Maternal ZIKV infection as an environmental risk factor for mental illness

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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.