Role of Hofbauer Cells in Fetal Infection/Inflammation

胎儿炎症和感染仍然是新生儿死亡和发病的主要原因。我们以前的 研究表明，组织学绒毛膜炎（HCA），微生物驱动的白细胞浸润到 母胎界面，与Hofbauer细胞（HBC）数量的局灶性增加相关（即HBC）。 胎儿起源的胎盘巨噬细胞，位于合胞体下方，邻近胎儿毛细血管）， 胎盘绒毛阐明细胞类型对多种微生物挑战的特异性反应将导致新的 降低不良结局发生率和/或严重程度的干预措施，包括胎儿炎症 反应综合征（FIRS），一种多系统/微生物驱动的脐带炎症（脐带炎）， 胎儿，这与显着的新生儿/儿科死亡率和发病率。微生物化合物 通过Toll样受体（TLR）和TAM触发先天免疫反应，这是一种最近表征的 在非胎盘细胞类型中显示抑制TLR功能的蛋白酪氨酸激酶受体亚家族。在 此外，对微生物的炎症反应通过炎性体（一种多蛋白复合物）来调节。 我们的中心假设是，HBC的疱疹病毒感染抑制了它们的炎症反应， 通过改变TAM受体和Nalp 3炎性体功能，从而抑制HBCs控制 细菌生长，从而加剧胎盘/胎儿感染和绒毛膜炎。我们的具体目标 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Nalp 3炎性体的表达和功能的修饰; 2）测试 HBC的HV感染增加TAM受体功能并抑制炎性体活性的假说 它促进细菌向胎儿的迁移和定植; 3）测试假设， 多微生物疱疹病毒-细菌感染增加胎盘巨噬细胞， 体内炎症表型，促进细菌从母亲迁移到胎儿。

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.