Neural progenitor cell pyroptosis contributes to Zika virus-induced brain atrophy and represents a therapeutic target

作者：Zhenjian He, Shu An, Jiahui Chen, Shuqing Zhang, Chahui Tan, Jianchen Yu, Hengming Ye, Yun Wu, Jie Yuan, Jueheng Wu, Xun Zhu, Mengfeng Li · 发表于：Proceedings of the National Academy of Sciences · 年份：2020 · DOI：10.1073/pnas.2007773117 · 被引用次数：85 · 研究领域：Mosquito-borne diseases and control、Inflammasome and immune disorders、Viral Infections and Vectors

Mounting evidence has associated Zika virus (ZIKV) infection with congenital malformations, including microcephaly, which raises global alarm. Nonetheless, mechanisms by which ZIKV disrupts neurogenesis and causes microcephaly are far from being understood. In this study, we discovered direct effects of ZIKV on neural progenitor cell development by inducing caspase-1- and gasdermin D (GSDMD)-mediated pyroptotic cell death, linking ZIKV infection with the development of microcephaly. Importantly, caspase-1 depletion or its inhibitor VX-765 treatment reduced ZIKV-induced inflammatory responses and pyroptosis, and substantially attenuated neuropathology and brain atrophy in vivo. Collectively, our data identify caspase-1- and GSDMD-mediated pyroptosis in neural progenitor cells as a previously unrecognized mechanism for ZIKV-related pathological effects during neural development, and also provide treatment options for ZIKV-associated diseases.