Journal of Immunology：病毒學國家重點實驗室在EV71誘導的免疫及炎症應答機制方面取得新進展

導 讀

腸道病毒71型（Enterovirus 71，EV71）是導致手足口病（hand foot and mouth disease，HFMD）的主要病原體之一，目前對與microRNA在EV71引起炎症反應、免疫應答的作用還知之甚少。2018年5月18日，國際學術期刊Journal of Immunology在線發表了病毒學國家重點實驗室朱應教授、劉實副教授團隊的最新研究成果，論文題為MicroRNA-302 Cluster Downregulates Enterovirus 71-Induced InnateImmune Response by Targeting KPNA2《MicroRNA-302家族通過KPNA2調控EV71誘導的免疫反應》。研究揭示了microRNA-302（miR-302）家族成員在EV71誘導的免疫及炎症反應中的作用及相關機制,為EV71的治療提供了新的思路。

Fig .miR-302家族通過KPNA2調控EV71誘導細胞因子表達的示意圖

研究背景

腸道病毒71型是導致手足口病（hand foot and mouth disease，HFMD）的主要病原體之一，目前對與microRNA在EV71引起炎症反應、免疫應答的作用還知之甚少。EV71感染可以誘導細胞因子和趨化因子水平的明顯升高,導致局部或全身炎症和嚴重併發症。

研究團隊前期研究工作發現，microRNA 302家族（簡稱miR-302家族）通過NIK調控流感病毒誘導的干擾素-β（IFN-β）的表達和分泌（FEBSLett 2015;589:4112-4118）（IF:3.623），並發現miR-302a通過IRF5調控流感病毒誘導的細胞因子風暴（J Biol Chem 2017;292:21291-21303）（IF:4.125）。然而,對miR-302家族在EV71-調節的促炎反應中的作用知之甚少。本研究則在前期工作基礎上，進一步闡明了miR-302家族在EV71誘導的免疫及炎症反應中的關鍵作用。

結果速覽

研究的主要結果和發現如下：

（1）miR-302家族成員均能抑制EV71誘導誘導炎症因子的表達（圖1）。

Fig. 1.The miR-302 clusterinhibits proinflammatory cytokine production in response to EV71 infection.

（2）進一步機制研究表明，miR-302家族成員通過結合核轉運蛋白（KPNA2）的3』-UTR抑制該蛋白的表達，進而抑制了NF-κB、JNK1/JNK2、p38等轉錄因子的入核。

Fig2 .Model of the biological effect of the miR-302/KPNA2 axis

結 語

本研究闡明了miR-302家族在EV71誘導的免疫及炎症反應中的關鍵作用,為EV71的治療提供了新的思路。該工作得到了國家自然科學基金和國家重點基礎研究發展計劃(973)等基金的支持。博士彭南方為論文第一作者，劉實副教授為通訊作者。

ABSTRACT

Enterovirus 71 (EV71) induces significantly elevated levels of cytokines and chemokines, leading to local orsystemic inflammation and severe complications. As shown in our previous study, microRNA (miR) 302c regulates influenza A virus–induced IFN expression by targeting NF-κB-inducing kinase. However, little is known about the role of the miR-302 cluster in EV71-mediated proinflammatory responses. In this study, we found that the miR-302 cluster controls EV71-induced cytokine expression. Further studies demonstrated that karyopherin α2 (KPNA2) is a direct target of the miR-302 cluster. Interestingly, we also found that EV71 infection upregulates KPNA2 expression by downregulating miR-302 cluster expression. Upon investigating the mechanisms behind this event, we found that KPNA2 intracellularly associates with JNK1/JNK2 and p38, leading to translocation of those transcription factors from the cytosol into the nucleus. In EV71-infected patients, miR-302 cluster expression was downregulated and KPNA2 expression was upregulated compared with controls, and their expression levels were closely correlated. Taken together, our work establishes a link between the miR-302/KPNA2 axis and EV71-induced cytokine expression and represents a promising target for future antiviral therapy.

參考文獻：

1.Nanfang Peng, Xuecheng Yang, Chengliang Zhu, Li Zhou,Haisheng Yu, Mengqi Li, Yong Lin, Xueyu Wang, Qian Li, Yinglong She, Jun Wang,Qian Zhao, Mengji Lu, Ying Zhu and Shi Liu. MicroRNA-302 Cluster Down regulates Enterovirus 71–Induced Innate Immune Response by Targeting KPNA2. J Immunol May18, 2018, ji1701692;

DOI:https://doi.org/10.4049/jimmunol.1701692

http://www.jimmunol.org/content/early/2018/05/17/jimmunol.1701692

2.病毒學國家重點實驗室朱應、劉實團隊在EV71誘導的免疫及炎症應答機制方面取得新進展

http://klv.whu.edu.cn/index.php/View/273.html?from=singlemessage&isappinstalled=0

本期編輯：Annabella

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