Mechanism of F. Nucleatum in Intrauterine Infection

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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.