Maternal ZIKV infection as an environmental risk factor for mental illness

摘要 大量证据表明，病毒感染后的母体免疫激活是一种 精神疾病的环境风险因素。母体免疫信号，包括炎性细胞因子，可以 在其他发育正常的情况下接触胎儿组织并永久改变大脑功能和行为 后代。事实上，母体感染多种病毒与婴儿的发病有关。 子代的情绪障碍和/或精神病，这些联系在患有 先前存在的精神疾病的遗传风险因素。寨卡病毒(Zika Virus，ZIKV)是近年来出现的新病原体 被确认为早期感染后严重神经发育综合征的病原体 怀孕的各个阶段。然而，孕妇在妊娠晚期感染寨卡病毒的影响尚未得到证实。 母亲感染寨卡病毒对儿童心理健康的潜在影响也没有得到充分解决 对发育正常的后代进行了调查。在这里，我们建议使用一种晚期的小鼠模型 母体ZIKV感染以表征母胎界面的神经免疫信号。为了研究 这一信号的后果，我们还将评估晚期母体ZIKV感染对 作为精神病学基础的运动、认知和社会领域的行为异常的发展 精神障碍(如自闭症、精神分裂症)。最后，我们将使用已建立的人类22q11.2小鼠模型 缺失综合征，一种常见的精神疾病遗传易感因素，以检查交互作用的影响 具有行为异常遗传风险的母体寨卡病毒感染。这些研究将确立 晚期寨卡病毒感染的潜在病理行为后果，为未来的研究和 监测受这种全球新出现的病原体影响的个人的努力。

Abstract A large body of evidence has identified maternal immune activation following viral infection as an environmental risk factor for mental illness. Maternal immune signals, including inflammatory cytokines, can access fetal tissues and permanently alter brain function and behavior in otherwise developmentally normal offspring. Indeed, maternal infection with a number of viruses has been associated with the development of mood disorders and/or psychosis in offspring, and these associations are intensified in offspring with preexisting genetic risk factors for mental illness. Zika virus (ZIKV) is an emerging pathogen recently identified as an etiologic agent of severe neurodevelopmental syndromes following infection during the early stages of gestation. However, the impacts of maternal ZIKV infection during late gestation have not been adequately addressed, nor has the potential impact of maternal ZIKV infection on the mental health of developmentally normal offspring been investigated. Here, we propose to use a murine model of late-term maternal ZIKV infection to characterize neuroimmune signaling at the maternal-fetal interface. To study the consequences of this signaling, we will also assess the impact of late-term maternal ZIKV infection on the development of behavioral abnormalities in motor, cognitive and social domains that underlie psychiatric disorders (e.g., autism, schizophrenia). Finally, we will use an established mouse model of human 22q11.2 deletion syndrome, a common genetic susceptibility factor for mental illness, to examine interaction effects of maternal ZIKV infection with genetic risk for behavioral abnormalities. These studies will establish the potential pathologic behavioral consequences of late-term ZIKV infection, informing future study and monitoring efforts for individuals affected by this globally emerging pathogen.