JVI：哈獸研發現冠狀病毒TGEV通過逃逸天然免疫應答的新機制

導 讀

近日，哈爾濱獸醫研究所馮力研究員領銜的豬消化道傳染病創新團隊在豬傳染性胃腸炎病毒（TGEV)逃逸干擾素抗病毒效應方面取得新進展，研究闡明了TGEV逃逸干擾素抗病毒效應的新機制，為研究冠狀病毒感染調控天然免疫應答和開發新的抗病毒藥物提供了重要理論基礎和思路。相關研究成果以「CoronavirusTGEV Evades the Type I Interferon Response through IRE1α-Mediated Manipulationof the miR-30a-5p/SOCS1/3 Axis」為題，發表在國際病毒學專業期刊Journalof Virology上(DOI:10.1128/JVI.00728-18.)。

研究背景

豬傳染性胃腸炎病毒（TransmissibleGastroenteritis Virus，TGEV）屬於α冠狀病毒屬，是一種有囊膜的單股正鏈RNA病毒，能引起豬嘔吐、脫水和嚴重腹瀉等癥狀，2周齡內的仔豬死亡率可達90%-100%。TGEV是引起規模化養豬場新生仔豬腹瀉性死亡的重要原因，給我國養豬業造成了嚴重的經濟損失。不同於豬流行性腹瀉病毒（PEDV），TGEV感染能夠誘導產生大量內源性干擾素，但是病毒卻依然能夠高效複製，其具體的分子機制並不清楚。

內質網作為蛋白質摺疊和翻譯後修飾的重要場所，是病毒複製和成熟的必需細胞器。病毒感染後，細胞內合成大量的病毒蛋白，從而增加內質網的負擔，進而增加未摺疊蛋白和錯誤摺疊蛋白的堆積。因此，病毒感染後通常會誘發內質網應激（ER stress）。

今年7月17日，馮力研究員研究團隊在Journalof Virology上發文，闡明了內質網應激抑制TGEV複製的分子機制，本研究是在前期內質網應激調控TGEV感染的研究基礎上又取得的新進展。

結果速覽

本研究中，研究者發現，TGEV感染能夠激活IRE1α介導的未摺疊蛋白反應，促進TGEV複製。進一步研究發現，IRE1α通過調控microRNA中miR-30a-5p的表達來促進病毒複製，下調錶達的miR-30a-5p通過靶向細胞因子信號抑制蛋白SOCS1和SOCS3,導致SOCS1和SOCS3在TGEV感染後期大量表達；上調錶達的SOCS1和SOCS3抑制了IFN的抗病毒效應，從而促進TGEV複製。該研究表明冠狀病毒通過激活內質網應激IRE1α信號通路調控miR-30a-5p表達來逃逸干擾素抗病毒應答，表明IRE1α在調控宿主天然免疫中發揮重要作用。

結 語

本研究發現冠狀病毒TGEV通過激活內質網應激IRE1α通路逃逸天然免疫應答的新機制，闡明了TGEV逃逸干擾素抗病毒效應的新機制，為研究冠狀病毒感染調控天然免疫應答和開發新的抗病毒藥物提供了重要理論基礎和思路。

研究受國家重點研發計劃（2016YFD0500100和2017YFD0502200）和黑龍江省留學歸國人員科學基金（LC2015013）的資助。碩士研究生馬艷龍和博士研究生王長林為論文共同第一作者，馮力研究員和劉平黃研究員為共同通訊作者。

ABSTRACT

Inhost innate immunity, type I interferons (IFN-I) are major antiviral molecules, and coronaviruses have evolved diverse strategies to counter the IFN-I responseduring infection. Transmissible gastroenteritis virus (TGEV), a member of the alphacoronavirus family, induces endoplasmic reticulum (ER) stress and significant IFN-I production after infection. However, how TGEV evades the IFN-I antiviral response despite the marked induction of endogenous IFN-I hasremained unclear. IRE1α, a highly conserved ER stress sensor with both kinase and RNase activities, is involved in the IFN response. In this study, IRE1α facilitated TGEV replication via downmodulating the host miR-30a-5p abundance. miR-30a-5p normally enhances IFN-I antiviral activity by directly targeting the negative regulators of JAK-STAT, SOCS1 and SOCS3. Furthermore, TGEV infection increased SOCS1 and SOCS3 expression, which dampened IFN-I antiviral response and facilitated TGEV replication. Importantly, compared with mock infection,TGEV infection in vivo resulted in decreased miR-30a-5p levels and significantly elevated SOCS1 and SOCS3 expression in piglet ileum. Taken together, our data reveal a new strategy used by TGEV to escape the IFN-Iresponse by engaging the IRE1α-miR-30a-5p-SOCS1/3 axis, thus improving our understanding of how TGEV escapes host innate immune defenses.

【IMPORTANCE】

TypeI interferons (IFN-I) play essential roles in restricting viral infections. Coronavirus infection induces ER stress and the interferon response, which reflects different adaptive cellular processes. An understanding of how coronavirus-elicited ER stress is actively involved in viral replication and manipulates the host IFN-I response has remained elusive. Here, TGEV inhibited host miR-30a-5p via the ER stress sensor IRE1α, which led to the increased expression of negative regulators of JAK-STAT signaling cascades, namely, SOCS1 and SOCS3.Increased SOCS1 or SOCS3 expression impaired the IFN-I antiviral response, promoting TGEV replication. These findings enhance our understanding of the strategies used by coronaviruses to antagonize IFN-I innate immunity via IRE1α-mediated manipulation of the miR-30a-5p-SOCS axis, highlighting the crucial role of IRE1α in innate antiviral resistance and the potential of IRE1α as a novel target against coronavirus infection.

參考文獻：

1.YanlongMa, Changlin Wang, Mei Xue, Fang Fu, Xin Zhang, Liang Li, Lingdan Yin, WanhaiXu, Li Feng, Pinghuang Liu. Coronavirus TGEV Evades the Type I InterferonResponse through IRE1α-Mediated Manipulation of the miR-30a-5p/SOCS1/3 Axis. DOI:10.1128/JVI.00728-18.

https://jvi.asm.org/content/early/2018/08/31/JVI.00728-18

2. Mei Xue, Fang Fu, Yanlong Ma, Xin Zhang, Liang Li, LiFeng, Pinghuang Liu. The PERK Arm of the Unfolded Protein ResponseNegatively Regulates Transmissible Gastroenteritis Virus Replication bySuppressing Protein Translation and Promoting Type I IFN Production. DOI:10.1128/JVI.00431-18.

https://jvi.asm.org/content/early/2018/05/10/JVI.00431-18

3. 哈獸研官網：我所發現冠狀病毒TGEV通過激活內質網應激IRE1α通路逃逸天然免疫應答的新機制。

http://www.hvri.ac.cn/html/zonghexinwen/keyanjinzhan/2018/0912/1840.html

本期編輯：Annabella

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