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Spatiotemporal transcriptomics at the maternal-fetal interface in COVID placenta

新冠肺炎胎盘母胎界面的时空转录组学

基本信息

批准号：
10618958
负责人：
YUPING WANG
金额：
$ 21.9万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-06 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618958
关键词：
2019-nCoV Brain COVID-19 COVID-19 patient COVID-19 prevention COVID-19 vaccination Cells Cerebrum Clinical Management Decidual Cell Defense Mechanisms Embryo Epithelial Cells Fetal Development Fetal Membranes Fetus Formalin Future Gene Expression Profiling Genes Genomics Gestational Diabetes Homeostasis Immune Immune system Immunologics Infection Innate Immune System Interferon-beta Interferons International Low Birth Weight Infant Maps Maternal Mortality Maternal-Fetal Exchange Mesenchymal Molecular Molecular Profiling Morphology Natural Immunity Neonatal Nucleic Acids Nucleocapsid Proteins Organ Organoids Outcome Paraffin Embedding Pathway interactions Pattern Placenta Pre-Eclampsia Pregnancy Pregnant Women Premature Birth Prevent viral transmission Production Proteins RNA Viruses Research Risk SARS-CoV-2 infection SARS-CoV-2 spike protein Signal Pathway Signal Transduction Pathway Stimulator of Interferon Genes Stromal Cells Symptoms Syncytiotrophoblast System TLR7 gene Techniques Testing Tissue Embedding Tissues Vaccination Vertical Transmission Villous Viral Virus Diseases Woman Women&apos s Group X Chromosome adverse pregnancy outcome cell type coronavirus disease cytokine cytotrophoblast epidemiology study fetal gene network global health insight maternal morbidity novel pandemic disease pathogen post SARS-CoV-2 infection pregnant response sensor spatiotemporal stillbirth transcriptome transcriptome sequencing transcriptomics transmission process trophoblast viral transmission

项目摘要

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged as the greatest threat to global health and significantly impact pregnant women worldwide. COVID-19 infection during pregnancy is associated with substantial risk of increases in maternal morbidity and mortality and neonatal complications, compared with their non-infected pregnant counterparts. However, vertical transmission of the virus is uncommon, which suggest that innate immune system must function at the maternal-fetal interface to shield the developing fetus from infection. Despite fast-tracked intensive research on many aspects of SARS- CoV-2, the impact of the viral infection in the placenta and the placental defense mechanism(s) are poorly explored. Placenta is the structural and immunological barrier of pathogen transmission. To explore the innate antiviral defense mechanism(s), in our preliminary study we specifically determined expression of interferon pathway-related molecules in placental tissues. Strikingly, we found distinct patterns of stimulator of interferon genes (STING), interferon regulator factor 3 (IRF3), and Type I IFN (such as IFNb) expression at the maternal- fetal interface of the placentas from women infected with COVID-19. STING is a sensor for viral infection. STING-IRF3 pathway signaling regulates Type I IFN production, and Type I IFNs are potent antiviral cytokines. We also noticed that Toll-like receptor 7 (TLR7) is upregulated in both syncytiotrophoblasts ( STs) and extravillous trophoblasts (EVTs) in placentas from patients with COVID-19 compared to those are not. TLR7, located on the X chromosome, is a sensor for single strand RNA (ssRNA) viruses. These findings are intriguing and indicate that an innate antiviral immune system is activated at the maternal-fetal interface in patients with COVID-19 during pregnancy. The objective of the study is to identify spatiotemporal transcriptomic signatures and networks of the innate antiviral immune system at the maternal-fetal interface. We will test the hypothesis an effective and robust innate antiviral immune system is activated at the maternal-fetal interface to prevent viral transmission and shield the fetus from infection, which will be tested in two specific aims. Aim 1 will identify spatiotemporal innate immunity gene profiles and networks in villous tissue that respond to maternal SARS-CoV-2 infection. Aim 2 will identify spatiotemporal innate immunity gene profiles and networks in fetal membrane and decidual tissue that respond to maternal SARS-CoV-2 infection. A state-of-the-art novel technique of 10x Genomics Visium Gene Expression assay in placental formalin-fixed paraffin embedded (FFPE) tissues combined with RNA-seq will be employed . Placentas from women with active COVID infection, recovered from COVID infection, and received COVID vaccination, etc. will be studied. This novel ideal approach will allow us to map the whole transcriptome with morphological context in placental FFPE tissue and discover the cellular and molecular profiles and networks in different cell types and gene activity at the maternal-fetal interface without disruption of the tissue integrity. Results of the study will provide novel insights into how SARS-CoV-2 infection impacts the innate immune system at the mater-fetal interface, and how the innate immune system at the maternal-fetal interface responds to COVID vaccination during pregnancy, which may help to identify new strategies to prevent COVID-19 infection and reduce maternal and fetal complications in women with COVID-19 infection in the future.

