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（Fusobacteriumnucleatum，Fn）是一种常见的革兰氏阴性口腔厌氧菌，是宫内感染的主要病原菌之一。由于牙齿菌血症，Fn可以通过血液从母亲的口腔转移到她的子宫。使用PI实验室开发的妊娠小鼠模型，我们已经表明，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。小鼠胎盘中Fn定植的模式与人类相似。Fn刺激小鼠胎盘炎症反应，导致胎儿死亡。胎盘炎症和胎儿丢失在Tlr 4-/-小鼠中减少，即使细菌仍然可以定殖。这些结果表明炎症是胎儿丢失的根本原因。在人类和小鼠中的观察结果之间的一致性验证了使用妊娠小鼠模型来研究Fn的发病机制。我们提出了一个单一的目标研究：探讨Fn在妊娠小鼠中的发病机制。本研究的结果将显著证实我们对宫内感染机制的理解，并确定保护孕妇及其胎儿的治疗靶点。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. Fn can translocate hematogenously from the mother¿s mouth to her uterus as a result of dental bacteremia. Using a pregnant mouse model developed in the PI¿s laboratory, 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. We propose a single-aim study: 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.