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）是一种常见的革兰氏阴性口腔厌氧菌，是宫内感染中最常见的物种之一。由于口腔菌血症，Fn可以从母亲的口腔血液转移到子宫。利用PI¿s实验室开发的怀孕小鼠模型，我们已经证明，Fn一旦通过血液传播，就会特异性地易位到小鼠胎盘，而不会引起全身感染。Fn在小鼠胎盘中的定植模式与在人类胎盘中的定植模式相似。Fn刺激小鼠胎盘炎症反应，导致胎儿死亡。在tlr1 -/-小鼠中，即使细菌仍然可以定植，胎盘炎症和胎儿丢失也减少了。这些结果表明，炎症是胎儿丢失的潜在原因。人类和小鼠观察结果的一致性验证了利用怀孕小鼠模型研究Fn的发病机制。我们提出一项单目的研究：探讨妊娠小鼠Fn的发病机制。本研究的结果将极大地支持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，本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.