寨卡病毒会引起神经系统相关重症疾病，但机理尚不清楚。有研究报道其感染引发神经系统损伤及产生大量炎症因子，推测其可能导致神经系统炎症性细胞死亡，并介导神经系统相关重症疾病的发生。我们前期研究发现寨卡病毒感染神经细胞诱发细胞焦亡（Pyroptosis）。进一步研究发现该现象由寨卡病毒编码蛋白NS1和NS5诱导产生。此外，利用抑制剂抑制细胞焦亡能阻遏寨卡病毒诱导的神经炎症及损伤。由此，本项目将在分子、细胞和动物水平上系统性证明寨卡病毒诱发细胞焦亡，介导过度神经炎症及细胞死亡的发生；证明其机理为寨卡病毒编码蛋白NS1和NS5协同激活NLRP3炎症小体介导细胞焦亡。进一步证明利用Caspase-1及GSDMD抑制剂（VX-765和NSA）抑制细胞焦亡的发生，能阻遏寨卡病毒诱导的神经炎症及损伤。本研究致力于阐明寨卡病毒相关神经系统疾病的致病机理，并为应用细胞焦亡抑制剂治疗寨卡病毒病提供理论依据。

Zika virus can cause serious diseases related to nervous system, but the pathogenic mechanism remains unclear. Previous studies reported that Zika virus infection caused nervous system damage and produced a large number of proinflammatory cytokines. It is speculated that Zika virus may cause inflammatory cell death in nervous system, mediating the occurrence of severe diseases related to nervous system. Our previous studies found that Zika virus infection induced the occurrence of pyroptosis. Further studies have shown that this phenomenon is induced by Zika virus-encoded proteins NS1 and NS5. In addition, inhibition of pyroptosis can repress Zika virus-induced neuroinflammation and injury. Therefore, in the current project, on the one hand, we are aiming to systematically investigate that Zika virus induces pyroptosis mediating excessive neuroinflammation and neuronal cell death. On the other hand, we are aiming to demonstrate the molecular mechanism of Zika virus-induced pyroptosis by which Zika virus-encoded protein NS1 and NS5 activate NLRP3 inflammasome to mediate pyroptosis. Furthermore, we are aiming to demonstrate the inhibition of pyroptosis by caspase 1 and GSDMD inhibitors (VX-765 and NSA) can prevent the neuroinflammation and injury induced by Zika virus. Overall, the aim of this project is to elucidate the pathogenesis of Zika virus in the nervous system, and provide theoretical basis for the application of pyroptosis inhibitors in treatment of Zika virus- associated diseases.