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

妊娠期或新生儿期感染每年在全球造成200多万人死亡。 通常，引起这些感染的病原体开始是母体阴道微生物群的居民， 在怀孕期间上升到子宫。一种这样的病原体，B组链球菌（GBS），是主要的病原体 新生儿发病率和死亡率，保守估计GBS归因于147，000例死产， 每年的婴儿死亡。新生儿GBS暴露的主要来源被认为是母体阴道 产程和分娩期间或子宫内GBS侵入胎盘屏障导致胎儿感染。妇女 妊娠期糖尿病（GDM）的孕妇患GBS新生儿败血症的风险增加20-50%， 但缺乏对发病机制的了解。虽然预防性抗生素降低了GBS的风险， 在生命的第一周内患病，GBS引起的死胎和早产的发生率仍然没有改善， 早期接触抗生素对健康的长期影响尚未完全阐明。因此，在本发明中， 迫切需要替代的预防和治疗方案，只有通过深化 我们对GBS发病机制的理解。这项建议的目的是确定机械因素， 妊娠期糖尿病宿主对GBS特别敏感。为此，我开发了一个GBS的体内模型， 妊娠糖尿病小鼠生殖道中的Ascension。初步数据表明，该模型显示， 妊娠期糖尿病胎儿GBS感染的风险增加，如在人类中所见。使用这种新颖的模型， 妊娠糖尿病小鼠子宫内GBS传播，我将描述妊娠糖尿病如何改变GBS 在母体生殖道中的毒力和宿主免疫力。我推测妊娠糖尿病 干扰宿主免疫力并增加GBS毒力。这一假设将通过具体的目的进行调查 旨在确定：1）妊娠期糖尿病对宿主免疫的影响，2）GBS基因， 对于健康和妊娠期糖尿病妊娠的子宫Ascension至关重要。这些新的和先进的目标使用 多种创新工具，包括最近建立的GBS在GDM子宫内传播的小鼠模型 小鼠和利用携带人源化微生物组的小鼠来探索生殖道的作用 微生物群在形成针对GBS的局部免疫中的作用。工作的广度，指导和培训计划概述， 该建议将使候选人具备粘膜免疫学，生物信息学和 生殖病理生理学，以实现独立作为一个令人兴奋的职业生涯轨迹的医生，科学家 在儿科学领域。总之，这项研究提案旨在为新的治疗策略提供信息，以更好地 保护母胎健康，同时推进我们目前对妊娠期复杂相互作用的观点， 糖尿病、免疫力、局部微生物群和母体生殖道中的GBS毒力。

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.