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率的主要原因。我们以前的 研究表明，组织性绒毛膜羊膜炎(HCA)是由微生物驱动的白细胞向 母胎界面的异常与Hofbauer细胞(HbCs)数量的局灶性增加有关。 胎儿来源的胎盘巨噬细胞位于合体下方和邻近胎儿毛细血管)，在 胎盘绒毛。阐明细胞类型对多菌种挑战的特定反应将导致新的 减少包括胎儿炎症在内的不良后果的发生率和/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(真菌炎)和 胎儿，这与严重的新生儿/儿童死亡率和发病率有关。微生物化合物 通过Toll样受体(TLRs)和TAMs触发先天性免疫反应，这是一种最近表征的 蛋白酪氨酸激酶受体亚家族在非胎盘细胞类型中抑制TLR功能。在……里面 此外，对微生物的炎症反应是通过炎性小体--一种多蛋白质复合体--来调节的。 我们的中心假设是，HBCs的疱疹病毒感染抑制了它们对 通过改变受体和NALP3炎症体功能抑制HbCs的调控能力 细菌生长，因此，加剧胎盘/胎儿感染和绒毛膜羊膜炎。我们的具体目标 将：1)验证疱疹病毒感染HBCs通过阻断内毒素诱导的肿瘤坏死因子-α和白介素1-β的假设 修饰受体和NALP3炎症体的表达和功能；2)检测 HV感染HBCs增强受体功能和抑制炎症体活性的假说 这促进了细菌向胎儿的迁移和定居；3)检验了一种假设 多菌疱疹病毒-细菌感染增加胎盘巨噬细胞抑制 体内的炎症表型，促进细菌从母亲向胎儿的迁移。

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.