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

• 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
• 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

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.

绒毛膜炎是自发性早产的主要危险因素，也是胎儿发育不良的主要原因。 新生儿结局绒毛膜炎，定义为炎症的胎膜（FM），通常是 亚临床并在分娩后诊断为组织学绒毛膜炎（HCA），根据中性粒细胞 浸润HCA和早产被认为是由细菌感染引起的。然而，没有一个 细菌导致早产，抗生素干预已被证明是不成功的。此外，委员会认为， 与HCA和早产相关的可识别细菌通常存在于女性生殖器官中， 道。因此，另一个触发器可能负责。我们假设一个可能的危险因素是病毒感染。在 我们的初步研究表明，人类FM的疱疹病毒感染增强了它们的炎症反应 低剂量的细菌脂多糖因此，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，引起炎症加重; 这些机制可能涉及先天免疫Toll样受体（TLR）及其调节因子。在初步研究中 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驱动的免疫应答并调节细胞存活。因此，我们的中心假设是， FM的多微生物病毒-细菌感染增加了妇女患HCA和早产的风险， 并且这是由FM TLR和TAM受体之间的串扰的变化介导的。我们的目标是 了解TLR和TAM受体在FM和中性粒细胞中的作用机制， 多微生物感染，并表征其在HCA和早产中的作用。我们将解决以下方面的主要差距： 我们的知识，例如病毒-细菌多微生物感染对以下的影响：1）FM TLR介导的 反应; 2）FM TAM受体功能;和3）中性粒细胞存活和功能。我们的研究将是 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， 改善妊娠结局，以及它们是否可以作为生物标志物。由于病毒大流行很可能 越来越普遍，女性感染性传播疾病的风险也越来越高，我们的研究表明， 对于指导在这些条件下的孕妇管理至关重要。我们的成果 定义新的病理机制、早产预测因子和治疗靶点的潜力。我们将 使用疱疹和流感病毒作为模型，可以告诉我们其他病毒如何影响怀孕。 因此，我们的具体目标是确定： 1. TAM受体和炎性小体在调节FM对细菌的病毒致敏性中的作用。 2.多微生物FM感染对中性粒细胞存活和功能的影响。 3. TAM受体激动剂是否可以预测或预防多微生物感染诱导的FM 炎症和早产。