Characterizing the impact of maternal immune response to urinary tract infection on preterm birth

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Preterm birth is the leading cause of mortality in infants under age one, resulting in over one million neonatal deaths annually. Surviving preterm infants experience increased risk of infection, neurodevelopmental disorders, and cardiovascular and pulmonary disease. Maternal extra-uterine infections, such as urinary tract infection (UTI), are associated with increased risk for preterm birth; however, the host-microbe dynamics in UTI- associated preterm birth are not well-described. To study this phenomenon, we have developed a murine model of UTI-associated preterm birth with uropathogenic E. coli (UPEC), the causative agent of over 70% of UTIs. In our model, approximately half of dams went into preterm labor while remaining dams did not go into labor before the experimental end point. This bimodal phenotype enables us to uniquely investigate factors contributing to preterm birth incidence. Preterm dams exhibited decreased bladder and placental bacterial burdens and increased fetal demise. Further, preterm birth was maintained when dams were infected with UV- inactivated bacteria, suggesting preterm birth is attributed to inflammation rather than bacterial dissemination. Additionally, placentae from preterm mice expressed elevated MIP2, a murine neutrophil chemokine, implicating neutrophils in preterm birth pathogenesis. This led us to the hypothesis that UTI-associated preterm birth is attributed to localized bladder inflammation and distinct systemic and reproductive immune profiles in preterm dams compared to term dams. This hypothesis will be investigated through two aims: one which compares localized bladder immune response in preterm and term dams, and one which elucidates divergences in maternal systemic and reproductive immune profiles in UTI-associated term and preterm pregnancy. Aim 1 couples unbiased, multiplexed immune profiling in the bladder of term and preterm mice with targeted depletion of LPS and neutrophils, two components implicated in preterm birth and adverse neonatal outcomes. Aim 2 seeks to understand the maternal immunological consequences of UTI and how they may be associated with preterm birth by investigating maternal systemic, uterine, and placental immune cell composition and function. We will utilize our novel murine model to investigate phenotypic changes in preterm birth incidence and adverse fetal outcomes coupled with molecular mechanism through multiparameter flow cytometry and cytokine analysis. These experiments will not only be the first to explore mechanisms that contribute to UTI-associated preterm birth, but they will also be the first to comprehensively characterize the bladder immune response to infection during pregnancy. The success of this work will reveal novel therapeutic opportunities to predict, reduce, or prevent preterm birth. This proposal will allow the applicant to further develop her technical skills and knowledge of immunology, while expanding her expertise to include murine models of infection and pregnancy and reproductive biology. Ultimately, this work will equip the applicant with the experience necessary to advance her career in academic research while addressing a critical gap in maternal and fetal health outcomes.