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 最近，寨卡病毒（ZIKV）感染被认为与该病发病率的增加有关 巴西的小头畸形，然而寨卡病毒在胎儿中的存在对神经发育的实际影响， 包括小头畸形，人们对此知之甚少。虽然持续的流行病学可能会加强怀孕 结果与 ZIKV 的关联，并可能揭示影响母体感染的动态 妊娠结局，直接询问影响胎儿结局的因素在人类中是不可能的 临床环境。非人类灵长类动物提供了一个绝佳的机会来深入了解这些 ZIKV 胎儿感染的病理生理过程。我们的总体目标是确定胎儿 ZIKV 感染 通过羊水输送模型来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 如果胎儿携带病毒，我们将绕过经胎盘传播的潜在瓶颈，这可能是一个 研究胎儿结局的限速步骤，因为在大多数情况下，胎盘会阻止并且不会 促进病原体向胎儿的传播。因此，将病毒直接引入羊水中将 是直接在胎儿室中定义病理事件的更有效方法。我们建议两个 具体目标是为了实现我们的目标。 具体目的 1. 为了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，监测胎儿的健康和发育 病毒学、免疫学、超声和 MRI 分析。 具体目标 2. 为了明确胎儿感染的个体发育和组织向性，我们将依次收集胎儿 宫内感染后的组织，以绘制病毒趋向性和胎儿发病机制，重点是全面 胎儿组织病理学。 该模型的开发和验证将建立快速筛查胎儿感染对胎儿的影响 中枢神经系统以及胎儿的整体发育。非人类灵长类动物的直接验证 研究胎儿神经病理学、生长受限以及可能的胎儿死亡的模型将非常有价值 在建立非人类灵长类动物平台方面向前迈出一步，以获得对严重疾病的机制理解 巴西疫情中出现的神经病理学变化。可预测的胎儿结局将允许选择性滴定 通过组织病理学判断剂量相关的神经系统影响，因此模型也会揭示更微妙的 神经行为损伤比小头畸形更可能是一种极端的结果。