Mechanism of F. Nucleatum in Intrauterine Infection

具核梭杆菌宫内感染机制

• 批准号: 9085258
• 负责人: Yiping Han
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9085258
• 关键词: Amniotic Fluid; Apical; Apoptosis; Area; Bacteremia; Bacteria; Bacterial Adhesins; Binding; Blood; Breathing; Cell surface; Cells; Chorion; Communicable Diseases; Decidua; Dental; Development; Endothelial Cells; Endothelium; Epithelial Cells; Fetal Membranes; Fetus; Figs - dietary; Fusobacterium nucleatum; Hematogenous; Human; Infection; Inflammation; Inflammatory Response; Invaded; Light; Mediating; Membrane; Mothers; Mus; Oral; Oral cavity; Organism; Pathogenesis; Patients; Pattern; Placenta; Pregnancy Complications; Pregnant Women; Premature Birth; Premature Labor; Prevalence; Process; Research; Route; Sepsis; Signal Transduction Pathway; Site; Systemic infection; TLR4 gene; Testing; Umbilical Cord Blood; Uterus; amnion; base; cadherin 5; early onset; fetal; frontier; innovation; intraamniotic infection; mouse model; mutant; neonatal sepsis; neutrophil; novel; oral anaerobes; oral bacteria; pathogen; pregnant; preterm premature rupture of membranes; prevent; response; stillbirth; therapeutic target; transmission process

Intrauterine infection is a major cause of pregnancy complications. Fusobacterium nucleatum (Fn), a gram-negative common oral anaerobe, is one of the most prevalent species in intrauterine infection. Studies from the PI’s lab have demonstrated that Fn can translocate hematogenously from the mother’s mouth to her uterus as a result of dental bacteremia. Fn adheres to and invades epithelial and endothelial cells, a mechanism likely utilized for systemic dissemination. Inside the intrauterine cavity, Fn has been detected in the maternal blood (consistent with hematogenous transmission), decidua, chorion, amnion, amniotic fluid (AF), and fetus. Among these sites, bacteria were found to be most concentrated in chorioamniotic membranes causing chorioamnionitis. The findings in humans have been corroborated with a pregnant mouse model developed in the PI’s lab. We have shown that once blood borne, Fn translocates specifically to the mouse placenta without causing systemic infections. The pattern of Fn colonization in the mouse placenta mimicked that in humans. Fn stimulated murine placental inflammatory responses resulting in fetal demise. Placental inflammation and fetal loss were diminished in Tlr4-/- mice even if the bacteria could still colonize. These results demonstrate inflammation is the underlying cause of fetal loss. The consistency between the observations in humans and in mice validates the use of the pregnant murine model to study the pathogenesis mechanisms of Fn. Based on our preliminary studies, we hypothesize that i) Fn colonizes the human fetal membranes causing inflammatory responses; and ii) Fn-induced innate inflammatory responses are critical for the development of intrauterine infection. To test these hypotheses, we propose the following two aims: Aim 1. To investigate Fn interaction with human fetal membranes. Aim 2. To investigate the pathogenesis mechanisms of Fn in pregnant mice. Results from this study will significantly substantiate our understanding of the mechanisms of intrauterine infection and identify therapeutic targets to protect pregnant women and their fetuses. Furthermore, this study will shed novel lights on how oral bacteria impact infections and inflammation at extra-oral sites.

介绍性感染是妊娠并发症的主要原因。核细菌核塔（FN），A 革兰氏阴性的普通口服厌氧菌是插入感染中最普遍的物种之一。 PI实验室的研究表明，FN可以从母亲的血液中脱脂 由于牙科细菌而嘴巴嘴巴。 FN坚持并入侵上皮和内皮 细胞，一种可能用于全身传播的机制。在内部腔内，FN一直 在母体血液中检测到（与血源传播一致），Decidua，绒毛膜，羊膜， 羊水（AF）和胎儿。在这些地点中，发现细菌最集中在 绒毛膜膜引起绒毛膜炎。人类的发现得到了证实 Pi的实验室中开发了一个怀孕的小鼠模型。我们已经表明，一旦血出生，FN 专门易位到小鼠plapeta而不会引起全身感染。 FN的模式 小鼠胎盘中的殖民化模仿了人类。 fn刺激鼠斑点 炎症反应导致胎儿死亡。胎盘炎症和胎儿流失减少 即使细菌仍然可以定植，TLR4 - / - 小鼠也是如此。这些结果表明创新是 胎儿流失的根本原因。人类和小鼠的观察结果之间的一致性 验证使用怀孕鼠模型来研究FN的发病机理。基于 我们的初步研究，我们假设I）fn在人类胎儿膜上定居 炎症反应； ii）FN引起的先天炎症反应对于 插入感染的发展。为了检验这些假设，我们提出以下两个目标：目标 1。研究FN与人胎膜的相互作用。目标2。调查 怀孕小鼠FN的发病机制。这项研究的结果将显着证实 我们对插入式感染机制的理解，并确定保护靶标 孕妇及其胎儿。此外，这项研究将为口腔细菌提供新颖的灯光 在外部位影响感染和感染。