Neurodevelopment after postnatal Zika virus infection in infant macaques

项目总结/摘要 密集的研究集中在产前寨卡病毒（ZIKV）感染的神经学影响上;然而， 出生后感染在生命早期的后果尚未得到充分研究。在子宫内暴露于ZIKV但出生的婴儿 没有小头畸形的人可能会患上出生后的小头畸形、神经功能障碍和神经发育缺陷。 这突出了ZIKV在出生后造成持续损害的潜力。这种损害可能与 在生命的头2年，大脑的指数成熟，特别是在颞叶， 前额叶和顶叶区域对情感、社会和执行功能很重要，包括学习、注意力、 记忆和记忆。我们的小组以前曾报道，出生后ZIKV感染导致大脑异常， 出生后感染的幼年恒河猴（RM）的初步研究中的结构、功能和行为。这里我们 建议扩大我们先前的试点研究的范围和持续时间，并生成有关以下影响的新数据： 出生后ZIKV感染对发育中的大脑的影响。 本申请的目的是为出生后ZIKV感染带来新的机制见解，以解决ZIKV感染。 关于结果和宿主-病毒相互作用的现有知识差距。我们将使用产后ZIKV-RM 模型来询问ZIKV感染在出生后大脑发育的不同阶段对神经行为的影响- 从单个细胞到整个动物的方法。这种产后ZIKV暴露模型允许 我们可以生成关于ZIKV和/或对感染的免疫反应导致以下机制的关键数据： 细胞变化，最终导致边缘结构和行为缺陷的出生后发育异常， 后来的生活。我们假设1）ZIKV和/或对感染的免疫应答不成比例地影响了ZIKV的表达。 出生后发育的大脑中的边缘结构; 2）这些边缘结构中的细胞变化导致异常的 神经发育和异常行为;和3）在后- 纳塔尔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 ZIKV感染不同脑发育阶段的婴儿RM后的异常行为和认知; 2)确定婴儿出生后ZIKV感染后大脑结构和功能的发育轨迹 在大脑发育的不同阶段的RM;和3）定义神经发育途径和细胞类型 出生后ZIKV感染的影响这项工作将包括在出生后1个月或6个月时感染ZIKV的RM婴儿。 年龄（相当于4个月和24个月大的人）以及年龄和饲养匹配的和病毒模拟物对照， 在他们生命的前两年，将进行一系列详细的评估，包括经过验证的soci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 细胞和大量细胞转录组学。我们的研究结果可能对生活在以下地区的儿童具有重要的公共卫生意义： ZIKV流行/流行地区以及前往这些地区的旅行者。

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.