Neural progenitor cell pyroptosis contributes to Zika virus-induced brain atrophy and represents a therapeutic target
Neural progenitor cell pyroptosis contributes to Zika virus-induced brain atrophy and represents a therapeutic target
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神经祖细胞焦亡导致寨卡病毒引起的脑萎缩，是一个治疗靶点
DOI：
10.1073/pnas.2007773117
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发表时间：
2020-09-22
影响因子：
11.1
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
He, Zhenjian;An, Shu;Li, Mengfeng
寨卡病毒（ZIKV）是寨卡病毒病的一种常见病毒。然而，ZIKV破坏神经发生并导致小头畸形的机制仍然知之甚少。在这里，我们首次报道了ZIKV暴露引起神经祖细胞焦亡，其通过体内和体外caspase-1和gasdermin D的活化介导，这将ZIKV与小头畸形的发展和进展联系起来。与这一观点一致，半胱天冬酶-1缺失或用半胱天冬酶-1抑制剂VX-765治疗减少了ZIKV诱导的炎症反应和焦亡，并有力地减弱了神经病变和脑萎缩。总之，我们的研究结果为ZIKV相关的神经发病机制及其潜在的临床适用治疗方案提供了独特的视角。越来越多的证据表明，寨卡病毒（ZIKV）感染与包括小头畸形在内的先天性畸形有关，这引起了全球的警觉。尽管如此，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，我们发现ZIKV通过诱导半胱天冬酶-1和Gasdermin D（GSDMD）介导的细胞死亡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耗竭或其抑制剂VX-765治疗减少了ZIKV诱导的炎症反应和焦亡，并在体内显著减弱了神经病理学和脑萎缩。总的来说，我们的数据将神经祖细胞中的caspase-1和GSDMD介导的焦亡确定为神经发育期间ZIKV相关病理效应的先前未被认识的机制，并且还为ZIKV相关疾病提供了治疗选择。
Significance Zika virus (ZIKV) has been identified as a cause of microcephaly. However, the mechanisms by which ZIKV disrupts neurogenesis and causes microcephaly remains poorly understood. Here, we first report that ZIKV exposure causes neural progenitor cell pyroptosis, mediated by activation of caspase-1 and gasdermin D in vivo as well as in vitro, which links ZIKV to the development and progression of microcephaly. Consistent with this notion, caspase-1 deletion or treatment with caspase-1 inhibitor VX-765 reduced ZIKV-induced inflammatory responses and pyroptosis, and robustly attenuated neuropathy and brain atrophy. Taken together, our findings provide unique perspectives on ZIKV-associated neuropathogenesis and potentially clinically applicable options for its treatment. 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.