Spatiotemporal analysis of gene regulatory programs associated with GBS infection during pregnancy

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PROJECT SUMMARY Infection during pregnancy or in the immediate postnatal period is associated with substantial morbidity and mortality worldwide. Group B Streptococcus (GBS) is a major cause of chorioamnionitis (CAM) and neonatal sepsis. The placenta acts as the initial interface between GBS and the host immune response during chorioamnionitis, constituting the locus of host-pathogen interaction. Current understanding of the pathogenesis of CAM has been limited by a lack of tools revealing the spatial and temporal components of placental infection. Specifically, we lack an understanding of how the infection unfolds over time and across the placental architecture. Breakthroughs in single-cell genomics and spatial transcriptomics now enable the unbiased and systematic analysis of the process of infection. Here we propose to apply these methods to GBS infection of the placenta: examining host-specific responses, the host-pathogen interface, and perturbations of the GBS infection program. In Aim 1 we will combine spatial transcriptomics and single-cell RNA-Seq to study the progression of GBS infection in a novel murine model of ascending infection and CAM. In Aim 2 we will simultaneously study host and pathogen gene expression programs during infection in primary human placental macrophages. In Aim 3 we will test a conceptual model of GBS infection by systematically assessing the effect of targeted deletions of specific GBS genes. Integrating these approaches will provide a rich view of host-pathogen interactions during CAM and will lead to the identification of new targets for intervention.