Role of Hofbauer Cells in Fetal Infection/Inflammation

霍夫鲍尔细胞在胎儿感染/炎症中的作用

基本信息

批准号：
9750631
负责人：
Vikki M Abrahams
金额：
$ 41.38万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750631
关键词：
Agonist Animal Model Bacteria Bacterial Infections Binding Blocking Antibodies Blood capillaries CASP1 gene Cells Childhood Chorionic villi Coculture Techniques Data Development EMSA Embryo Transfer Endothelium Escherichia coli Exposure to Fetus Gatekeeping Genes Giant Cells Growth Herpesviridae Histologic Human Human Herpesvirus 2 In Vitro Incidence Individual Infection Infectious Agent Infiltration Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Interleukin-1 beta Intervention Label Lead Leukocytes Location Maternal-Fetal Exchange Mediating Methodology Microbe Modeling Modification Morbidity - disease rate Mothers Movement Multiprotein Complexes Murine herpesvirus 68 Mus Neonatal Neonatal Mortality Newborn Infant Nuclear Pathologic Phenotype Placenta Pregnancy Pregnancy Complications Premature Birth Process Receptor Protein-Tyrosine Kinases Receptor Signaling Role Severities Site Small Interfering RNA TLR4 gene TNF gene Testing Tissues Toll-like receptors Transcription Factor AP-1 Umbilical cord structure Vertical Disease Transmission Viral Virus Virus Diseases adverse outcome bactericide base cell type chromatin immunoprecipitation fetal fetal infection fetal inflammatory response syndrome in vivo innate immune function insight interleukin-1beta-converting enzyme inhibitor intraamniotic infection macrophage microbial microorganism migration mortality mouse model neonatal morbidity novel receptor receptor function response transmission process

项目摘要

Fetal inflammation and infcetion remains a major cause of neonatal mortality and morbidity. Our previous studies showed that histological chorioamnionitis (HCA), microbial-driven infiltration of leukocytes to the maternal-fetal interface, was associated with a focal increase in the number of Hofbauer cells (HBCs) (i.e. placental macrophages of fetal origin located beneath the syncytium and adjacent to fetal capillaries), in the placental villus. Elucidation of cell type-specific responses to polymicrobial challenges would lead to new interventions which reduce the incidence of and/or severity of adverse outcomes including fetal-inflammatory response syndrome (FIRS), a multisystemic/microbial-driven inflammation in the umbilical cord (funisitis) and fetus, which is associated with significant neonatal/pediatric mortality and morbidity. Microbial compounds trigger innate immune response through Toll-like receptors (TLRs), and TAMs, a recently characterized subfamily of protein tyrosine kinase receptors shown to inhibit TLR function in non-placental cell types. In addition, inflammatory response to microbes is regulated through the inflammasome, a multi-protein complex. Our central hypothesis is that herpes virus infection of HBCs suppresses their inflammatory responses to bacteria by altering TAM receptor and Nalp3 inflammasome function, thus inhibiting HBCs' ability to control bacterial growth and, therefore, exacerbating placental/fetal infection, and chorioamnionitis. Our Specific Aims will: 1) Test the hypothesis that herpes virus infection of HBCs blocks LPS-induced TNF-α and IL-1β through modification of the expression and function of TAM receptors and the Nalp3 inflammasome; 2) Test the hypothesis that HV infection of HBCs increases TAM receptor function and inhibits inflammasome activity which promotes the migration and colonization of bacteria to the fetus; 3) Test the hypothesis that a polymicrobial herpes virus-bacterial infection increases placental macrophages with a suppressed inflammatory phenotype in vivo, promoting the migration of bacteria from mother to the fetus.

胎儿炎症和感染仍然是新生儿死亡和发病的主要原因。研究表明，组织学绒毛膜羊膜炎（HCA）是微生物驱动的白细胞浸润母胎界面，与霍夫鲍尔细胞（HBC）（即，Hofbauer 细胞）数量的局部增加有关。胎儿起源的胎盘巨噬细胞位于合胞体下方并邻近胎儿毛细血管），阐明胎盘绒毛对多种微生物挑战的细胞类型特异性反应将带来新的结果。减少不良后果（包括胎儿炎症）的发生率和/或严重程度的干预措施反应综合征（FIRS），一种多系统/微生物驱动的脐带炎症（腱炎）和胎儿，这与显着的新生儿/儿童死亡率和发病率相关。通过 Toll 样受体 (TLR) 和最近鉴定的 TAM 触发先天免疫反应蛋白酪氨酸激酶受体亚家族可抑制非胎盘细胞类型中的 TLR 功能。此外，对微生物的炎症反应是通过炎症小体（一种多蛋白复合物）调节的。我们的中心假设是，HBC 的疱疹病毒感染会抑制其炎症反应通过改变 TAM 受体和 Nalp3 炎性体功能来抑制细菌，从而抑制 HBC 的控制能力细菌生长，从而加剧胎盘/胎儿感染和绒毛膜羊膜炎。将： 1) 检验 HBC 的疱疹病毒感染通过以下途径阻断 LPS 诱导的 TNF-α 和 IL-1β 的假设： TAM受体和Nalp3炎症小体的表达和功能的修饰2)测试 HV 感染 HBC 会增加 TAM 受体功能并抑制炎症小体活性的假设促进细菌向胎儿迁移和定植；3) 检验以下假设：多种微生物疱疹病毒细菌感染增加胎盘巨噬细胞，并抑制体内炎症表型，促进细菌从母体迁移到胎儿。