Project 1: Impact of sustained ZIKV viremia in pregnancy

项目 1：妊娠期持续 ZIKV 病毒血症的影响

• 批准号: 10220702
• 负责人: THADDEUS G GOLOS
• 金额: $ 41.67万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220702
• 关键词: Animal Model; Antibody Therapy; Area; Auditory; Autopsy; Behavioral; Biological Markers; Blood Circulation; Brazil; Case Study; Characteristics; Choroid; Clinical; Cognitive; Collaborations; Congenital Abnormality; Defect; Development; Evaluation; Exhibits; Eye; Fetal Development; Fetal Growth; Fetal Monitoring; Fetus; First Pregnancy Trimester; Functional disorder; Growth and Development function; Hearing; Histopathology; Human; Image; Immune response; Incidence; Individual; Infant; Infection; Inflammation; Injury; Interruption; Intervention; Link; Macaca; Macaca mulatta; Measures; Motor; Neonatal; Newborn Infant; Observational Study; Occupational Therapist; Ocular Pathology; Ophthalmologist; Optic Nerve; Outcome; Pathogenicity; Physical Examination; Physiology; Plasma; Pregnancy; Pregnant Women; Prevalence; Process; Public Health; Publishing; Registries; Reporting; Retina; Rhesus; Risk; Sensory; Severities; Study models; System; Third Pregnancy Trimester; Tissues; Ultrasonography; Vertical Disease Transmission; Viral; Viral Load result; Viremia; Virus Shedding; Visual; Visual system structure; ZIKA; ZIKV infection; Zika Virus; congenital zika syndrome; cross reactivity; fetal; fetal infection; in utero; infection risk; insight; malformation; model development; neonatal outcome; neonate; nonhuman primate; postnatal; protective effect; therapeutic evaluation; unethical; vector mosquito; viral RNA; viral transmission

Project 1 - Project Summary/Abstract Infection with Zika virus (ZIKV) has been associated with an increased incidence of a spectrum of birth defects in Brazil. Natural infection in pregnant women, and experimental infection in rhesus macaques has demonstrated that pregnancy is associated with prolonged viremia, in comparison with infection of nonpregnant individuals. In our published and unpublished studies, we have found that maternal infec- tion with ZIKV in the first but not the third trimester results in inflammation tissue damage in the visual system (choroid, retina, optic nerve), and in one case, severe developmental malformations of the fetal eye. In addition, regardless of the gestational stage of infection, there vertical transmission to the fetus was common. Thus, there may be a more significant risk to the fetus in areas where ZIKV and the mos- quito vector is endemic than is currently appreciated. Rigorous examination of maternal viremia and fetal growth and development, and comprehensive eval- uation of neonatal sensorineural characteristics and viral burden will not be possible in human clinical settings. The nonhuman primate offers an outstanding opportunity to gain insight into pathophysiologi- cal processes in fetal infection with ZIKV. Our overall hypothesis is that duration of maternal viremia >28 provides unequivocal evidence of vertical transmission is associated with elevated fetal risk for infection and thus, fetal neurodevelopmental impact. To link maternal viremia and fetal ZIKV infection, we pro- pose two Specific Aims. Specific Aim 1. To determine the impact of maternal ZIKV viremia on fetal development in utero, as assessed by fetal growth, vertical transmission, and tissue damage. Specific Aim 2. To define the impact of in utero ZIKV transmission on the incidence of birth defects. We will assess maternal viremia and fetal growth, and associate maternal viremia and the maternal immune response with the impact on the fetus, using ultrasound to monitor fetal development. We will evaluate neonates for malformations of, and assess functional deficits in visual, auditory, and behavioral capacity. Viral distribution and tissue histopathology will be determined at necropsy. The development of this model to study impact of maternal infection on neonatal sensorineural injury will be a valuable step forward in building the nonhuman primate platform for studying interactions with DENV in Project 2, and testing therapeutic interruption of these fetal effects with antibody treatments in Project 3.

项目1-项目摘要/摘要 寨卡病毒（ZIKV）的感染与出生频谱的发生率增加有关 巴西的缺陷。孕妇的自然感染和恒河猕猴的实验感染 与感染相比 未怀孕的个体。在我们发表和未发表的研究中，我们发现母亲的不传统 在第一个但未第三个孕期与ZIKV造成炎症组织损伤 系统（脉络膜，视网膜，视神经），在一种情况下，胎儿的严重发育畸形 眼睛。此外，无论感染的妊娠期如何 很常见。因此，在ZIKV和MOS- Quito矢量比目前所欣赏的地方是地方性的。 严格检查母体病毒血症以及胎儿的生长和发育，以及全面的评估 在人类临床中，新生儿感觉神经特征和病毒负担不可能 设置。非人类的灵长类动物提供了一个很棒的机会，可以深入了解病理生理学 ZIKV胎儿感染的CAL过程。我们的总体假设是孕产妇病毒血症的持续时间> 28 提供垂直传播的明确证据与感染的胎儿风险升高有关 因此，胎儿神经发育影响。为了将母体病毒血症和胎儿ZIKV感染联系起来，我们 构成两个具体目标。 具体目的1。确定母体ZIKV病毒血症对子宫内胎儿发育的影响 通过胎儿生长，垂直传播和组织损伤评估。 具体目的2。定义子宫zikv传播对出生缺陷发生率的影响。 我们将评估母体病毒血症和胎儿的生长，并使母体病毒血症和孕产妇关联 免疫反应对胎儿的影响，使用超声来监测胎儿的发育。我们将 评估新生儿的畸形，并评估视觉，听觉和行为的功能缺陷 容量。病毒分布和组织组织病理学将在尸检时确定。发展 该模型研究产妇感染对新生儿感觉神经性损伤的影响将是有价值的 向前迈进，构建非人类灵长类动物平台，用于研究与项目中的DENV互动 2，在项目3中使用抗体治疗测试这些胎儿作用的治疗中断。