Neurodevelopment after postnatal Zika virus infection in infant macaques

幼年猕猴出生后感染寨卡病毒后的神经发育

基本信息

批准号：
10322427
负责人：
Ann M Chahroudi
金额：
$ 71.04万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10322427
关键词：
2 year old Address Adult Affect Age Age-Months Amygdaloid structure Animals Area Attention Basal Ganglia Behavior Behavioral Birth Blood Brain Brain imaging Cells Child Childhood Cognition Cognitive Communicable Diseases Congenital Abnormality Data Defect Development Disease Disease Outbreaks Emotional Epidemic Event Exposure to Financial compensation Flavivirus Future Goals Growth Hippocampus (Brain)Histologic Histology Human Immune response Infant Infection Knowledge Lead Learning Life Longitudinal Studies Macaca Macaca mulatta Measures Memory Microcephaly Modeling Motor Neurodevelopmental Deficit Neurodevelopmental Disorder Neurodevelopmental Problem Neuroglia Neurologic Dysfunctions Neurologic Effect Neurons Neurosciences Normalcy Outcome Parietal Pathway interactions Pilot Projects Pregnancy Public Health Recovery of Function Reporting Research Research Personnel Rest Series Short-Term Memory Social Functioning Social Interaction Structure Symptoms Testing Time Viral Virus Visual Work ZIKV infection Zika Virus acute stress base behavioral response brain abnormalities cell type congenital zika syndrome early childhood emotional functioning executive function functional MRI scan gray matter in utero in vivo infant infection insight longitudinal analysis memory recognition neurobehavioral neurodevelopment neuroimaging nonhuman primate novel postnatal postnatal development postnatal period prenatal prenatal exposure skills transcriptomics virology virus host interaction white matter

项目摘要

PROJECT SUMMARY / ABSTRACT Intense research has focused on the neurologic effects of prenatal Zika virus (ZIKV) infection; however, the consequences of postnatal infection early in life are understudied. Infants exposed to ZIKV in utero but born without microcephaly can develop postnatal microcephaly, neurologic dysfunction, and neurodevelopmental ab- normalities, highlighting the potential of ZIKV to cause ongoing damage after birth. This damage is likely related to the exponential maturation of the brain that occurs during the first 2 years of life, particularly in temporal, prefrontal and parietal regions important for emotional, social and executive functions, including learning, atten- tion and memory. Our group has previously reported that postnatal ZIKV infection causes abnormalities in brain structure, function, and behavior in a pilot study of infant rhesus macaques (RMs) infected postnatally. Here, we propose to extend the scope and duration our prior pilot study and generate novel data regarding the impact of postnatal ZIKV infection on the developing brain. The Objective of this application is to bring new mechanistic insights into postnatal ZIKV infection to address the existing knowledge gap regarding outcomes and host-virus interactions. We will use our postnatal ZIKV-RM model to interrogate the neurobehavioral impact of ZIKV infection at different stages of postnatal brain develop- ment, with approaches that span from single cells to whole animal. This model of postnatal ZIKV exposure allows us to generate key data on the mechanisms by which ZIKV and/or the immune response to infection leads to cellular changes that ultimately result in aberrant postnatal development of limbic structures and behavioral def- icits later in life. We hypothesize that 1) ZIKV and/or the immune response to infection disproportionately affects limbic structures in the postnatally developing brain; 2) cellular changes in these limbic structures lead to aberrant neurodevelopment and abnormal behaviors; and 3) there may be a period of vulnerability to ZIKV during post- natal brain development. We will test our hypotheses in these Specific Aims: 1) Determine the spectrum of abnormal behavior and cognition following ZIKV infection of infant RMs at different stages of brain development; 2) Identify developmental trajectories of brain structure and function following postnatal ZIKV infection of infant RMs at different stages of brain development; and 3) Define the neurodevelopmental pathways and cell types impacted by postnatal ZIKV infection. This work will include RM infants infected with ZIKV at 1 or 6 months of age (equivalent to 4 and 24 month old humans) as well as age- and rearing-matched and viral mimic controls, that over their first 2 years of life will undergo a series of detailed assessments including validated tests of soci- oemotional behavior and cognition, structural and functional brain imaging, brain histology, stereology and single cell and bulk cell transcriptomics. Our results may have important public health implications for children living in ZIKV-endemic/epidemic areas as well as for travelers to these regions.

项目概要/摘要大量研究集中在产前寨卡病毒 (ZIKV) 感染对神经系统的影响；然而，生命早期产后感染的后果尚未得到充分研究。婴儿在子宫内暴露于 ZIKV 但出生时没有小头畸形的婴儿也会出现出生后小头畸形、神经功能障碍和神经发育缺陷。正常情况，突显寨卡病毒在出生后造成持续损害的潜力。这种损害可能与生命最初两年内大脑呈指数级成熟，特别是在时间上，前额叶和顶叶区域对情感、社交和执行功能很重要，包括学习、注意力化和记忆。我们课题组此前曾报道，产后寨卡病毒感染导致大脑异常出生后感染的幼年恒河猴（RM）的结构、功能和行为的初步研究。在这里，我们建议扩大我们之前试点研究的范围和持续时间，并生成有关影响的新数据出生后 ZIKV 感染对发育中的大脑的影响。该应用的目的是为产后 ZIKV 感染带来新的机制见解，以解决关于结果和宿主-病毒相互作用的现有知识差距。我们将使用我们的产后 ZIKV-RM 研究 ZIKV 感染对出生后大脑发育不同阶段神经行为影响的模型方法涵盖从单细胞到整个动物。这种产后 ZIKV 暴露模型允许我们生成有关 ZIKV 和/或感染免疫反应导致的机制的关键数据最终导致出生后边缘结构发育异常和行为缺陷的细胞变化会在以后的生活中发作。我们假设 1) ZIKV 和/或对感染的免疫反应不成比例地影响出生后大脑发育中的边缘结构； 2）这些边缘结构的细胞变化导致异常神经发育和异常行为； 3) 后期可能存在一段时期的 ZIKV 易受攻击性出生时的大脑发育。我们将在这些具体目标中测试我们的假设：1）确定范围大脑发育不同阶段的婴儿 RM 感染 ZIKV 后行为和认知异常； 2）确定婴儿出生后ZIKV感染后大脑结构和功能的发育轨迹大脑发育不同阶段的 RM； 3) 定义神经发育途径和细胞类型受产后 ZIKV 感染的影响。这项工作将包括在 1 个月或 6 个月大时感染 ZIKV 的 RM 婴儿。年龄（相当于 4 个月和 24 个月大的人类）以及年龄和饲养匹配的病毒模拟对照，在他们生命的头两年里，他们将接受一系列详细的评估，包括经过验证的社会测试情绪行为和认知、结构和功能脑成像、脑组织学、体视学和单一细胞和大细胞转录组学。我们的结果可能对生活在以下地区的儿童产生重要的公共卫生影响 ZIKV 流行/流行地区以及前往这些地区的旅行者。