Coronavirus TGEV Evades the Type I Interferon Response through IRE1α-Mediated Manipulation of the miR-30a-5p/SOCS1/3 Axis.
Ma Y, Wang C, Xue M, Fu F, Zhang X, Li L, Yin L, Xu W, Feng L, Liu P.
J Virol. 2018 Sep 5. pii: JVI.00728-18. doi: 10.1128/JVI.00728-18

Abstract
In host innate immunity, type I interferons (IFN-I) are major antiviral molecules, and coronaviruses have evolved diverse strategies to counter the IFN-I response during 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 has remained 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 vivoresulted 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-I response by engaging the IRE1α-miR-30a-5p-SOCS1/3 axis, thus improving our understanding of how TGEV escapes host innate immune defenses.Importance: Type I 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.