寨卡病毒非结构蛋白NS2A介导神经突触粘附分子ELFN1与ELFN2降解的机制及其在寨卡病毒致病中的作用

基于CRISPR筛选，我们发现突触粘附分子ELFN2是参与ZIKV复制活动的关键宿主因子。初步实验表明，ZIKV感染的神经祖细胞（hNPCs）和SF268细胞中ELFN2显著下调。进一步研究发现，ZIKV非结构蛋白NS2A特异地介导ELFN2及ELFN1的降解。ZIKV感染孕妇出生的小脑症婴儿表现出运动障碍、癫痫等症状。Elfn1及Elfn2敲除小鼠均表现出惊厥、多动等。由此，我们首次提出ZIKV NS2A降解ELFN1、ELFN2影响神经突触功能，可能参与了ZIKV导致的发育缺陷和癫痫等。本项目拟进一步采用基因敲除、AAV转导等方法，旨在回答ZIKV NS2A介导的ELFN1及ELFN2降解如何影响神经突触功能这一关键科学问题。本项目将揭示NS2A介导ELFN1及ELFN2降解的分子机制及其在ZIKV致病中的作用，为理解ZIKV的致病机制及寻找潜在的干预方法提供科学依据。

ELFN2, a postsynaptic cell adhesion molecule, was identified as an important host factor of Zika virus (ZIKV) by genome-wide CRISPR screening. Our preliminary results showed that ELFN2 expression was significantly decreased in both human neural progenitor cells and SF268 cells. Further experiments showed that ZIKV encoded non-structural protein NS2A specifically mediated ELFN2 degradation. Motor abnormalities and epilepsy in infants and children with Zika-related microcephaly are observed. Loss of Elfn1 or Elfn2 in mice also causes seizures and hyperactivity. We hypothesize for the first time that ZIKA NS2A mediated ELFN1 and ELFN2 degradation may damage synapse formation and play a role in ZIKV caused neurological disorders. In this project, we will answer the key question how ZIKV NS2A mediated ELFN1 and ELFN2 degradation destroys synapse formation with different approaches, including gene knockout and AAV transduction. We will decipher the underlying mechanisms of NS2A mediating ELFN1 and ELFN2 degradation and investigate its roles in ZIKV caused neurological disorders, which would shed light on the neuropathogenesis of ZIKV and development of potential interventions.