The Maternal-Fetal Interface in Listeria-Induced Pregnancy Loss

描述(由申请人提供)：受污染的食物感染单核细胞增多性李斯特菌对脆弱人群的公共健康构成重大威胁。孕妇的感染率是一般人群的20倍，而且流产、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，但恒河猴与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研究感染和不良妊娠结局的绝佳机会。在妊娠猴体内感染试验数据的支持下，我们假设，在母体感染单核细胞增多性李斯特菌的母体中，传播到胎儿之前是蜕膜感染、蜕膜和胎盘炎症，以及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，母体免疫保护在母胎界面受到损害。为了验证这些假说，我们设定了三个特定目标：特定目标1.检验恒河猴单核细胞增多性李斯特菌感染与早孕蜕膜感染、蜕膜免疫细胞激活和有害的炎性血管事件有关的假说。具体目的2.检验不良妊娠结局与早孕期李斯特菌感染剂量有关的假设。具体目的3.检验恒河猴孕前感染不能保护母胎界面的假说，因为在随后的妊娠中再次感染。单核细胞增多性李斯特菌是研究蜕膜和胎盘感染对流产和不良妊娠结局影响的理想微生物。随着明确的细胞发病机制和广泛的分子工具可用，它提供了一个出色的细胞内病原体影响母胎界面的模型。这些研究还将建立与影响宫内环境中胎儿编程的其他传染病、代谢、毒理学和内分泌应激源进行组合研究的范例。生殖生物学、微生物发病机制和免疫学的研究人员的集体专业知识将通过与恒河猴建立一种新颖和创新的方法来推动该领域的发展，以解决人类感染中的关键问题，包括胎盘在体内感染的途径，蜕膜对李斯特菌感染的Locl免疫反应的性质，以及蜕膜免疫/炎症反应在妊娠丢失和死产中的作用。

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.