School of Public Health, Sun Yat-Sen University, 510080 Guangzhou, China.
Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, 510080 Guangzhou, China.
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23869-23878. doi: 10.1073/pnas.2007773117. Epub 2020 Sep 9.
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.
越来越多的证据表明寨卡病毒（ZIKV）感染与先天性畸形有关，包括小头畸形，这引起了全球的警惕。然而，ZIKV 破坏神经发生并导致小头畸形的机制还远未被理解。在这项研究中，我们通过诱导半胱天冬酶-1 和 gasdermin D（GSDMD）介导的细胞焦亡，发现了 ZIKV 对神经祖细胞发育的直接影响，将 ZIKV 感染与小头畸形的发展联系起来。重要的是，半胱天冬酶-1 的耗竭或其抑制剂 VX-765 的治疗减少了 ZIKV 诱导的炎症反应和细胞焦亡，并在体内显著减轻了神经病理学和脑萎缩。总之，我们的数据表明，神经祖细胞中的半胱天冬酶-1 和 GSDMD 介导的细胞焦亡是 ZIKV 相关神经发育过程中病理效应的一个以前未被认识的机制，并为 ZIKV 相关疾病提供了治疗选择。
