The Maternal-Fetal Interface in Listeria-Induced Pregnancy Loss

描述（由申请人提供）：受污染的食物导致的单核细胞增生李斯特菌感染是弱势人群的重大公共卫生威胁。孕妇的感染率是普通人群的20倍，流产、胎儿死亡和新生儿感染的风险很大。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学、形态学和免疫学上的密切相似性使恒河猴成为感染和不良妊娠结局转化研究的绝佳机会。在妊娠猴体内试验数据的支持下，我们假设母体感染L。在单核细胞增多症中，传播给胎儿之前是蜕膜感染、蜕膜和胎盘炎症以及对蜕膜血管和胎盘完整性的损害。此外，生殖道特异性白细胞的激活先于组织病理学，母体免疫保护在母胎界面受到损害。为了验证这些假设，我们设定了三个具体目标：具体目标1。为了检验L.恒河猴中的单核细胞增多症感染与早孕期的蜕膜感染、蜕膜免疫细胞活化和有害的炎性血管事件有关。具体目标2。检验恒河猴妊娠早期李斯特菌感染剂量与不良妊娠结局相关的假设。具体目标3。检验恒河猴孕前感染不能保护母-胎界面并在随后的妊娠中再次感染的假设。单核细胞增生李斯特菌是一种理想的微生物，以探讨蜕膜和胎盘感染对流产和不良妊娠结局的影响。由于明确的细胞发病机制和广泛的分子工具，它提供了一个突出的模型，细胞内的病原体对母胎界面的影响。这些研究还将建立与其他影响宫内环境中胎儿编程的感染、代谢、毒理学和内分泌应激源的组合研究的范例。研究人员在生殖生物学、微生物发病机理和免疫学方面的集体专业知识将协同作用，通过用恒河猴建立一种新的创新方法来解决人类感染中的关键问题，包括胎盘在体内感染的途径、蜕膜内对李斯特菌感染的局部免疫反应的性质、以及蜕膜免疫/炎症反应在流产和死胎中的作用。

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.