Porphyromonas gingivalis strain specific effects on the deep placental bed

描述(由申请人提供)：Pg是人类常见的牙周病原体，也与低出生体重、宫内生长受限、先兆子痫和自发早产密切相关。流行病学研究表明，PG可能通过直接途径通过血源性分娩进入子宫和胎儿间隔室而促进不良妊娠结局。然而，PG促进产科疾病的环境或机制仍然难以捉摸，目前治疗/预防妊娠期牙周病的方法在减少早产方面的效果有限。我们小组最近的工作表明PG可以从口腔移位并在未怀孕的子宫定植。此外，在妊娠期间，PG优先定植于妊娠大鼠的胎盘深层，共表达特定毒力因子(多糖囊和菌毛)的PG菌株诱导子宫动脉粥样硬化，这与滋养细胞侵入子宫肌层的不良反应相吻合。基于这些特征，我们认为PG通过定植子宫间质(怀孕前)或深胎盘床(怀孕早期)来促进不良妊娠结局。根据PG的毒力表型，该微生物可诱导子宫动脉炎/动脉粥样硬化，在怀孕期间扰乱子宫螺旋动脉重构的生理过程，导致异常胎盘形成，并促进产科并发症。这个应用程序的目的是在我们的慢性口腔感染大鼠模型中使用具有不同毒力表型的常见人类PG分离株来验证我们的假设。这项建议的目的是：1)确定在慢性口腔感染期间在非妊娠子宫中产生持续性子宫动脉炎/动脉粥样硬化的PG毒力表型，以及2)确定PG诱导的炎症特征，导致绒毛外滋养细胞侵袭不良、螺旋动脉重塑受损以及慢性口腔感染后的IUGR。与公共卫生相关：这一应用解决了围产期医学中的一个重大问题，称为深度胎盘缺陷，它发生在几种产科综合征中，包括流产、胎儿宫内发育迟缓(IUGR)、先兆子痫和早产。因此，阐明破坏螺旋动脉生理性重塑的早期病理事件是研究的重点，因为这可能导致开发新的方法来预防胎盘床紊乱或改善对这种综合征风险个体的早期发现。

DESCRIPTION (provided by applicant): Porphyromonas ingivalis (Pg) is a common periodontal pathogen of humans that is also strongly associated with low birth weight, intrauterine growth restriction, preeclampsia, and spontaneous preterm birth. Epidemiologic studies suggest that Pg may promote adverse pregnancy outcomes through the direct pathway via hematogenous delivery into the uterine and fetal compartment. However, the circumstances or mechanisms whereby Pg promotes obstetric disease remains elusive, and current approaches to treat/prevent periodontal disease during pregnancy have had limited efficacy in reducing the incidence of preterm birth. Recent work by our group indicates that Pg can translocate from the oral cavity and colonize the non-pregnant uterus. Further, during pregnancy, Pg preferentially colonizes the deep placental bed of pregnant rats, and that Pg strains that co-express particular virulence factors (polysaccharide capsule and fimbriae) induce uterine atherosis that coincides with poor trophoblast invasion into the myometrium. Based on these features we propose that Pg promotes adverse pregnancy outcomes by colonizing the uterine stroma (before pregnancy) or the deep placental bed (during early pregnancy). Depending on the Pg virulence phenotype, the microbe induces uterine arteritis/atherosis, which during pregnancy, disrupts the physiologic process of uterine spiral artery remodeling resulting in abnormal placentation and promoting obstetric complications. The objectives of this application are to test our hypothesis using common human Pg isolates with varying virulence phenotypes in our rat model of chronic oral infection. The aims of this proposal are 1) Define the Pg virulence phenotype that produces persistent uterine arteritis/atherosis in the non-pregnant uterus during chronic oral infection, and 2) Characterize the Pg induced inflammatory profile that results in poor extravillous trophoblast invasion, impaired spiral artery remodeling, and IUGR following chronic oral infection. Relevance to public health: This application address a significant problem in perinatal medicine referred to as defective deep placentation, which occurs in several obstetrical syndromes including miscarriages, intrauterine growth retardation (IUGR), preeclampsia, and preterm birth. Therefore, elucidating the early pathologic events that disrupt physiologic remodeling of the spiral arteries is a research priority since this could lead o the development of novel methods that may prevent placental bed disorders or improve early detection of individuals at risk for this syndrome.