Mechanisms regulating fetal membrane and neutrophil responses to polymicrobial infection

绒毛膜羊膜炎是自然早产的主要危险因素，也是导致胎儿和胎儿窘迫的主要因素。 新生儿结局。绒毛膜羊膜炎，定义为胎膜炎症，通常是 根据中性粒细胞的证据，分娩后亚临床和诊断为组织性绒毛膜羊膜炎(HCA) 渗透。HCA和早产被认为是由细菌感染引起的。然而，没有单一的 细菌被归因于早产，而抗生素干预被证明是不成功的。此外， 与HCA和早产相关的可识别细菌通常存在于女性生殖器中 一条小路。因此，可能是另一个触发器负责。我们推测一个可能的危险因素是病毒感染。在……里面 初步研究表明，人类疱疹病毒感染可增强FMS的炎症反应 到低剂量细菌脂多糖。因此，我们推测，怀孕期间的病毒感染可能会改变FMS的方式 对通常存在于生殖道中的细菌产生反应，导致炎症加剧；以及 机制可能涉及先天免疫Toll样受体(TLRs)及其调节因子。在初步研究中 发现FM表达功能性酪氨酸激酶受体，这是一类新的负性调节因子家族， 抑制TLR驱动的免疫反应，调节细胞存活。因此，我们的中心假设是 FMS的多微生物病毒-细菌感染增加了妇女患HCA和早产的风险， 这是通过调频受体和受体之间的串扰变化来调节的。我们的目标是 了解TLRs和受体在FM和中性粒细胞反应中的作用机制 一种多菌感染，并描述它们在HCA和早产中的作用。我们将在以下方面解决主要差距 我们的知识，如病毒-细菌多菌感染对以下方面的影响：1)FM TLR介导 反应；2)FM受体功能；3)中性粒细胞存活和功能。我们的研究将是 通过确定受体激动剂是否可以逆转多菌素诱导的FM炎症和 改善妊娠结局，以及它们是否可以作为生物标志物。因为病毒大流行很可能 变得越来越普遍，女性感染性传播疾病的风险增加，我们的研究是 这对于指导这些情况下的孕妇管理至关重要。我们的结果是 定义新的病理机制、早产儿预测因子和治疗靶点的可能性。我们会 使用疱疹和流感病毒作为模型，可能会告诉我们其他病毒是如何影响怀孕的。 因此，我们的具体目标是确定： 1.受体和炎性小体在调节FM对细菌的病毒致敏中的作用。 2.多菌FM感染对中性粒细胞存活和功能的影响。 3.受体激动剂能否预测或预防多菌感染所致FM 炎症和早产。

Chorioamnionitis is a major risk factor for spontaneous preterm birth and a leading contributor to poor fetal and neonatal outcomes. Chorioamnionitis, defined as inflammation of the fetal membranes (FM), is usually subclinical and diagnosed as histological chorioamnionitis (HCA) after delivery, by evidence of neutrophil infiltration. HCA and preterm birth are thought to be initiated by bacterial infection. However, no single bacterium has been attributed to preterm birth, and antibiotic intervention has proven unsuccessful. Moreover, identifiable bacteria associated with HCA and preterm birth are normally present in the female reproductive tract. Thus, another trigger may be responsible. We postulate that one possible risk factor is a viral infection. In preliminary studies we show that a herpes viral infection of human FMs augments their inflammatory response to low-dose bacterial LPS. Thus, we postulate that a viral infection during pregnancy may change the way FMs respond to bacteria normally present in the genital tract, giving rise to aggravated inflammation; and the mechanisms likely involve innate immune Toll-like receptors (TLRs) and their regulators. In preliminary studies found that FMs express functional TAM tyrosine kinase receptors, a novel family of negative regulators that inhibit TLR-driven immune responses and regulate cell survival. Thus, our central hypothesis is that a polymicrobial viral-bacterial infection of the FMs increases a woman's risk for HCA and preterm birth, and this is mediated by changes in the crosstalk between FM TLRs and TAM receptors. Our goals are to understand the mechanisms by which TLRs and TAM receptors function in FMs and neutrophils in response to a polymicrobial infection, and to characterize their role in HCA and preterm birth. We will address major gaps in our knowledge, such as the impact a viral-bacterial polymicrobial infection has on: 1) FM TLR-mediated responses; 2) FM TAM receptor function; and 3) neutrophil survival and function. Our studies will be translational by determining if TAM receptor agonists can reverse polymicrobial-induced FM inflammation and improve pregnancy outcome, and whether they can serve as biomarkers. Since viral pandemics are likely to become more common, and women are at increasing risk for sexually transmitted infections, our studies are critical for guiding the management of pregnant women under these conditions. Our outcomes have the potential of defining new mechanisms of pathology, predictors of prematurity, and therapeutic targets. We will use herpes and influenza viruses as models that may inform us about how other viruses impact pregnancy. Thus, our specific aims are to determine: 1. The role of TAM receptors and the inflammasome in regulating viral sensitization of FMs to bacteria. 2. The impact a polymicrobial FM infection has on neutrophil survival and function. 3. Whether TAM receptor agonists can predict or prevent polymicrobial infection-induced FM inflammation and preterm birth.