Nonhuman Primate Model to Assess Fetal Zika Virus Infection Complications

用于评估胎儿寨卡病毒感染并发症的非人类灵长类动物模型

• 批准号: 9262695
• 负责人: THADDEUS G GOLOS
• 金额: $ 22.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-04 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262695
• 关键词: Address; Affect; Amniotic Fluid; Area; Brain; Brazil; Bypass; Central American; Clinical; Congenital Abnormality; Country; Data; Defect; Dental; Development; Developmental Delay Disorders; Disease; Disease Outbreaks; Dose; Epidemiology; Etiology; Event; Experimental Animal Model; Fetal Development; Fetal Growth; Fetal Monitoring; Fetal Tissues; Fetus; First Pregnancy Trimester; Flavivirus Infections; Future; Goals; Growth; Growth and Development function; Histopathology; Human; Immunologics; Incidence; Infant; Infection; Macaca; Magnetic Resonance Imaging; Maps; Maternal-Fetal Transmission; Microcephaly; Minority; Modeling; Nervous system structure; Neuraxis; Neurologic; Outcome; Pathogenesis; Pathologic; Phenotype; Placenta; Pregnancy; Pregnancy Outcome; Process; Role; South American; Third Pregnancy Trimester; Titrations; Tropism; Ultrasonography; Validation; Viral; Virus; Virus Diseases; Zika Virus; adverse outcome; body system; craniofacial; fetal; fetal infection; insight; malformation; neurobehavioral; neurodevelopment; neuropathology; nonhuman primate; pathogen; prevent; skeletal; tissue tropism; transmission process; virology

ABSTRACT Infection with Zika virus (ZIKV) has been very recently implicated in an increase in the incidence of microcephaly in Brazil, however the actual impact of the presence of ZIKV in the fetus on neural development, including microcephaly, is poorly understood. While ongoing epidemiology will likely strengthen pregnancy outcome associations with ZIKV and possibly reveal the dynamics of maternal infection that influence pregnancy outcome, direct interrogation of factors that drive fetal outcomes will not be possible in human clinical settings. The nonhuman primate offers an outstanding opportunity to gain insight into these pathophysiological processes in fetal infection with ZIKV. Our overall goal is to establish a fetal ZIKV infection model by amniotic fluid delivery to study its effects on fetal growth and CNS development. By directly infecting the fetus with the virus, we will bypass the potential bottleneck of transplacental transmission, which may be a rate-limiting step in studying fetal outcomes, since in most circumstances the placenta prevents, and does not facilitate, transmission of pathogens to the fetus. Thus, direct introduction of the virus into the amniotic fluid will be a more efficient approach for defining pathological events directly in the fetal compartment. We propose two Specific Aims to address our goal. Specific Aim 1. To determine whether the macaque fetus is sensitive to ZIKV infection, we will bypass the potential placental barrier and directly inoculate the amniotic fluid, monitoring fetal well-being and development with virological, immunological, ultrasound and MRI analyses. Specific Aim 2. To define the ontogeny and tissue tropism of fetal infection, we will sequentially collect fetal tissues following intrauterine infection to map viral tropism and fetal pathogenesis, focusing on comprehensive fetal histopathology. The development and validation of this model will establish a rapid screen for the impact of fetal infection on the central nervous system as well as overall fetal development. Direct validation of the nonhuman primate model to study fetal neuropathology, growth restriction, and possibly fetal demise will be an incredibly valuable step forward in building the nonhuman primate platform to obtain a mechanistic understanding of the severe neuropathology seen in the outbreak in Brazil. A predictable fetal outcome will allow selective titration of the dose-related neurological impact as judged by histopathology, so that the model will also reveal more subtle neurobehavioral insults than microcephaly, likely to be an extreme outcome.

抽象的 寨卡病毒（ZIKV）的感染最近与 但是，巴西的小头畸形，但是ZIKV在胎儿中存在对神经发育的实际影响， 包括小头畸形，知之甚少。而持续的流行病学可能会增强怀孕 结局与ZIKV的关联，并可能揭示了影响的孕产妇感染的动态 怀孕结果，直接询问人类无法驱动胎儿结局的因素 临床环境。非人类灵长类动物提供了一个很棒的机会来洞悉这些 ZIKV胎儿感染中的病理生理过程。我们的总体目标是建立胎儿ZIKV感染 通过羊水递送模型，研究其对胎儿生长和中枢神经系统发育的影响。通过直接感染 带有病毒的胎儿，我们将绕过移植传播的潜在瓶颈，这可能是 研究胎儿结局的限制步骤，因为在大多数情况下，胎盘可防止，并且不会 促进病原体向胎儿传播。因此，将病毒直接引入羊水将 成为直接在胎儿室中定义病理事件的更有效的方法。我们提出了两个 具体目的是解决我们的目标。 特定目的1。确定猕猴胎儿是否对ZIKV感染敏感，我们将绕过 潜在的胎盘屏障并直接接种羊水，监测胎儿健康和发育 通过病毒学，免疫学，超声和MRI分析。 特定目的2。为了定义胎儿感染的本体发育和组织的偏向主义，我们将依次收集胎儿 宫内感染后的组织，以绘制病毒性疗法和胎儿发病机理，重点是综合 胎儿组织病理学。 该模型的开发和验证将建立一个快速筛选胎儿感染对 中枢神经系统以及整体胎儿发育。直接验证非人类灵长类动物 研究胎儿神经病理学，生长限制和可能的胎儿灭亡的模型将是一种非常有价值的 向前迈进，建立非人类灵长类动物平台，以获得对严重的机械理解 在巴西爆发中看到的神经病理学。可预测的胎儿结果将允许选择性滴定 组织病理学判断，与剂量有关的神经系统影响，该模型还将揭示更微妙的 神经行为侮辱比小头畸形，可能是一个极端的结果。