The Coronavirus PEDV Evades Type III Interferon Response Through the miR-30c-5p/SOCS1 Axis

Abstract

Porcine epidemic diarrhea virus (PEDV) is an economically important pathogen that has evolved several mechanisms to evade type I IFN responses. Type III interferon (IFN-λ), an innate cytokine that primarily targets the mucosal epithelia, is critical in fighting mucosal infection in the host and has been reported to potently inhibit PEDV infection in vitro. However, how PEDV escapes IFN-λ antiviral response remains unclear. In this study, we found that PEDV infection induced significant IFN-λ expression in type I IFN-defective Vero E6 cells, but virus-induced endogenous IFN-λ did not reduce PEDV titers. Moreover, we demonstrated that PEDV escaped IFN-λ responses by substantially upregulating the suppressor of cytokine signaling protein 1 (SOCS1) expression, which impaired the induction of IFN-stimulated genes (ISGs) and dampened the IFN-λ antiviral response and facilitated PEDV replication in Vero E6 cells. We further showed that PEDV infection increased SOCS1 expression by decreasing host miR-30c-5p expression. MiR-30c-5p suppressed SOCS1 expression through targeting the 3 ′ untranslated region (UTR) of SOCS1. The inhibition of IFN-λ elicited ISGs expression by SOCS1 was specifically rescued by overexpression of miR-30c-5p. Collectively, our findings identify a new strategy by PEDV to escape IFN-λ-mediated antiviral immune responses by engaging the SOCS1/miR-30c axis, thus improving our understanding of its pathogenesis.

SARS-CoV-2 genomic surveillance identifies naturally occurring truncation of ORF7a that limits immune suppression

“…The ORF7a D115 variant shows limited replication in HEK293T-hACE2, as well as in Vero E6, the latter of which does not express type I IFN genes (Emeny and Morgan, 1979;Osada et al, 2014). Although type I IFN genes are deleted in Vero E6 cells, the type III IFNs are intact and are activated upon infection with RNA viruses, which results in ISG upregulation (Stoltz and Klingströ m, 2010;Wang et al, 2020). ISGs exert anti-viral activities that combat the infection (Schoggins, 2019).…”

ORF3a Protein of Severe Acute Respiratory Syndrome Coronavirus 2 Inhibits Interferon-Activated Janus Kinase/Signal Transducer and Activator of Transcription Signaling via Elevating Suppressor of Cytokine Signaling 1

“…Zika virus promotes the expression of SOCS1 to modulate viral replication ( Seong et al, 2020 ). Coronavirus transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV) increase SOCS1 expression to dampen the type I or type III IFN antiviral response and facilitate viral replication ( Ma et al, 2018 ; Wang et al, 2020 ). SOCS1 contains a kinase inhibitory region (KIR), which is crucial for its viral virulence effect.…”

“…Virus upregulate SOCS1 levels through distinct mechanisms. For example, TGEV, PEDV, respiratory syncytial virus (RSV), and rhinoviruses increase SOCS1 expression by manipulating microRNA levels (such as miR-30a-5p, miR-155, and miR-122) ( Zheng et al, 2015 ; Ma et al, 2018 ; Wang et al, 2020 ; Collison et al, 2021 ). Murine gammaherpesvirus-68 (MHV-68), porcine reproductive and respiratory syndrome virus (PRRSV), and IAV elevate SOCS1 expression via different signaling pathways (such as NF-κB signaling, p38/AP-1, and JNK/AP-1 signaling, RIG-I/MAVS/IFNAR1 axis) ( Pothlichet et al, 2008 ; Shen et al, 2018 ; Luo et al, 2020 ).…”

SARS-CoV-2 genomic surveillance identifies naturally occurring truncations of ORF7a that limit immune suppression

“…The ORF7a Δ115 variant impairs viral replication in HEK 293T-hACE2 as well as in Vero E6, the latter of which do not express type I IFN genes (Emeny and Morgan, 1979; Osada et al, 2014). While type I IFN genes are deleted in Vero E6 cells, the type III IFNs are intact and are activated upon infection with RNA viruses, which results in ISG upregulation (Stoltz and Klingstrom, 2010; Wang et al, 2020). Taken together, these data suggest that the growth defect of the ORF7a Δ115 strain in Vero E6 cells might result from a type III IFN-dependent response that the virus fails to suppress.…”