Maturation of the glymphatic system confers innate resistance of the brain to Zika virus infection

The maturation of the glymphatic system initiates fluid dynamics in the central nervous system (CNS). Here, we demonstrate that the initiating glymphatic function results in a steep reduction in the susceptibility of the CNS to Zika virus (ZIKV) infection. In mice, ZIKV injection before glymphatic system maturation leads to widespread infection, vascular deformation, and disruption of Aqp4 ⁺ astrocytic networks. After the glymphatic system formation, the same challenge fails to cause disease or persistent infection. Pharmacological inhibition of vasopressin receptor 1a, which reduces perivascular fluid dynamics, reopens the window of susceptibility to ZIKV-related disease. These findings reveal the glymphatic system as an innate protective barrier that limits viral spread in the brain parenchyma and suggest a possible explanation for why late-gestation human fetuses and newborns are less susceptible to ZIKV. Moreover, these data indicate that children with ZIKV-caused malformations can have continuous brain inflammation due to a defective glymphatic system.