Mechanism of F. Nucleatum in Intrauterine Infection

宫内感染是妊娠并发症的主要原因。具核梭杆菌（Fn），a 革兰氏阴性常见的口腔厌氧菌，是宫内感染最常见的菌种之一。 PI实验室的研究表明，Fn可以从母亲的血液中易位， 口腔感染到了子宫Fn粘附并侵入上皮和内皮细胞 细胞，这是一种可能用于全身传播的机制。在子宫腔内，Fn已经 在母体血液（与血行传播一致）、蜕膜、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 引起绒毛膜炎的绒毛膜羊膜。在人类身上的发现已经被证实 用私家侦探实验室里的怀孕老鼠模型我们已经证明，一旦血液传播，Fn 特异性地转移到小鼠胎盘而不引起全身感染。Fn的模式 在小鼠胎盘中的定殖与在人类中的相似。Fn刺激的小鼠胎盘 炎症反应导致胎儿死亡。胎盘炎症和胎儿丢失减少， tlr 4-/-小鼠，即使细菌仍然可以定植。这些结果表明炎症是 胎儿丢失的根本原因在人类和小鼠中观察到的一致性 验证了利用妊娠小鼠模型研究Fn发病机制的可行性。基于 在我们的初步研究中，我们假设i）Fn定殖于人类胎膜， 炎症反应;和ii）Fn诱导的先天性炎症反应对于炎症反应的发生至关重要。 子宫内感染的发展。为了验证这些假设，我们提出了以下两个目标： 1.探讨Fn与人胎膜的相互作用。目标二。探讨 Fn在妊娠小鼠中的致病机制。这项研究的结果将显著证实 我们对宫内感染机制的理解，并确定治疗靶点，以保护 孕妇和胎儿此外，这项研究将揭示口腔细菌如何 影响口腔外部位的感染和炎症。

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.