DISSECTING MECHANISMS OF INFLAMMATORY SIGNALING ACROSS THE MATERNAL FETAL INTERFACE

PROJECT SUMMARY/ABSTRACT Infants exposed in utero to maternal inflammatory disorders are at risk of long-lasting health impacts, such as altered neurodevelopmental outcomes or dysregulated immune responses. When maternal infections are the inflammatory stimulus, these adverse neonatal outcomes can occur in the absence of congenital infection. Our preliminary data show that infants who are HIV-exposed, but uninfected experience high rates of morbidity and mortality that are associated with maternal inflammation in a dose-dependent fashion. Early reports suggest that acute maternal infection with COVID-19 can have profound impacts on fetal immune development. Inflammatory signaling across the maternal-fetal interface during a critical fetal developmental window is likely to be responsible for these adverse neonatal outcomes. However, critical gaps exist in our understanding of how inflammatory signals are transferred across the placenta. The overarching goal of this proposal is to determine the cellular and molecular mechanisms involved in the transfer of inflammatory signals across the maternal-fetal interface in the setting of acute or chronic viral infection. We will capitalize upon access to samples from pregnancies complicated by either HIV, which results in chronic inflammation, or SARS-CoV-2, which causes severe acute inflammation, to address the following Specific Aims: 1) to profile the transcriptomic signatures of heterogenous maternal and fetal cell types in their in situ environment within placentas from pregnancies affected by HIV or SARS-CoV-2 versus healthy pregnancies; 2) to compare concentrations of inflammatory and regulatory biomarkers in maternal and infant peripheral blood, cord blood and placentas from term pregnancies affected by HIV or SARS-CoV-2 versus healthy pregnancies and determine their association with placental gene expression; and 3) to characterize inflammatory signaling across the maternal-fetal interface using a 3- dimensional in vitro model that incorporates key placental cell types. This proposal includes several innovative components, including the use of advanced bioinformatics to directly correlate placental gene expression data from a single-cell spatial transcriptomics assay to the peripheral concentrations of inflammatory biomarkers within the same participants, and the development of a novel Transwell-based model of the human placenta that can be used to mechanistically interrogate the role of each cell type in the transfer or inflammatory signals. Disentangling the mechanisms responsible for the transfer of inflammation across the maternal-fetal interface will ultimately allow for the identification of therapeutic agents to modulate inflammation in pregnancy, thereby preventing adverse neurodevelopmental and/or immunologic consequences to the fetus.