The Maternal-Fetal Interface in Listeria-Induced Pregnancy Loss

描述（由申请人提供）：受污染食品感染单核细胞增生李斯特菌是脆弱人群的重大公共卫生威胁。孕妇的感染比一般人群高20倍，并且存在流产、胎儿死亡和新生儿感染的重大风险。虽然实验感染在孕妇中是不可行的，但恒河猴和人类母胎界面在生理、形态和免疫学上的相似之处，使恒河猴成为在感染和不良妊娠结局方面进行转化研究的绝佳机会。根据怀孕猴子体内感染的实验数据，我们假设在母体感染单核增生乳杆菌时，在传给胎儿之前会发生蜕膜感染、蜕膜和胎盘炎症以及蜕膜血管和胎盘完整性受损。此外，生殖道特异性白细胞的激活先于组织病理，母体免疫保护在母胎界面受损。为了验证这些假设，我们设定了三个具体目标：为了验证恒河猴单核细胞增生乳杆菌感染与妊娠早期蜕膜感染、蜕膜免疫细胞激活和有害炎症血管事件相关的假设。具体目标2。目的：验证不良妊娠结局与恒河猴妊娠早期李斯特菌感染剂量有关的假说。具体目标3。为了验证这一假设，即恒河猴妊娠前感染不能保护母胎界面，在随后的妊娠中再次感染。单核细胞增生李斯特菌是探讨蜕膜和胎盘感染对流产和不良妊娠结局影响的理想菌体。有了明确的细胞发病机制和广泛的分子工具，它为细胞内病原体对母胎界面的影响提供了一个杰出的模型。这些研究还将为宫内环境中影响胎儿编程的其他感染、代谢、毒理学和内分泌应激源的组合研究建立范例。研究人员在生殖生物学、微生物发病机制和免疫学方面的集体专业知识将通过在恒河猴身上建立一种新颖和创新的方法来解决人类感染的关键问题，包括胎盘在体内感染的途径、蜕膜对李斯特菌感染的局部免疫反应的性质，从而协同推进该领域的发展。以及个体免疫/炎症反应在流产和死产中的作用。

DESCRIPTION (provided by applicant): Infection with Listeria monocytogenes by contaminated food is a significant public health threat in vulnerable populations. Infection of pregnant women is 20-fold higher than the general population, and there is significant risk for miscarriage, fetal demise, and neonatal infection. While experimental infection is not feasible in pregnant women, the close similarities in the physiology, morphology and immunology of the rhesus monkey and human maternal-fetal interface make the rhesus an outstanding opportunity for translational research in infection and adverse pregnancy outcomes. Supported by in vivo pilot data with infection in pregnant monkeys, we hypothesize that in maternal infection with L. monocytogenes, transmission to the fetus is preceded by decidual infection, decidual and placental inflammation, and damage to decidual vessels and placental integrity. Furthermore, activation of reproductive tract-specific leukocytes precedes tissue pathology, and maternal immune protection is compromised at the maternal-fetal interface. To test these hypotheses we have set three Specific Aims: Specific Aim 1. To test the hypothesis that L. monocytogenes infection in rhesus monkeys is associated with decidual infection, decidual immune cell activation, and deleterious inflammatory vascular events in early pregnancy. Specific Aim 2. To test the hypothesis that adverse pregnancy outcomes are related to the infectious dose of Listeria in early rhesus gestation. Specific Aim 3. To test the hypothesis that pregestational infection in rhesus monkeys fails to protect the maternal-fetal interface with reinfection in subsequent pregnancy. Listeria monocytogenes is an ideal organism to probe the impact of decidual and placental infection on miscarriage and adverse pregnancy outcomes. With well-defined cellular pathogenesis and a wide range of molecular tools available, it provides an outstanding model of intracellular pathogen impact on the maternal- fetal interface. These studies will also establish paradigms for combinatorial studies with other infectious, metabolic, toxicological and endocrine stressors that impact on fetal programming in the intrauterine environment. The collective expertise of the investigators in reproductive biology, microbial pathogenesis and immunology will synergize to move the field forward by establishing a novel and innovative approach with the rhesus monkey to address critical questions in human infection, which include the route by which the placenta is infected in vivo, the nature of the locl immunological response within the decidua to Listeria infection, and the role of a decidual immunological/inflammatory response in pregnancy loss and stillbirths.