Mechanisms regulating fetal membrane and neutrophil responses to polymicrobial infection

调节胎膜和中性粒细胞对多种微生物感染反应的机制

基本信息

批准号：
9302657
负责人：
Vikki M Abrahams
金额：
$ 56.66万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-25 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302657
关键词：
Address Agonist Alpha Cell Antibiotics Autophagocytosis Bacteria Bacterial Infections Bacterial Model Bacterial Pneumonia Biological Markers Cell Death Process Cell Survival Cessation of life Coculture Techniques Coupled Data Diagnosis Dose Escherichia coli Family Female Fetal Membranes Goals Herpesviridae Herpesviridae Infections Histologic Human Immune Immune response In Vitro Infection Inflammasome Inflammation Inflammatory Response Influenza Influenza A Virus, H1N1 Subtype Interleukin-1 beta Intervention Knockout Mice Knowledge Ligands Longevity Measures Mediating Mediator of activation protein Modeling Mus Neutrophil Infiltration Outcome Pathology Patients Placenta Play Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Women Premature Birth Receptor Protein-Tyrosine Kinases Receptor Signaling Risk Risk Factors Role Secondary to Serum Sexually Transmitted Diseases Stimulus System Testing Toll-like receptors Viral Virus Virus Diseases Woman extracellular fetal fetal infection improved in vivo influenzavirus inhibitor/antagonist intraamniotic infection killings neonatal outcome neutrophil novel pandemic disease pandemic influenza premature prevent receptor receptor function reproductive tract response therapeutic target

项目摘要

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.

绒毛膜羊膜炎是自发性早产的主要危险因素，也是导致胎儿和胎儿发育不良的主要原因。新生儿结局。绒毛膜羊膜炎，定义为胎膜炎症 (FM)，通常是亚临床并在分娩后根据中性粒细胞证据诊断为组织学绒毛膜羊膜炎 (HCA) 浸润。 HCA 和早产被认为是由细菌感染引发的。然而，没有一个单独的细菌已被归因于早产，抗生素干预已被证明是不成功的。而且，与 HCA 和早产相关的可识别细菌通常存在于女性生殖系统中道。因此，另一个触发因素可能是造成这种情况的原因。我们假设一种可能的危险因素是病毒感染。在初步研究表明，人类 FM 的疱疹病毒感染会增强其炎症反应低剂量细菌脂多糖。因此，我们假设怀孕期间的病毒感染可能会改变 FM 的方式对生殖道中通常存在的细菌产生反应，导致炎症加剧；和机制可能涉及先天免疫 Toll 样受体 (TLR) 及其调节因子。初步研究中发现 FM 表达功能性 TAM 酪氨酸激酶受体，这是一个新的负调节因子家族抑制 TLR 驱动的免疫反应并调节细胞存活。因此，我们的中心假设是 FM 的多种微生物病毒细菌感染会增加女性 HCA 和早产的风险，这是由 FM TLR 和 TAM 受体之间串扰的变化介导的。我们的目标是了解 TLR 和 TAM 受体在 FM 和中性粒细胞中发挥作用的机制多种微生物感染，并描述它们在 HCA 和早产中的作用。我们将解决以下方面的重大差距我们的知识，例如病毒-细菌多种微生物感染对以下方面的影响：1) FM TLR 介导回应； 2）FM TAM受体功能； 3) 中性粒细胞的存活和功能。我们的学习将是通过确定 TAM 受体激动剂是否可以逆转多种微生物诱导的 FM 炎症来进行转化改善妊娠结局，以及它们是否可以作为生物标志物。由于病毒大流行可能变得越来越普遍，女性患性传播感染的风险也越来越大，我们的研究是对于指导这些条件下孕妇的管理至关重要。我们的成果有定义新的病理学机制、早产预测因素和治疗目标的潜力。我们将使用疱疹和流感病毒作为模型，可以让我们了解其他病毒如何影响怀孕。因此，我们的具体目标是确定： 1. TAM受体和炎症小体在调节FM对细菌的病毒敏感性中的作用。 2. 多种微生物 FM 感染对中性粒细胞存活和功能的影响。 3. TAM受体激动剂能否预测或预防多种微生物感染引起的FM 炎症和早产。