenital ZIKV infection, an effect that results from IFN-λ signaling in maternal tissues. Furthermore, we found that contemporary Asian-lineage ZIKV strains differ in their ability to induce IFN-λ-dependent pathology. This property corresponds to enhanced sensitivity to IFN-γ in non-pregnant mice, as well as to the severity of disease observed in non-human primate models of congenital ZIKV infection. We hypothesize that ZIKV strain-specific IFN-λ responses regulate both protective antiviral responses in the placenta and pathologic maternal immune responses. The balance between the protective and pathologic effects of IFN-λ signaling is important for controlling TORCH pathogens such as ZIKV and rubella virus, as well as for autoimmune conditions associated with elevated IFN production and poor pregnancy outcomes. We will define the IFN-λ specific antiviral response in mice, placental cell lines, and primary human trophoblasts. We will determine whether ZIKV is better able to antagonize this response compared to other flaviviruses and whether TORCH pathogens, such as ZIKV and RUBV, share an ability to antagonize IFN-λ-mediated immunity in the placenta. We will use a mouse model of congenital ZIKV infection to characterize the pathologic immune response elicited by maternal IFN-λ signaling and generate conditional knockout lines to define the cell types that mediate this response. We will use reverse genetics approaches to define the viral determinants of pathogenesis, particularly a role for a balanced polymorphism in domain III of the viral E protein.