The Maternal-Fetal Interface in Listeria-Induced Pregnancy Loss

李斯特菌引起的流产中的母婴界面

• 批准号: 9107815
• 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
• 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/9107815
• 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 Contamination; 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; Metabolic; Milk; Modeling; Molecular; Monkeys; Morbidity - disease rate; Morphology; Nature; Neonatal; Organism; Outcome; Pathogenesis; Pathology; Peripheral; Physiological; Physiology; Placenta; Pregnancy; Pregnancy loss; Pregnant Women; Premature Labor; Processed Meats; 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; adverse pregnancy outcome; 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; reproductive tract; research study; response; stillbirth; stressor; success; tool; transmission process; trophoblast; unpasteurized; vector vaccine

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）：受污染的食物感染单核细胞增生李斯特菌的感染是脆弱人群的重大公共卫生威胁。孕妇的感染比普通人群高20倍，流产，胎儿丧生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，但恒河猴和人类母亲婚礼的生理学，形态和免疫学的紧密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。在孕妇猴子中感染的体内试验数据的支持下，我们假设在单核细胞增生李斯特氏菌的母体感染中，向胎儿传播的是骨骼感染，判决和胎盘炎症，以及对缩减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，而母体免疫保护在母体界面界面受到损害。为了检验这些假设，我们设定了三个特定的目的：特定目的1。用于检验以下假设：恒河猴中的单核细胞增生李斯特氏菌感染与决定期感染，dec骨免疫细胞激活以及早期怀孕早期的炎症性血管事件有关。具体目的2。检验以下假设：不良妊娠结局与早期恒河猴的感染剂量有关。具体目的3。检验以下假设：恒河猴前的寄生性感染无法在随后的怀孕中恢复产妇界面。单核细胞增生李斯特菌是一种理想的生物体，可以探测判决和胎盘感染对流产和不良妊娠结局的影响。具有定义明确的细胞发病机理和各种分子工具，它提供了对母体胎儿界面影响的出色模型。这些研究还将建立与其他感染性，代谢，毒理学和内分泌压力源对宫内环境中影响胎儿程序的组合研究的范例。 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怀孕丧失和死产中的免疫/炎症反应。