Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly

Accumulating evidence support a causal link between Zika virus (ZIKV) infection during pregnancy and congenital microcephaly. However, the mechanism of ZIKV- associated microcephaly remains unclear. We combined analyses of ZIKV-infected human foetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show here that ZIKV triggers ER stress and UPR in the cerebral cortex of infected postmortem human foetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we also show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex whereupon sustained ER stress leads to apoptotosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of UPR counteracts these pathophysiological mechanisms, and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV as they were not observed upon intraplacental injection of other related flaviviruses in mice.