Neurodevelopment after postnatal Zika virus infection in infant macaques

项目摘要/摘要 密集的研究集中在产前感染寨卡病毒(ZIKV)对神经系统的影响；然而， 对生命早期出生后感染的后果研究不足。在宫内暴露于ZIKV但出生时的婴儿 如果没有小头畸形，可能会发展为出生后小头畸形、神经功能障碍和神经发育障碍。 正常情况下，突显了ZIKV在出生后造成持续损害的潜力。这一损害很可能与 大脑的指数成熟发生在生命的头两年，特别是在时间上， 前额叶和顶叶区域对情绪、社会和执行功能非常重要，包括学习。 记忆和记忆。我们小组此前曾报道，出生后ZIKV感染会导致大脑异常 婴儿猕猴(RMS)出生后感染的结构、功能和行为的初步研究。在这里，我们 建议延长我们之前的试点研究的范围和持续时间，并生成关于以下影响的新数据 出生后ZIKV感染对发育中的大脑。 此应用程序的目标是为出生后ZIKV感染带来新的机械性见解，以解决 关于结果和宿主-病毒相互作用的现有知识差距。我们将使用我们出生后的ZIKV-RM ZIKV感染对出生后大脑发育不同阶段神经行为影响的模型- 通过从单个细胞到整个动物的方法。这种出生后接触ZIKV的模型允许 美国将生成有关寨卡病毒和/或对感染的免疫反应导致 细胞变化，最终导致出生后边缘结构和行为障碍的异常发育。 在以后的生活中会发生一些事情。我们假设1)ZIKV和/或对感染的免疫反应对 出生后大脑发育中的边缘结构；2)这些边缘结构中的细胞变化导致异常 神经发育和异常行为；3)ZIKV在后一段时间可能处于易受攻击期 出生时大脑发育。我们将在这些特定的目标中测试我们的假设：1)确定光谱 不同脑发育阶段婴幼儿RMS感染ZIKV后的行为和认知异常； 2)确定婴儿出生后感染寨卡病毒后脑结构和功能的发育轨迹 大脑发育不同阶段的RMS；3)定义神经发育途径和细胞类型 受出生后寨卡病毒感染的影响。这项工作将包括在出生后1或6个月感染ZIKV的RM婴儿 年龄(相当于4个月和24个月大的人)以及年龄和养育相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，包括对SOI- 情绪化行为和认知、结构和功能脑成像、脑组织学、体视学和单项 细胞和批量细胞转录学。我们的结果可能对生活在中国的儿童有重要的公共卫生影响 寨卡病毒--地方病/疫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.