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

Changlin Wang,Lu Wang,Keliang Wang,Ziqi Wang,Wanhai Xu,Lingling Shan,Mei Xue,Li Feng,Fang Fu,Pinghuang Liu,Shuxin Qu

doi:10.3389/fmicb.2020.01180

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.

Highlights

Porcine epidemic diarrhea virus (PEDV), a member of the Alphacoronavirus family, is an enteropathogenic coronavirus with economic importance (Madson et al, 2014; Wang et al, 2014; Zhang and Yoo, 2016)
Compared with a mock uninfected control, PEDV did not increase the expression of IFNλ transcripts as observed until 12 hpi, and gradually induced IFN-λ expression, indicating that PEDV infection elicits type III IFN expression at the late stage of infection instead of the early stage of infection in the Vero E6 cells (Figure 1A), which was consistent with the results in porcine enteroids (Li et al, 2019)
To verify whether PEDV escape the IFN-λ antiviral signaling through miR-30c-5p mediated modification of suppressor of cytokine signaling protein 1 (SOCS1) expression, we explored the effect of miR-30c-5p on PEDV infection and IFN-λ antiviral signaling

Summary

Introduction

Porcine epidemic diarrhea virus (PEDV), a member of the Alphacoronavirus family, is an enteropathogenic coronavirus with economic importance (Madson et al, 2014; Wang et al, 2014; Zhang and Yoo, 2016). PEDV infection in newborn piglets is characterized by vomiting, anorexia, watery diarrhea, and dehydration (Song and Park, 2012). The virus primarily infects small intestinal epithelial cells in vivo and causes high morbidity and mortality in piglets (Li et al, 2012). Interferons (IFNs) are the key components of innate immunity in response to viral infection (Zhang et al, 2018). Among three types of IFNs (types I, II, and III), type III IFN-lambda (IFN-λ) primarily acts on mucosal surfaces, including epithelial surfaces of the liver, respiratory, and gastrointestinal systems, and plays vital roles in controlling viral infection within mucosal surfaces (Mordstein et al, 2010; Pott et al, 2011; Lazear et al, 2015). We and other groups previously demonstrated that porcine IFN-λdisplays powerful antiviral activity against PEDV infection in both Vero E6 cells and porcine intestinal epithelia (Li et al, 2017, 2019).

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Conclusion