Spatiotemporal analysis of gene regulatory programs associated with GBS infection during pregnancy

妊娠期GBS感染相关基因调控程序的时空分析

基本信息

批准号：
10509389
负责人：
Adam Jonathan Ratner
金额：
$ 73.4万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-09 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509389
关键词：
Adult Architecture Birth Cells Data Analyses Development Event Fetal Development Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Genome Genomics Goals Human Immune response Infection Intervention Knock-out Macrophage Measures Methods Modeling Molecular Morbidity - disease rate Pathogenesis Placenta Pregnancy Premature Birth Process RNA Regulator Genes Reporting Research Resolution Serotyping Site Streptococcal Infections Streptococcus Group B Study models System Testing Time Transcriptional Regulation experience fetal fetal infection gastrointestinal in vivo Model innovation insight intraamniotic infection mortality mouse model neonatal infection neonatal sepsis novel pathogen placental infection postnatal period programs response single cell analysis single-cell RNA sequencing spatial integration spatiotemporal tool transcriptome transcriptome sequencing transcriptomics vaginal mucosa

项目摘要

PROJECT SUMMARY Infection during pregnancy or in the immediate postnatal period is associated with substantial morbidity and mortality worldwide. Group B Streptococcus (GBS) is a major cause of chorioamnionitis (CAM) and neonatal sepsis. The placenta acts as the initial interface between GBS and the host immune response during chorioamnionitis, constituting the locus of host-pathogen interaction. Current understanding of the pathogenesis of CAM has been limited by a lack of tools revealing the spatial and temporal components of placental infection. Specifically, we lack an understanding of how the infection unfolds over time and across the placental architecture. Breakthroughs in single-cell genomics and spatial transcriptomics now enable the unbiased and systematic analysis of the process of infection. Here we propose to apply these methods to GBS infection of the placenta: examining host-specific responses, the host-pathogen interface, and perturbations of the GBS infection program. In Aim 1 we will combine spatial transcriptomics and single-cell RNA-Seq to study the progression of GBS infection in a novel murine model of ascending infection and CAM. In Aim 2 we will simultaneously study host and pathogen gene expression programs during infection in primary human placental macrophages. In Aim 3 we will test a conceptual model of GBS infection by systematically assessing the effect of targeted deletions of specific GBS genes. Integrating these approaches will provide a rich view of host-pathogen interactions during CAM and will lead to the identification of new targets for intervention.

项目摘要怀孕期间或出生后立即感染与大量发病率有关全球死亡率。 B组链球菌（GBS）是绒毛膜膜炎（CAM）和新生儿的主要原因败血症。胎盘充当GBS和宿主免疫反应之间的初始接口绒毛膜炎，构成宿主病原体相互作用的轨迹。当前对 CAM发病机理受到缺乏工具的限制，揭示了空间和时间成分胎盘感染。具体而言，我们对感染如何随着时间的流逝和整个整个胎盘建筑。单细胞基因组学和空间转录组学的突破现在使得对感染过程的无偏和系统分析。在这里，我们建议将这些方法应用于GB 胎盘感染：检查宿主特异性反应，宿主 - 病原体界面和扰动 GBS感染计划。在AIM 1中，我们将结合空间转录组学和单细胞RNA-Seq来研究 GBS感染在新型的升高感染和CAM模型中的进展。在目标2中，我们将在原发性人中感染期间，同时研究宿主和病原体基因表达程序胎盘巨噬细胞。在AIM 3中，我们将通过系统评估来测试GBS感染的概念模型特定GBS基因的目标缺失的影响。整合这些方法将提供丰富的观点 CAM期间的宿主 - 病原体相互作用将导致鉴定新目标进行干预。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-Wide fitness analysis of group B Streptococcus in human amniotic fluid reveals a transcription factor that controls multiple virulence traits.

DOI：
10.1371/journal.ppat.1009116
发表时间：
2021-03
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Dammann AN;Chamby AB;Catomeris AJ;Davidson KM;Tettelin H;van Pijkeren JP;Gopalakrishna KP;Keith MF;Elder JL;Ratner AJ;Hooven TA
通讯作者：
Hooven TA

The tempo and mode of gene regulatory programs during bacterial infection.

DOI：
10.1016/j.celrep.2022.111477
发表时间：
2022-10-11
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Avital, Gal;Kuperwaser, Felicia;Pountain, Andrew W.;Lacey, Keenan A.;Zwack, Erin E.;Podkowik, Magdalena;Shopsin, Bo;Torres, Victor J.;Yanai, Itai
通讯作者：
Yanai, Itai

Exploring tissue architecture using spatial transcriptomics.

DOI：
10.1038/s41586-021-03634-9
发表时间：
2021-08
期刊：
Nature
影响因子：
64.8
作者：
Rao A;Barkley D;França GS;Yanai I
通讯作者：
Yanai I

Transcription-replication interactions reveal principles of bacterial genome regulation.

转录-复制相互作用揭示了细菌基因组调控的原理。

DOI：
10.21203/rs.3.rs-2724389/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Pountain,AndrewW;Jiang,Peien;Yao,Tianyou;Homaee,Ehsan;Guan,Yichao;Podkowik,Magdalena;Shopsin,Bo;Torres,VictorJ;Golding,Ido;Yanai,Itai
通讯作者：
Yanai,Itai