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 In our published and unpublished studies, we have found that maternal infec- tion with ZIKV in the first but not the third trimester results in inflammation tissue damage in the visual system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) 感染与一系列出生的发病率增加有关 巴西的缺陷。孕妇的自然感染和恒河猴的实验感染 已经证明，与感染相比，怀孕与延长病毒血症有关 未怀孕的个体。在我们已发表和未发表的研究中，我们发现孕产妇感染 在妊娠早期而非妊娠晚期使用 ZIKV 会导致视觉炎症组织损伤 系统（脉络膜、视网膜、视神经），并且在一个病例中，胎儿出现严重发育畸形 眼睛。另外，无论孕期感染，均存在垂直传播给胎儿的情况。 很常见。因此，在 ZIKV 和 MOS 存在的地区，胎儿可能面临更大的风险。 基多病媒的流行程度超出了目前的认识。 严格检查母体病毒血症和胎儿生长发育情况，综合评估 新生儿感音神经特征和病毒负荷的评估在人类临床中是不可能的 设置。非人类灵长类动物提供了深入了解病理生理学的绝佳机会 ZIKV 胎儿感染的钙过程。我们的总体假设是母体病毒血症持续时间 >28 提供了明确的证据，证明垂直传播与胎儿感染风险升高有关 因此，胎儿神经发育的影响。为了将母体病毒血症与胎儿 ZIKV 感染联系起来，我们赞成 提出两个具体目标。 具体目标 1. 确定母体 ZIKV 病毒血症对子宫内胎儿发育的影响，如 通过胎儿生长、垂直传播和组织损伤进行评估。 具体目标 2. 明确寨卡病毒宫内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生长，并将母体病毒血症与母体病毒血症联系起来。 免疫反应对胎儿的影响，利用超声波来监测胎儿的发育。我们将 评估新生儿的畸形，并评估视觉、听觉和行为方面的功能缺陷 容量。病毒分布和组织病理学将在尸检时确定。发展历程 利用该模型研究母体感染对新生儿感音神经损伤的影响将具有重要价值。 项目中在建立非人类灵长类动物平台以研究与登革热病毒相互作用方面取得了进展 2，并在项目 3 中测试用抗体治疗对这些胎儿效应的治疗中断。