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.
Inositol-requiring
enzyme 1 α (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
microRNA (miR) miR-30a-5p abundance. miR-30a-5p normally enhances IFN-I
antiviral activity by directly targeting the negative regulators of Janus family
kinase (JAK)-signal transducer and activator of transcription (STAT), the
suppressor of cytokine signaling protein 1 (SOCS1), and SOCS3. Furthermore, TGEV
infection increased SOCS1 and SOCS3 expression, which dampened the 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 the 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.