Mechanism of F. nucleatum in intrauterine infection

具核梭菌宫内感染机制

• 批准号: 8477449
• 负责人: Yiping Han
• 金额: $ 38.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477449
• 关键词: Amniotic Fluid; Apical; Apoptosis; Area; Bacteremia; Bacteria; Bacterial Adhesins; Binding; Blood; Breathing; Cell surface; Cells; Chorion; Communicable Diseases; Decidua; Dental; Endothelial Cells; Endothelium; Epithelial Cells; Fetal Membranes; Fetus; Figs - dietary; Fusobacterium nucleatum; Hematogenous; Human; Infection; Infection of amniotic sac and membranes; Inflammation; Inflammatory Response; Intercellular Junctions; Invaded; Laboratories; Light; Mediating; Membrane; Modeling; Mothers; Mus; Oral; Oral cavity; Organism; Pathogenesis; Patients; Pattern; Placenta; Pregnancy Complications; Pregnant Women; Premature Birth; Premature Labor; Process; Research; Route; Sepsis; Signal Transduction Pathway; Site; Systemic infection; TLR4 gene; Testing; Umbilical Cord Blood; Uterus; amnion; cadherin 5; fetal; frontier; innovation; mouse model; mutant; neonatal sepsis; neutrophil; novel; oral anaerobes; oral bacteria; pathogen; pregnant; prevent; response; stillbirth; therapeutic target; transmission process

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.

宫内感染是妊娠并发症的主要原因。核梭杆菌是一种常见的革兰氏阴性口腔厌氧菌，是宫内感染最常见的菌种之一。由于牙菌血症，FN可从母亲S的口腔向子宫进行血源性移位。使用在皮埃S实验室开发的怀孕小鼠模型，我们已经证明，一旦血液传播，FN特异性地转移到小鼠胎盘，而不会引起全身感染。FN在小鼠胎盘中的定植模式与在人类中的定植模式相似。FN刺激小鼠胎盘炎性反应，导致胎儿死亡。TLR4-/-小鼠的胎盘炎症和胎儿丢失减轻，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。在人类和小鼠身上观察到的一致性证实了使用怀孕小鼠模型来研究FN的发病机制。我们提出了一项单一目的的研究：探讨FN在妊娠小鼠中的发病机制。这项研究的结果将极大地充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，这项研究将为口腔细菌如何影响口腔外部位的感染和炎症提供新的线索。