Interferon-Inducible Oligoadenylate Synthetase-Like Protein Acts as an Antiviral Effector against Classical Swine Fever Virus via the MDA5-Mediated Type I Interferon-Signaling Pathway.

Lian-Feng Li,Lingkai Zhang,Yuexiu Zhang,Yuzi Luo,Qian Yang,Jiahui Yu,Yuan Sun,Yongfeng Li,Hua-Ji Qiu,Jinghan Wang,Su Li,Michael S Diamond

doi:10.1128/jvi.01514-16

Abstract

ABSTRACTClassical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), which poses a serious threat to the global pig industry. Interferons (IFNs) and IFN-stimulated genes (ISGs) play a key role in host antiviral defense. We have previously screened the porcine 2′-5′-oligoadenylate synthetase-like protein (pOASL) as a potential anti-CSFV ISG using a reporter CSFV. This study aimed to clarify the underlying antiviral mechanism of pOASL against CSFV. We confirmed that CSFV replication was significantly suppressed in lentivirus-delivered, pOASL-overexpressing PK-15 cells, whereas silencing the expression of endogenous pOASL by small interfering RNAs markedly enhanced CSFV growth. In addition, the transcriptional level of pOASL was upregulated both in vitro and in vivo upon CSFV infection. Interestingly, the anti-CSFV effects of pOASL are independent of the canonical RNase L pathway but depend on the activation of the type I IFN response. Glutathione S-transferase pulldown and coimmunoprecipitation assays revealed that pOASL interacts with MDA5, a double-stranded RNA sensor, and further enhances MDA5-mediated type I IFN signaling. Moreover, we showed that pOASL exerts anti-CSFV effects in an MDA5-dependent manner. In conclusion, pOASL suppresses CSFV replication via the MDA5-mediated type I IFN-signaling pathway.IMPORTANCE The host innate immune response plays an important role in mounting the initial resistance to viral infection. Here, we identify the porcine 2′-5′-oligoadenylate synthetase-like protein (pOASL) as an interferon (IFN)-stimulated gene (ISG) against classical swine fever virus (CSFV). We demonstrate that the anti-CSFV effects of pOASL depend on the activation of type I IFN response. In addition, we show that pOASL, as an MDA5-interacting protein, is a coactivator of MDA5-mediated IFN induction to exert anti-CSFV actions. This work will be beneficial to the development of novel anti-CSFV strategies by targeting pOASL.

Highlights

Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), which poses a serious threat to the global pig industry
We have demonstrated that overexpression of porcine OASL (pOASL) inhibits rCSFV-firefly luciferase (Fluc) replication [19]
The results showed that the inhibition of CSFV at an multiplicities of infection (MOI) of 1 by pOASL reached a peak at 12 hpi and decreased thereafter (Fig. 1E)

Summary

Introduction

Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), which poses a serious threat to the global pig industry. We have previously screened the porcine 2=-5=-oligoadenylate synthetase-like protein (pOASL) as a potential anti-CSFV ISG using a reporter CSFV. The anti-CSFV effects of pOASL are independent of the canonical RNase L pathway but depend on the activation of the type I IFN response. We identify the porcine 2=5=-oligoadenylate synthetase-like protein (pOASL) as an interferon (IFN)-stimulated gene (ISG) against classical swine fever virus (CSFV). Initiation of innate immunity in response to viral infections relies on sensing of viral nucleic acids by retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) in the cytoplasm [7]. Upon binding to viral RNAs, RIG-I or melanoma differentiation-associated gene 5 (MDA5) initiates a signaling cascade to induce the production of type I interferons (IFNs) [8, 9]. The porcine OAS family consists of OAS1, OAS2, and OASL [13]

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