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

全球每年有200多万人死于孕期或新生儿期的感染。 通常情况下，引起这些感染的病原体开始于产妇阴道微生物区系和 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，保守估计将GBS归因于147,000死产和 每年的婴儿死亡人数。新生儿接触GBS的主要来源被认为是母亲的阴道 产程中、分娩时或宫内GBS侵入胎盘屏障，导致胎儿感染。女人 患有妊娠期糖尿病(GDM)的孕妇患GBS新生儿败血症的风险增加20%-50% 侵袭性疾病，但缺乏机械性的洞察力。虽然预防性抗生素降低了GBS的风险 出生第一周的疾病，GBS引起的死产和早产的发生率仍然没有改善， 早期接触抗生素具有长期的健康后果，但尚未完全阐明。因此， 迫切需要替代的预防和治疗选择，只有通过深化 我们对GBS发病机制的认识。这项提议的目的是确定使 妊娠期糖尿病宿主是唯一易患GBS的人。为了做到这一点，我开发了GBS的体内模型 妊娠糖尿病小鼠生殖道的提升。初步数据表明，这一模型展示了 妊娠期糖尿病中胎儿GBS感染的风险增加，如人类所见。使用这一新的智能网模型 妊娠期糖尿病小鼠子宫GBS的传播，我将描述妊娠期糖尿病如何改变GBS 母体生殖道中的毒力和宿主免疫。我假设妊娠期糖尿病 扰乱宿主免疫，增强GBS毒力。这一假设将通过特定的目标进行验证。 旨在确定：1)妊娠期糖尿病对宿主免疫的影响；2)GBS基因 对健康和妊娠期糖尿病妊娠的子宫提升至关重要。这些新颖和先进的目标使用 多种创新工具，包括最近建立的妊娠期糖尿病小鼠宫内GBS传播模型 小鼠及其利用含有人源化微生物群的小鼠探索生殖道的作用 微生物区系在形成对GBS的局部免疫力中的作用。中概述的工作、指导和培训计划的范围 这项建议将使候选人具备必要的粘膜免疫学、生物信息学和 生殖病理生理学作为一名拥有激动人心职业轨迹的内科科学家实现独立 在儿科领域。总而言之，这项研究提案试图为新的治疗策略提供信息，以更好地 在保护母婴健康的同时，提出我们目前关于妊娠复杂相互作用的观点 糖尿病、免疫、当地微生物区系和母体生殖道中的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.