Immune Control of Group B Streptococcal Placental

B 族链球菌胎盘的免疫控制

基本信息

批准号：
10228644
负责人：
KRISTINA M. ADAMS WALDORF
金额：
$ 86.9万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228644
关键词：
37 weeks gestation Allogenic Amniotic Fluid Bacteria Bacterial Infections Bacterial Model Bioinformatics Birth Catheters Cells Cesarean section Chorionic villi Chronic Clinical Computer Models Control Groups Data Decidua Event Fetus Flow Cytometry Gene Expression Gene Proteins Genetic Transcription Genital Genitalia Hemolysin Histopathology Host Defense Hour Human Immune Immune Tolerance Immune response Immune system Immunohistochemistry Immunologics Infection Inflammation Inflammatory Response Injury Invaded Lead Link Maps Maternal-Fetal Exchange Membrane Metadata Methods Microbe Modeling Mutation Nature Neonatal Neonatal Mortality Organism Pathogenicity Pathway interactions Peripheral Blood Mononuclear Cell Phase Placenta Population Pregnancy Premature Birth Premature Labor Protein Array Regulator Genes Resolution Saline Sampling Signal Transduction Signaling Protein Streptococcal Infections Streptococcus Group B Time Transcription Repressor Uterus Virulent Woman adverse pregnancy outcome amniotic cavity cell type combat cytokine early onset experimental study fetal immune activation innovation intraamniotic infection microbial myometrium neonatal death neonatal morbidity nonhuman primate pathogen placental infection pregnant prevent programs response single-cell RNA sequencing stillbirth therapeutic development transcriptome

项目摘要

PROJECT SUMMARY/ABSTRACT Intra-amniotic infection and inflammation remain a significant cause of preterm birth, stillbirth and neonatal morbidity and mortality. The objective of this proposal is to define early maternal and placental immune responses that are critical for resolution of bacterial infections at the maternal-fetal interface. Elucidation of immune events occurring at the maternal-fetal interface in human pregnancy is complicated by the inaccessibility of maternal and fetal compartments, which also imposes limitations on our understanding of the nature of the invading organism and cell types directing bacterial clearance. We have overcome these challenges by using a unique chronically catheterized pregnant nonhuman primate (NHP) model that closely emulates human pregnancy. In this proposal, we will elucidate early immune mechanisms that result in bacterial clearance and define the key immune cell-types and host defense networks that protect the fetus from invasive bacterial infections. We will use the established NHP model of GBS infection to study bacterial clearance at the maternal-fetal interface using innovative methods including: 1) multidimensional flow cytometry to quantitate immune cell populations at the maternal-fetal interface, 2) single cell RNA-Seq to generate a transcriptional map of cell types and regulatory gene networks, 3) reverse phase protein array to analyze signalling cascades and host translational networks and 4) sophisticated computational modelling to link clinical metadata (e.g. bacterial burden, peak uterine activity) with single cell RNA-Seq and protein array data. The proposed aims will thus establish the temporal and spatial nature of immune responses and host transcriptional and translational networks essential for bacterial clearance at the maternal-fetal interface during pregnancy.

项目概要/摘要羊膜内感染和炎症仍然是早产、死产和新生儿的重要原因发病率和死亡率。该提案的目的是定义早期母体和胎盘免疫对于解决母婴界面细菌感染至关重要的反应。阐明人类妊娠期间母胎界面发生的免疫事件因以下因素而变得复杂母体和胎儿的隔室难以接近，这也限制了我们对母体和胎儿隔室的理解入侵生物体的性质和指导细菌清除的细胞类型。我们已经克服了这些通过使用独特的长期插管怀孕非人灵长类动物 (NHP) 模型来应对挑战，该模型密切关注模拟人类怀孕。在本提案中，我们将阐明导致以下情况的早期免疫机制：细菌清除并确定关键的免疫细胞类型和宿主防御网络，以保护胎儿免受细菌感染侵袭性细菌感染。我们将利用已建立的GBS感染NHP模型来研究细菌使用创新方法在母胎界面进行清除，包括：1）多维流细胞计数法对母胎界面的免疫细胞群进行定量，2) 单细胞 RNA 测序生成细胞类型和调控基因网络的转录图谱，3) 反相蛋白阵列分析信号级联和宿主翻译网络，4) 复杂的计算模型将临床元数据（例如细菌负荷、峰值子宫活动）与单细胞 RNA-Seq 和蛋白质阵列联系起来数据。因此，拟议的目标将确定免疫反应和宿主的时间和空间性质转录和翻译网络对于母胎界面细菌清除至关重要怀孕。