Neuromodulation of maternal immune adaptations in pregnancy

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PROJECT SUMMARY Pregnancy relies on finely-tuned adaptations of the maternal immune system to establish and maintain immune-tolerance to the semi-allogeneic fetus, which appear to be imbalanced in women experiencing complications, such as preterm birth. Outside the pregnancy context, the central nervous system can modulate systemic immunity via the sympathetic nervous system, while its role in modulating maternal immune system adaptations during pregnancy remains unknown. Understanding the determinants of immune regulation throughout pregnancy is a prerequisite to advance the early risk assessment and treatment of pathological pregnancies. This research project proposes to target the interaction between the brain, pregnancy, and the immune system. State-of-the-art immunology (mass cytometry) and neuroscience (neuromodulation of discrete neuronal circuitry) approaches will be combined to comprehensively investigate neuroimmune regulation of human term and preterm pregnancies and mouse models of pregnancy. Specifically, we hypothesize that a hyperactive sympathetic (adrenergic) tone enhances systemic pro-inflammatory monocyte responses, thereby contributing to a compromised fetal tolerance in preterm pregnancies. The first aim of this proposal will monitor the responsiveness innate pro-inflammatory monocytes to adrenergic signals (using single-cell high-dimensional mass cytometry), and the nervous-system associated proteome (e.g., adrenergic analytes, Brice Gaudilliere lab) throughout the human third trimester. This aim is based on my current expertise in human pregnancy immunology and multi-parameter approaches, and a continuation of my prior in-depth analyses of the pre-labor plasma signature and immunome in the last 100 days of healthy pregnancy, which accurately predict the onset of labor. In aim 2, to understand brain-pregnancy communication on a mechanistic level, neuroscience approaches (fiber photometry and chemogenetics) will be used under supervision of the Luis de Lecea lab, who pioneered cutting-edge neuro-modulatory techniques. Here, I will manipulate discrete neural populations, known to either suppress or enhance peripheral immunity, throughout late gestation in mouse pregnancies with the aim to monitor their link to peripheral monocyte responsiveness. Reciprocally, fiber photometry will track pregnancy- specific alterations in activity of these neural populations. In the third and final aim 3, I will determine whether monocyte responses to sympathetic signals differ throughout preterm vs. term pregnancies by analyzing maternal blood collected in each trimester of pregnancy, using high-dimensional single-cell mass cytometry. Machine learning approaches will be utilized to train a model for preterm vs. term sample classification. In the independent R00 phase, I envision to apply techniques from immunology and neuroscience to understand pregnancy biology and pathology from a central nervous system perspective. Together, the set of proposed studies will answer fundamental questions in the nascent field of brain- peripheral immunity cross-talk, and elucidate understudied mechanism of neuroimmunomodulation in pregnancy, while significantly aiding in my career development and academic transition to independence.