Control of influenza virus induced type I interferon signaling during pregnancy

PROJECT SUMMARY/ABSTRACT Infectious insults are common during pregnancy; over the nine months of gestation ~60% of pregnant women self-report at least one illness, with viral upper respiratory tract (URT) infections being the most common. Although URT-trophic viruses replicate in the respiratory epithelium, the induced inflammatory cytokines like type I interferon (IFN) circulate systemically and can access the placenta. Recent work has shown that virally induced type I IFNs can be major drivers of adverse effects on fetal development. URT infections during pregnancy, however, are not typically linked to birth defects or miscarriage. It was therefore unclear why maternal infection with a pathogen like an influenza virus, which also induces to fetal IFN exposure, would not compromise fetal health. We hypothesized that an uncharacterized IFN regulatory pathway was the answer to this apparent discrepancy. By performing a genome-wide CRISPR/Cas screen, we identified a G-protein coupled estrogen receptor 1 (GPER1) dependent signaling pathway that protected fetal health from type I IFN signaling during maternal influenza A virus (IAV) infection. Disruption of this pathway led to fetal phenotypes as severe as those caused by direct congenital infections. Importantly, the activities of this pathway were restricted to reproductive and fetal tissues; alterations of its activity had no measurable effect on maternal health during IAV infection. The major goal of this application is to understand how GPER1-mediated signaling normally protects fetal health from inflammatory maternal cytokines such as type I IFN. In aim 1, we will define how GPER1-induced GPCR signaling suppresses IFN-induced JAK/STAT signaling and interferon-stimulated gene expression. These experiments will define a previously unknown mechanism for control of IFN signaling. In aim 2, we will characterize where and when GPER1 signaling is required to protect fetal health, as well as the effects of GPER1 dysregulation on cell physiology both in vivo and in primary human placental organoid cultures. These experiments will allow basic mechanistic insights into how maternal inflammation compromises fetal development. Finally, in aim 3, we will explore the consequences of IFN signaling on placental structure/function when GPER1 is absent and also evaluate the potential of hyper-activating GPER1 signaling under the inflammatory conditions that normally harm fetal development. Together, these studies will not only allow for a more complete understanding of IFN regulatory mechanisms and the fetal/maternal immune response but could also serve as the basis for an eventual first-in-class treatment designed to protect the fetus from inflammation without compromising maternal immunity.