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

妊娠糖尿病对 B 族链球菌毒力和宿主免疫反应的影响

基本信息

批准号：
10738456
负责人：
Katy Patras
金额：
$ 25.36万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738456
关键词：
Amniotic Fluid Animal Model Antibiotic Prophylaxis Antibiotics Antimicrobial Resistance Automobile Driving Biological Cells Cessation of life Clinical Clinical Data Clinical Research Complex Control Groups Diabetic mouse Diet Disease Elderly Employment Environment Exposure to Female Fetal Tissues Fetus Gene Expression Genes Genetic Genetic Transcription Gestational Diabetes Glucose Hemolysin Host Defense Human Hyperglycemia Immune Immune response Impairment In Vitro Incidence Individual Infant Infection Inflammatory Insulin Resistance Integration Host Factors Invaded Macrophage Maternally-Acquired Immunity Measures Medical center Medicine Membrane Metabolic Metabolic Diseases Modeling Mothers Mus Neonatal Neonatal Mortality Newborn Infant Onset of illness Outcome Pathogenesis Pathway interactions Physiology Population Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Premature Birth Prevention Process Production Prognostic Marker Regulation Research Risk Risk Factors Sampling Streptococcal Infections Streptococcus Streptococcus Group B Support Groups Testing Texas Therapeutic Time Tissues Uterus Vagina Virulence Virulence Factors Woman Work adverse birth outcomes adverse outcome amniotic cavity collaborative environment college comparative cytokine design diabetes control diabetic fetal fitness healthy pregnancy in vitro activity in vivo infant death innovation insight maternal risk microbial microbiota mouse model neonatal death neonatal morbidity neonatal period neutrophil non-diabetic novel novel therapeutic intervention novel therapeutics overexpression pathogen permissiveness pregnant prevent pup recruit reproductive tract resistance gene response standard of care stillbirth streptococcal group B hemolysin therapeutic target tool transcriptome transcriptome sequencing vaginal microbiota virulence gene

项目摘要

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.

项目概要全球每年有超过 200 万人因怀孕或新生儿期感染而死亡。通常，引起这些感染的病原体最初是母体阴道微生物群的居民，怀孕期间上升到子宫。 B 族链球菌 (GBS) 就是其中一种病原体，是一种主要病原体新生儿发病率和死亡率，但驱动 GBS 上升到子宫的因素尚不清楚。这目前的护理标准，即对 GBS 阳性母亲进行抗生素预防，不足以预防 GBS- 相关的早产和死产，每年约有 100 万美国婴儿接触抗生素。理解控制 GBS 宿主动态的生物学原理对于制定明确、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。临床研究已确定妊娠期糖尿病（GDM）是孕产妇定植和新生儿疾病的关键危险因素。的目标该提案旨在探讨母体免疫和 GBS 转录适应在 GDM 相关侵袭性 GBS 疾病的传播和不良出生结果。我们的初步小鼠研究表明，糖尿病小鼠对 GBS 胎儿传播和不良后果的易感性增加，改变细胞因子谱，以及新型小鼠 GDM 模型中 GBS 基因表达的差异。我们假设 GDM 通过扰乱母体免疫力和改变 GBS 转录而使宿主更容易受到 GBS 的影响以增强毒力和适应性。这一假设将通过旨在确定：1) GDM 对基线和 GBS 期间母体和胎儿免疫反应的影响上行感染，以及 2) 妊娠宿主 GBS 发病机制所需的转录适应是否存在 GDM。使用多种创新工具来推进这些目标，包括最近的建立了 GDM 和 GBS 阴道定植的小鼠模型，以及母体和胎儿的免疫分析组织，以及来自共生和侵入生态位的 GBS 转录比较分析。这项研究发生在贝勒医学院和德克萨斯州充满活力的跨学科环境中医疗中心在女性生殖道的 GBS 宿主相互作用、雇佣研究妊娠糖尿病和链球菌发病机制遗传学的动物模型。这项研究该策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和孕产妇代谢疾病的背景。这些研究将启动机制研究到关键决定妊娠结局的途径，并将为检测和预防的新治疗策略提供信息健康女性和妊娠期糖尿病患者均存在 GBS 感染。