Role of microglia in neural infection

摘要 寨卡病毒（ZIKV）感染与先天性ZIKV综合征（CZS）有关，包括各种大脑异常 和小头畸形我们最近的研究表明，卵黄囊（YS）衍生的小胶质细胞（初级免疫细胞， 脑）和Peli 1（E3泛素连接酶）参与ZIKV感染及其相关的CZS。但 目前尚不清楚Peli 1是否以及如何促进YS-小胶质细胞介导的ZIKV向大脑的传播， 病毒感染影响小胶质细胞的正常功能，以及这种影响如何影响神经分化。 基于初步数据，我们假设Peli 1通过以下途径在胎儿脑ZIKV感染中起关键作用： 促进YS-小胶质细胞介导的ZIKV向胎脑中的传播并通过改变小胶质细胞功能来影响 神经分化这一假设将通过两个具体目标进行检验：1）确定Peli 1如何促进 胎儿脑中YS-小胶质细胞的ZIKV感染和从小胶质细胞到神经干细胞的病毒传播;和2） 以确定Peli 1如何介导小胶质细胞活化并改变ZIKV感染后的神经分化。这 综合研究在体内动物模型和体外动物模型中采用生物化学和遗传操作。 小鼠和人细胞平台。将通过分子、细胞和神经解剖学评价结局 分析。了解小胶质细胞在ZIKV相关脑中作用的分子机制 感染可能导致鉴定用于预防和治疗ZIKV和其他病毒介导的疾病的新靶标。 先天性神经感染

ABSTRACT Zika virus (ZIKV) infection is associated with congenital ZIKV syndrome (CZS), including various brain anomalies and microcephaly. Our recent studies suggested that yolk sac (YS)-derived microglia (primary immune cells in the brain) and Peli1 (an E3 ubiquitin ligase) are involved in ZIKV infection and its associated CZS. However, it is unknown whether and how Peli1 contributes to the YS-microglia-mediated spread of ZIKV into brain, whether viral infection affects the normal function of microglia, and how such effects influence neural differentiation. Based on preliminary data, we hypothesize that Peli1 plays a critical role in fetal brain ZIKV infection via promoting YS-microglia-mediated ZIKV dissemination into fetal brain and via altering microglial function to affect neural differentiation. This hypothesis will be tested by two specific aims: 1) to determine how Peli1 promotes ZIKV infection of YS-microglia and virus dissemination from microglia to neural stem cells in fetal brains; and 2) to determine how Peli1 mediates microglial activation and alters neural differentiation after ZIKV infection. This integrative study employs biochemical and genetic manipulations in both in vivo animal models and in vitro mouse and human cell platforms. The outcomes will be evaluated by molecular, cellular, and neuroanatomical analyses. Understanding the molecular mechanisms underlying the role of microglia in ZIKV-related brain infection may lead to identification of new targets for prevention and treatment of ZIKV and other virus-mediated congenital neural infections.