Aberrant microglia activation promotes synaptic loss and neuronal dysfunction after recovery from ZIKV infection

Abstract

Zika virus (ZIKV) is a member of the Flaviviridae family, transmitted by Aedes mosquitoes and spreading globally from 2007 to 2016. ZIKV can be transmitted from pregnant woman to fetus and causes microcephaly and neuronal defects. Recent studies have shown that adults are also susceptible to neurological complications following ZIKV infection. Patients infected with ZIKV showed increased levels of proinflammatory cytokines compared to healthy individuals and neurological changes even after recovery. However, the detailed mechanism of how neuronal defects occurs after recovery from ZIKV infection has never been investigated in vivo. Here, we found that viral RNA loads were highest in mouse brain tissue 7 days after ZIKV infection and were equivalent to uninfected controls after 21 days, suggesting that mice recovered after 21 days of ZIKV infection. To explore the pathological mechanisms of neuronal defects after recovery from ZIKV infection, we performed RNA-sequencing in mouse cerebral cortex obtained 7 days and 21 days after ZIKV infection. RNA-seq results showed that genes related to neuroinflammatory response and microglial activation, which are signs of neurodegeneration, were significantly increased after 7 and 21 days of ZIKV infection. Histological analysis also revealed neuronal cell death and change in neurite morphology due to severe neuroinflammation 7 days and 21 days after infection. In addition, phospho-Tau levels associated with microglial activation and neurodegeneration diseases were remarkably increased in the mouse cerebral cortex. These results suggest that ZIKV infection induces neuronal dysfunction through aberrant microglia cell activation. These findings provide the fundamental knowledge needed to understand the molecular pathogenesis of ZIKV-induced brain abnormalities after ZIKV infection and after recovery.