The impact of gestational diabetes on Group B Streptococcal virulence and host immune response

项目摘要 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，但驱动GBS Ascension到子宫的因素还不清楚。的 目前的护理标准，对GBS阳性母亲进行抗生素预防，不足以预防GBS- 与死产相关的早产，每年约有100万美国婴儿暴露于抗生素。理解 控制GBS-宿主动态的生物学原理对于开发确定的、持久的预防措施至关重要 用于妊娠期和新生儿早期的GBS感染。临床研究已经确定妊娠 糖尿病（GDM）是母体定植和新生儿疾病的关键危险因素。的目标 这项建议是询问母体免疫和GBS转录适应在免疫系统中的作用。 GDM相关的侵袭性GBS疾病的传播和不良的出生结果。我们初步的实验鼠 研究表明，糖尿病小鼠对GBS胎儿传播和不良结局的易感性增强， 细胞因子谱和新型鼠GDM模型中GBS基因表达差异。我们假设 GDM通过干扰母体免疫和改变GBS转录，使宿主对GBS更易感 来增强毒力和适应性。这一假设将通过特定的目的进行调查， 确定：1）GDM对基线和GBS期间母体和胎儿免疫应答的影响 上行感染，和2）转录适应所需的GBS发病机制在怀孕的主机， 是否存在GDM。这些目标是利用多种创新工具推进的，包括最近 建立了GDM和GBS阴道定植的小鼠模型，母体和胎儿的免疫谱分析 组织，和比较的GBS转录分析从寄生虫和侵入性小生境。本研究 发生在贝勒医学院和得克萨斯州的动态和跨学科的环境 医学中心在女性生殖道的GBS-宿主相互作用方面具有不同的专业知识， 研究妊娠期糖尿病的动物模型及链球菌的遗传学发病机制。本研究 该战略旨在更全面地了解控制宿主和病原体动态的复杂过程， 妊娠背景和母体代谢疾病。这些研究将启动关键的机制研究 决定妊娠结局的途径，并将为检测和预防 健康妇女和妊娠期糖尿病妇女的GBS感染。

PROJECT SUMMARY 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 neonatal morbidity and mortality, yet the factors driving GBS ascension into the uterus are poorly defined. The current standard of care, antibiotic prophylaxis to GBS-positive mothers, is insufficient to prevent GBS- associated preterm births of stillbirths and exposes ~1 million U.S. infants to antibiotics each year. Understanding the biological principles controlling GBS-host dynamics is critical to developing defined, long-lasting preventions for GBS infections in pregnancy and the early neonatal period. Clinical studies have identified gestational diabetes mellitus (GDM) as a key risk factor for maternal colonization and neonatal disease. The objective of this proposal is to interrogate the contribution of maternal immunity and GBS transcriptional adaptions in the propagation of GDM-associated invasive GBS disease and adverse birth outcomes. Our preliminary murine studies show enhanced susceptibility of diabetic mice to GBS fetal dissemination and adverse outcomes, altered cytokine profiles, and differential GBS gene expression in a novel murine GDM model. We hypothesize that GDM renders the host more susceptible to GBS by perturbing maternal immunity and altering GBS transcription to enhance virulence and fitness. This hypothesis will be interrogated through specific aims designed to determine: 1) the impact of GDM on the maternal and fetal immune responses at baseline and during GBS ascending infection, and 2) the transcriptional adaptions required for GBS pathogenesis in the pregnant host in the presence or absence of GDM. These aims are advanced using multiple innovative tools including recently established murine models of GDM and GBS vaginal colonization, immune profiling across maternal and fetal tissues, and comparative GBS transcriptional analyses from commensal and invasive niches. This research takes place in the dynamic and interdisciplinary environment of Baylor College of Medicine and the Texas Medical Center with diverse expertise in GBS-host interactions of the female reproductive tract, employment of animal models to study gestational diabetes mellitus, and genetics of Streptococcal pathogenesis. This research strategy seeks to more fully understand the complex processes governing host and pathogen dynamics in the context of pregnancy and maternal metabolic disease. These studies will launch mechanistic studies into key pathways dictating pregnancy outcomes, and will inform new therapeutic strategies for detecting and preventing GBS infections in both healthy women and those with gestational diabetes.