Porphyromonas gingivalis strain specific effects on the deep placental bed

描述（由申请人提供）：牙龈卟啉单胞菌（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、先兆子痫和自发性早产密切相关。流行病学研究表明，Pg可能通过直接途径通过血源性递送进入子宫和胎儿室而促进不良妊娠结局。然而，Pg促进产科疾病的情况或机制仍然难以捉摸，目前治疗/预防妊娠期间牙周病的方法在降低早产发生率方面的效果有限。我们小组最近的工作表明，Pg可以从口腔移位并定殖于非妊娠子宫。此外，在妊娠期间，Pg优先定殖于妊娠大鼠的胎盘床深部，并且共表达特定毒力因子（多糖荚膜和菌毛）的Pg菌株诱导子宫动脉粥样硬化，这与滋养层侵入子宫肌层的不良相一致。基于这些特点，我们建议，PG促进不良妊娠结局的殖民子宫基质（怀孕前）或深胎盘床（在怀孕早期）。根据Pg毒力表型，微生物诱导子宫动脉炎/动脉粥样硬化，其在妊娠期间破坏子宫螺旋动脉重塑的生理过程，导致异常胎盘形成并促进产科并发症。本申请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分离株来检验我们的假设。该提案的目的是1）定义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，和2）表征Pg诱导的炎症特征，其导致绒毛外滋养层浸润不良、螺旋动脉重塑受损和慢性口腔感染后的IUGR。 与公共卫生的相关性：本申请解决了围产期医学中被称为缺陷性深胎盘形成的重要问题，其发生在包括流产、宫内生长迟缓（IUGR）、先兆子痫和早产的几种产科综合征中。因此，阐明破坏螺旋动脉生理重塑的早期病理事件是研究的优先事项，因为这可能导致开发新的方法，可以预防胎盘床疾病或改善这种综合征风险个体的早期检测。

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.