Of Mice and Children: Zika Virus Infection Leads to Variable Defects in Multiple Neurological Functions and Behaviors

Abstract

Zika virus (ZIKV) has evolved into a global health threat because of its causal link to congenital Zika syndrome. Different case reports indicate that ZIKV infection of pregnant women may cause a spectrum of abnormalities in children. Here we evaluated a large cohort of children with perinatal exposure to ZIKV and identified a spectrum of neurodevelopmental abnormalities in the group. In addition, we show that infection of the mouse neonatal brain by a contemporary ZIKV strain instead of an Asian ancestral strain can cause microcephaly and various abnormal neurological functions. These include defects in social interaction and depression, impaired learning and memory, in addition to severe motor defects, which are present in adult mice as well as in our cohort of children. Importantly, although mouse brains infected later after birth do not have apparent abnormal brain structure, those mice still show significant impairments of visual cortical functions, circuit organization and experience-dependent plasticity. Thus, our study suggests that special attention should be paid to all children born to ZIKV infected mothers for screening of abnormal behaviors and sensory function during childhood. Funding Statement: This work was supported by the Strategic Priority Research Program and Innovation Program of the Chinese Academy of Sciences (No. XDB32020100, QYZDJ-SSW-SMC007), the National Natural Science Foundation of China (NSFC) (31730108, 31430037, U170220023, 81772176, 31670883, 91542201, 81590765, and 31500145), Beijing Municipal Science & Technology Commission (Z181100001518001), the Interdisciplinary Research Funds of Beijing Normal University, the CAMS Initiative Innovative Medicine (No. 2016-I2M-1-005), Major Project for Significant New Drugs Innovation and Development (2015ZX09102023), NIH R01 AI140718, AI069120, AI056154 and AI078389 502 grants, MOST (China, 2016YFD0500304). C.L. was supported by the PUMC Youth Fund (No. 3332016125). Declaration of Interests: The authors confirm that there are no known conflicts of interest associated with this publication. Ethics Approval Statement: The experimental procedures on mice were performed under biosafety level 2 (BSL-2) at Beijing Institute of Microbiology and Epidemiology with Institutional Biosafety Committee approval. The mouse care and experimentation were approved by the Animal Care and Use Committees of the Institutional Animal Care and Use Committee at Institute of Genetics and Developmental Biology (IGDB), Chinese Academy of Sciences, Beijing Institute of Microbiology and Epidemiology and the State Key Laboratory of Cognitive Neuroscience & Learning at Beijing Normal University. For the infant cohort, the study protocol was approved by the institutional review boards at Fundacao Oswaldo Cruz (Fiocruz) and the University of California, Los Angeles. All mothers provided written informed consent for themselves and for their children.