Investigating Transplacental Immune Pathways Contributing to Fetal Brain Pathology in Maternal Influenza

Project Summary/Abstract The overarching goal of this application is to identify targetable transplacental immune signaling pathways for optimizing antenatal therapies that improve maternal and offspring health outcomes during seasonal influenza outbreaks. Influenza viruses pose ever-present threats to the health of pregnant women and escalate the risk of neurodevelopmental disorders in their offspring. Yet, how and which immune signals propagate across the maternal-fetal interface to impact fetal brain development during gestational influenza virus infection are unknown. The objective of this proposal is to assess the extent to which transplacental immune signaling drives fetal brain pathologies during maternal respiratory influenza virus infection. The central hypothesis is that gestational influenza causes leukocyte and lymphocyte infiltration into the placenta and enhances transplacental inflammation that is ultimately sensed by fetal microglia and border-associated macrophages, leading to subsequent fetal brain pathologies. The premise for this proposal is that influenza-driven immune signaling must cross the maternal-fetal interface before reaching the fetal brain. Surprisingly little is known about the contribution of transplacental immune signaling in directing aberrant fetal brain development during gestational influenza virus infection. This is significant because noninvasive antenatal therapies directed at curbing inflammation at the maternal-fetal interface could mitigate fetal neuroinflammation and subsequent neurodevelopmental disorders. The current proposal will use cutting-edge spatial transcriptomics to define time-dependent phenotypic and functional shifts in immune and non-immune cells at the maternal-fetal interface during maternal respiratory influenza infection. Rates of placental vascular permeability and leukocyte diapedesis as well as their dependence upon IL-6 signaling will be defined throughout mid-to-late gestation. The extent to which fetal brain microglia and macrophages shift their proliferation, activation, and colonization patterns in response to transplacental IL-6 signaling will help determine whether this cytokine could be targeted in clinical settings. Overall, these studies will illuminate transplacental immune mechanisms by which gestational influenza predisposes individuals to neurodevelopmental disorders and will provide insights for mitigating fetal neuroinflammation during related viral pandemics.