The Maternal-Fetal Interface in Listeria-Induced Pregnancy Loss

李斯特菌引起的流产中的母婴界面

基本信息

批准号：
8901923
负责人：
THADDEUS G GOLOS
金额：
$ 39.93万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-04 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901923
关键词：
Address Attention Bacteria Blood Cells Blood Vessels Cells Cheese Chlamydia Clinical Pathology Clinical Research Communities Data Decidua Dose Endocrine Environment Epithelium Event Experimental Animal Model Failure Female Fetus Fibrinoid necrosis Food Food Supply General Population Growth Health Histopathology Human Immune Immune Cell Activation Immune system Immunity Immunology In Vitro Indium Infection Infectious Agent Inflammation Inflammatory Inflammatory Response Leukocytes Listeria Listeria monocytogenes Listeriosis Liver Macaca Macaca mulatta Maternal-Fetal Exchange Meat Metabolic Milk Modeling Molecular Monkeys Morbidity - disease rate Morphology Nature Neonatal Organism Outcome Pathogenesis Pathology Peripheral Physiological Physiology Placenta Pregnancy Pregnancy Outcome Pregnancy loss Pregnant Women Premature Labor Process Public Health Regulation Reproductive Biology Research Personnel Resources Risk Role Route Spiral Artery of the Endometrium Spleen Spontaneous abortion T cell response Testing Thrombosis Tissues Toxoplasma Translational Research Tropism Vulnerable Populations base combinatorial expectation fetal fetal infection fetal medicine fetal programming gastrointestinal in vivo innovation leukocyte activation microbial mortality neonatal death nonhuman primate novel pathogen pregnant reproductive research study response stillbirth stressor success tool transmission process trophoblast unpasteurized vector vaccine

项目摘要

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.

描述（由申请人提供）：受污染食品引起的单核细胞增多性李斯特菌感染对弱势群体构成重大公共卫生威胁。孕妇的感染率比一般人群高20倍，存在流产、胎儿死亡和新生儿感染的显着风险。虽然实验性感染在孕妇中不可行，但恒河猴与人类母胎界面的生理学、形态学和免疫学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。在怀孕猴感染的体内试验数据的支持下，我们假设，在母体感染单核细胞增多性李斯特菌时，在传播给胎儿之前会出现蜕膜感染、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学，并且母体免疫保护在母胎界面处受到损害。为了检验这些假设，我们设定了三个具体目标：具体目标 1. 检验恒河猴中单核细胞增生李斯特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. 检验不良妊娠结局与恒河猴妊娠早期李斯特菌感染剂量相关的假设。具体目标 3. 检验以下假设：恒河猴的孕前感染无法保护母胎界面，并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微生物。凭借明确的细胞发病机制和广泛的可用分子工具，它提供了细胞内病原体对母胎界面影响的出色模型。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与恒河猴建立一种新颖和创新的方法来协同推动该领域向前发展，以解决人类感染的关键问题，其中包括胎盘感染的途径体内，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/炎症反应在妊娠丢失和死产中的作用。