由严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）引起的COVID-19已成为对全球健康的最大威胁，并对全球孕妇产生重大影响。COVID-19感染期间怀孕与产妇发病率和死亡率以及新生儿死亡率增加的风险密切相关。并发症，与未感染的孕妇相比。然而，病毒是罕见的，这表明先天免疫系统必须在母胎界面发挥作用，保护发育中的胎儿免受感染。尽管对SARS的许多方面进行了快速深入的研究， CoV-2、病毒感染对胎盘的影响和胎盘防御机制较差探讨了胎盘是病原体传播的结构和免疫屏障。去探索与生俱来的抗病毒防御机制，在我们的初步研究中，我们专门确定了干扰素的表达，胎盘组织中的通路相关分子。引人注目的是，我们发现了干扰素刺激剂的不同模式，基因（STING）、干扰素调节因子3（IRF 3）和I型IFN（如IFNb）在母体中的表达。感染COVID-19的妇女胎盘的胎儿界面。STING是病毒感染的传感器。 STING-IRF 3通路信号传导调节I型IFN的产生，并且I型IFN是有效的抗病毒细胞因子。我们还注意到Toll样受体7（TLR 7）在合体滋养细胞（ ST）和 COVID-19患者胎盘绒毛外滋养细胞（EVT）与非COVID-19患者胎盘绒毛外滋养细胞（EVT）相比。TLR7，位于X染色体上，是单链RNA（ssRNA）病毒的传感器。这些发现很有趣并表明先天性抗病毒免疫系统在母胎界面被激活，怀孕期间的COVID-19。这项研究的目的是确定时空转录组签名和先天性抗病毒免疫系统在母胎界面的网络。我们将检验这个假设在母胎界面激活有效和强大的先天抗病毒免疫系统，病毒传播和保护胎儿免受感染，这将在两个特定的目标进行测试。目标1将在绒毛组织中鉴定对母体免疫应答时空先天免疫基因谱和网络 SARS-CoV-2感染。目的2将确定胎儿先天免疫基因的时空分布和网络膜和蜕膜组织对母体SARS-CoV-2感染的反应。一部最新的小说 10 x Genomics Visium技术在福尔马林固定石蜡包埋胎盘中的基因表达测定将采用与RNA-seq组合的FFPE组织 .活动性COVID感染妇女的胎盘，从COVID感染中康复，并接受COVID疫苗接种等。这个新奇的理想这种方法将使我们能够在胎盘FFPE组织中绘制具有形态学背景的整个转录组，发现不同细胞类型和基因活性的细胞和分子概况和网络，母胎界面，而不破坏组织完整性。研究结果将提供新的见解对如何 SARS-CoV-2感染影响母胎界面的先天免疫系统，以及母亲-胎儿界面的先天免疫系统对怀孕期间的COVID疫苗接种有反应，可能有助于确定预防COVID-19感染和减少孕产妇和胎儿并发症的新策略在未来感染COVID-19的女性中。