Characterizing the Impact of Gestational Diabetes on Immunity and Group B Streptococcal Virulence in the Maternal Reproductive Tract

点击翻译按钮获取中文摘要

Infections during pregnancy or the neonatal period account for more than two million deaths globally each year. Frequently, the pathogens causing these infections begin as residents of the maternal vaginal microbiota and ascend to the uterus during pregnancy. One such pathogen, group B Streptococcus (GBS), is a leading agent of neonatal morbidity and mortality with conservative approximations attributing GBS to 147,000 stillbirths and infant deaths annually. The primary sources of neonatal GBS exposure are thought to be the maternal vaginal tract during labor and delivery or in utero GBS invasion of placental barriers resulting in fetal infection. Women with gestational diabetes mellitus (GDM) have a 20-50% increased risk for GBS neonatal sepsis and maternal invasive disease but mechanistic insight is lacking. While prophylactic antibiotics have decreased the risk of GBS disease in the first week of life, incidence of GBS-induced stillbirth and preterm birth remains unimproved and early exposure to antibiotics has long-term health consequences that are yet to be fully elucidated. Thus, alternative preventative and therapeutic options are urgently needed and can only be achieved by deepening our understanding of GBS pathogenesis. The aim of this proposal is to determine mechanistic factors that render gestational diabetic hosts uniquely susceptible to GBS. To do so, I have developed an in vivo model of GBS ascension in the reproductive tract of gestational diabetic mice. Preliminary data suggests that this model exhibits increased risk of fetal GBS infection in gestational diabetes as seen in humans. Using this novel model of in utero GBS dissemination in gestational diabetic mice, I will characterize how gestational diabetes alters GBS virulence and host immunity in the maternal reproductive tract. I hypothesize that gestational diabetic conditions perturb host immunity and increase GBS virulence. This hypothesis will be interrogated through specific aims designed to determine: 1) The impact of gestational diabetes on host immunity and 2) the GBS genes that are critical for uterine ascension in healthy and gestational diabetic pregnancy. These novel and advanced aims use multiple innovative tools including a recently established murine model of in utero GBS dissemination in GDM mice and utilization of mice that harbor a humanized microbiome to explore the role of reproductive tract microbiota in shaping local immunity against GBS. The breadth of work, mentorship and training plan outlined in this proposal will equip the candidate with the necessary expertise in mucosal immunology, bioinformatics and reproductive pathophysiology to achieve independence as a physician-scientist with an exciting career trajectory in the field of pediatrics. Together, this research proposal seeks to inform novel therapeutic strategies to better protect maternal-fetal health while advancing our current viewpoint on the complex interplay of gestational diabetes, immunity, local microbiota and GBS virulence in the maternal reproductive tract.