ENTEROVIRUS INFECTIONS OF THE PLACENTA AND FETUS

胎盘和胎儿的肠道病毒感染

• 批准号: 3470373
• 负责人: MARK J ABZUG
• 金额: $ 7.51万
• 依托单位: CHILDREN'S HOSPITAL OF DENVER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1996-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3470373
• 关键词: Enterovirus; communicable disease transmission; disease /disorder model; embryo /fetus; encephalitis virus; encephalomyelitis; gestational age; immunocytochemistry; immunotherapy; in situ hybridization; laboratory mouse; model design /development; mutant; placenta; virus cytopathogenic effect; virus infection mechanism

Enteroviruses (EVs) are ubiquitous viruses which pose a significant risk to human pregnancies. In utero infections may lead to maternal illness; neonatal illnesses, including meningoencephalitis, myocarditis, hepatitis, and/or sepsis; premature delivery; fetal myocarditis and death; fetal hepatic and adrenal necrosis and demise; and congenital malformations of the cardiovascular, gastrointestinal, genitourinary, and central nervous systems. The pathogenesis of these gestational infections is poorly understood. The proposed project will investigate the significance of transplacental EV infection, the mechanisms employed by the placenta to protect against fetal infection, and factors which may cause those mechanisms to break down. The effects of intrauterine EV infection on the placenta and fetus will be elucidated, and factors influencing fetal outcome will be delineated. Immunologic and pharmacologic strategies to prevent fetal morbidity associated with EV infections will be evaluated. Studies will be performed in a murine model of gestational EV infection which utilizes a natural EV of mice, Theiler's murine encephalomyelitis virus (TMEV). In this model, placentas and fetuses are readily infected following maternal inoculation with TMEV in early gestation, while in late gestation, placentas are infected but the fetus is never infected. Experiments will be performed in this model to determine whether the evolution of this placental barrier to viral transmission is based on anatomic and structural features (examining placentas containing virus and placentas containing inert particles of similar size by electron microscopy), immunologic phenomena (studying infected placentas with immunohistochemistry and studying viral infection of distinct placental cell populations in vitro), and/or changes in placental cell susceptibility to viral infection (employing placental cell culture techniques). Morphologic studies, tissue culture, in situ hybridization, and immunohistochemistry will be used to elucidate the effects of TMEV infection on the placenta and the fetus. Host and viral factors which may affect the rate of transplacental infection and/or the outcome of fetal infection will be assessed by varying maternal physiologic parameters (age, physical stress, nutrition, uteroplacental blood flow) and by studying viral mutants in this model. Finally, immunologic and pharmacologic strategies to prevent transplacental infection and/or prevent adverse outcome of fetal infection will be tested in this animal model. These studies will shed light on protective mechanisms employed by the human placenta, effects of EVs on human fetuses, and possible treatment strategies for human pregnancies at risk. The results will have relevance not only for EV infections, but also for infections by other viruses which threaten the human fetus.

肠道病毒(EV)是一种普遍存在的病毒，它会引起 对人类怀孕有重大风险。宫内感染可能导致 产妇疾病；新生儿疾病，包括脑膜脑炎， 心肌炎、肝炎和/或败血症；早产；胎儿 心肌炎和死亡；胎儿肝和肾上腺坏死和死亡；以及 先天性心血管畸形，胃肠畸形， 泌尿生殖系统和中枢神经系统。这些疾病的发病机制 人们对妊娠期感染知之甚少。拟议的项目将 探讨经胎盘EV感染的意义 胎盘用于保护胎儿免受感染的机制， 以及可能导致这些机制崩溃的因素。其影响 宫内感染EV对胎盘和胎儿的影响 并将描述影响胎儿结局的因素。 预防胎儿发病率的免疫学和药理学策略 将对与EV感染相关的疾病进行评估。 研究将在妊娠EV的小鼠模型中进行 利用自然EV感染的小鼠--泰勒氏小鼠 脑脊髓炎病毒(TMEV)。在这个模型中，胎盘和胎儿 早期孕妇接种TMEV后易感染 妊娠，而在妊娠晚期，胎盘被感染，但胎儿 从未被感染过。将在此模型中进行实验，以 确定这种胎盘屏障对病毒的进化是否 传输基于解剖和结构特征(检查 含有病毒的胎盘和含有惰性颗粒的胎盘 电子显微镜下的相似大小)，免疫现象(研究 感染胎盘的免疫组织化学和病毒感染的研究 体外培养的不同胎盘细胞群)和/或 胎盘细胞对病毒感染的易感性(使用胎盘 细胞培养技术)。形态研究、组织培养、原位 杂交和免疫组织化学将被用来阐明 TMEV感染对胎盘及胎儿的影响宿主和病毒 可能影响经胎盘感染率和/或胎盘感染率的因素 胎儿感染的结局将通过不同的母体进行评估 生理参数(年龄、身体压力、营养、子宫胎盘 血液流动)，并在这个模型中研究病毒突变。最后， 预防胎盘移位的免疫学和药理学策略 感染和/或预防胎儿感染的不良后果 在这个动物模型上进行了测试。这些研究将对保护 人类胎盘的作用机制，EVS对人类的影响 胎儿，以及对有风险的人类怀孕的可能的治疗策略。 这些结果不仅与EV感染有关，而且与 被威胁人类胎儿的其他病毒感染。