Intra-amniotic infection and inflammation remain a significant cause of preterm birth, stillbirth and neonatal morbidity and mortality. The objective of this proposal is to define early maternal and placental immune responses that are critical for resolution of bacterial infections at the maternal-fetal interface. Elucidation of immune events occurring at the maternal-fetal interface in human pregnancy is complicated by the inaccessibility of maternal and fetal compartments, which also imposes limitations on our understanding of the nature of the invading organism and cell types directing bacterial clearance. We have overcome these challenges by using a unique chronically catheterized pregnant nonhuman primate (NHP) model that closely emulates human pregnancy. In this proposal, we will elucidate early immune mechanisms that result in bacterial clearance and define the key immune cell-types and host defense networks that protect the fetus from invasive bacterial infections. We will use the established NHP model of GBS infection to study bacterial clearance at the maternal-fetal interface using innovative methods including: 1) multidimensional flow cytometry to quantitate immune cell populations at the maternal-fetal interface, 2) single cell RNA-Seq to generate a transcriptional map of cell types and regulatory gene networks, 3) reverse phase protein array to analyze signalling cascades and host translational networks and 4) sophisticated computational modelling to link clinical metadata (e.g. bacterial burden, peak uterine activity) with single cell RNA-Seq and protein array data. The proposed aims will thus establish the temporal and spatial nature of immune responses and host transcriptional and translational networks essential for bacterial clearance at the maternal-fetal interface during pregnancy.
Infection and inflammation at the maternal-fetal interface remains a significant cause of adverse pregnancy outcomes such as preterm birth, stillbirth and neonatal death. The inaccessibility of compartments at the maternal and fetal interface during human pregnancy imposes limitations on our understanding of the immune responses that are key to pathogen surveillance. We will use the innovative nonhuman primate model of bacterial infections to elucidate early immune mechanisms and cell-specific transcriptional and translational programs at the maternal-fetal interface that lead to pathogen clearance. These data will determine key mechanisms for fetal protection and support development of therapeutics to prevent adverse pregnancy outcomes.
