中科院武漢病毒研究所研究發現寨卡病毒致神經損傷新機制

導 讀

Zika病毒（ZIKV）感染與胎兒和新生兒小頭畸形和一些嚴重的神經系統併發症密切相關，但其潛在的機制仍有待進一步闡明，近日中國科學院武漢病毒研究所羅敏華課題組在寨卡病毒致神經損傷機制的研究方面取得新進展，相關研究結果以「Proteomic Analysis of Zika Virus Infected Primary Human Fetal Neural Progenitors Suggests a Role for Doublecortin in the Pathological Consequences of Infection in the Cortex」為題在線發表於Frontiers in Micorbiology雜誌。

已有研究顯示ZIKV 可感染人類神經祖細胞 ( hNPCs ) 使細胞周 期 進 程 失 調 、抑 制 細 胞 生 長、 促進細胞死亡，進而抑制神經球和大腦類器官的生長，這表明通過ZIKV引起的神經病理學改變可能與NPC細胞命運密切相關。然而，ZIKV影響神經發生的分子機制仍有待闡明。

該研究通過對ZIKV感染人原代NPC進行蛋白質組學分析，發現細胞內影響NPC增殖、分化、遷移的重要標誌分子的蛋白水平都有所改變，其中作為NPC分化、遷移過程中的重要分子雙皮質素（DCX）在病毒感染NPC後，其蛋白質水平及mRNA水平。而在寨卡病毒感染胎鼠腦模型中，DCX的蛋白水平也有明顯下調，且伴隨著胎鼠體重、胎腦重和胎腦大小的異常及腦皮質結構的破壞。通過進一步篩查寨卡病毒蛋白，並使其NPC中逐一表達，結果發現NS4A和NS5與DCX蛋白水平和mRNA水平的下調存在相關性。這些數據說明寨卡病毒對DCX的調節是發生於感染之後，而病毒蛋白NS4A，NS5參與DCX的調控。

該研究工作揭示了寨卡病毒與NPC細胞命運及胎腦發育異常之間的聯繫，指出了關鍵分子DCX在皮層感染病理結果發揮的重要作用。同時，篩選到病毒蛋白NS4A，NS5下調關鍵分子DCX，進一步揭示了寨卡病毒影響胎腦發育的分子機制。後續將繼續確認是病毒蛋白與DCX 相互作用的機制。

中科院武漢病毒所神經病毒學科組博士後姜旋為第一作者，羅敏華研究員和廣州婦女兒童醫療中心唐亞平教授為共同通訊作者，該工作獲得國家自然科學基金、國家重點實驗室和廣州婦女兒童醫療中心的合作與支持。

Abstract

Zika virus (ZIKV) infection is associated with severe neurological defects in fetuses and newborns, such as microcephaly. However, the underlying mechanisms remain to be elucidated. In this study, proteomic analysis on ZIKV-infected primary human fetal neural progenitor cells (NPCs) revealed that virus infection altered levels of cellular proteins involved in NPC proliferation, differentiation and migration. The transcriptional levels of some of the altered targets were also confirmed by qRT-PCR. Among the altered proteins, doublecortin (DCX) plays an important role in NPC differentiation and migration. Results showed that ZIKV infection downregulated DCX, at both mRNA and protein levels, as early as 1 day post infection (1 dpi), and lasted throughout the virus replication cycle (4 days). The downregulation of DCX was also observed in a ZIKV-infected fetal mouse brain model, which displayed decreased body weight, brain size and weight, as well as defective cortex structure. By screening the ten viral proteins of ZIKV, we found that both the expression of NS4A and NS5 were correlated with the downregulation of both mRNA and protein levels of DCX in NPCs. These data suggest that DCX is modulated following infection of the brain by ZIKV. How these observed changes of DCX expression translate in the pathological consequences of ZIKV infection and if other cellular proteins are equally involved remains to be investigated.

本期編輯：rojjer 本文來源： 中國科學院武漢病毒研究所

喜歡這篇文章嗎？立刻分享出去讓更多人知道吧！