Mechanism of F. Nucleatum in Intrauterine Infection

宫内感染是妊娠并发症的主要原因。核梭杆菌FN，a 革兰氏阴性菌是常见的口腔厌氧菌，是宫内感染最常见的菌种之一。 来自PI实验室的研究表明，FN可以从母亲的 口腔到子宫是牙菌血症的结果。FN黏附和侵袭上皮细胞和内皮细胞 细胞，一种可能用于系统性传播的机制。在宫腔内，Fn一直是 在母体血液(与血液传播一致)、蜕膜、绒毛膜、羊膜、 羊水(AF)和胎儿。在这些地点中，细菌被发现最集中在 引起绒毛膜羊膜炎的绒毛膜。在人类身上的发现已经得到证实。 在PI的实验室里开发了一个怀孕的小鼠模型。我们已经证明，一旦输血，FN 专门转位到小鼠胎盘，不会引起全身感染。FN的模式 在小鼠胎盘中的定植与在人类中的定植相似。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在 TLR4-/-小鼠，即使细菌仍然可以定植。这些结果表明炎症是 胎儿丧失的根本原因。在人类和老鼠身上观察到的结果之间的一致性 验证了用妊娠小鼠模型研究FN发病机制的可行性。基于 我们的初步研究，我们假设i)FN定植于人的胎膜，导致 炎症反应；以及ii)FN诱导的先天炎症反应对 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.研究FN与人胎膜的相互作用。目的2.调查 FN对妊娠小鼠的致病作用机制。这项研究的结果将显著证实 我们对宫内感染机制的认识和确定保护的治疗靶点 孕妇和她们的胎儿。此外，这项研究将为口腔细菌如何 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.