Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Nsp4 Cleaves VISA to Impair Antiviral Responses Mediated by RIG-I-like Receptors.

Chen Huang,Yihao Liu,Yinping Du,Jun Tang,Qiong Zhang,Jishu Shi,Zhibin Yu,Wen-Hai Feng

doi:10.1038/srep28497

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most significant etiological agents in the swine industry worldwide. It has been reported that PRRSV infection can modulate host immune responses, and innate immune evasion is thought to play a vital role in PRRSV pathogenesis. In this study, we demonstrated that highly pathogenic PRRSV (HP-PRRSV) infection specifically down-regulated virus-induced signaling adaptor (VISA), a unique adaptor molecule that is essential for retinoic acid induced gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) signal transduction. Moreover, we verified that nsp4 inhibited IRF3 activation induced by signaling molecules, including RIG-I, MDA5, VISA, and TBK1, but not IRF3. Subsequently, we demonstrated that HP-PRRSV nsp4 down-regulated VISA and suppressed type I IFN induction. Importantly, VISA was cleaved by nsp4 and released from mitochondrial membrane, which interrupted the downstream signaling of VISA. However, catalytically inactive mutant of nsp4 abolished its ability to cleave VISA. Interestingly, nsp4 of typical PRRSV strain CH-1a had no effect on VISA. Taken together, these findings reveal a strategy evolved by HP-PRRSV to counteract anti-viral innate immune signaling, which complements the known PRRSV-mediated immune-evasion mechanisms.

Highlights

The type I IFN receptor (IFNAR) and initiate the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway, resulting in the expression of hundreds of IFN stimulated genes (ISGs)[13,14]
We showed that IFNβinduction and ISGs expression were inhibited by HP-Porcine reproductive and respiratory syndrome virus (PRRSV) through negatively regulating IRF3 signaling pathway in infected cells
We verified that HP-PRRSV inhibited the production of IFNαand IFNβin porcine alveolar macrophages (PAMs) by qPCR30

Summary

Introduction

The type I IFN receptor (IFNAR) and initiate the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway, resulting in the expression of hundreds of IFN stimulated genes (ISGs)[13,14]. Pp1a and pp1ab are processed into at least 16 nonstructural proteins: nsp1α, nsp1β, nsp[2,3,4,5,6], nsp2TF, nsp2N, nsp7α, nsp7βand nsp8-1220–23 In addition to their activities in viral replication processing, some of these proteins participate in modulating host immune responses. We demonstrated that HP-PRRSV and its protein nsp[4] antagonized type I IFN expression by cleaving NF-κB essential modulator (NEMO) to block NF-κB signaling pathways[30]. This involves the nsp[4] protein that down-regulates NF-κB, the precise role of PRRSV nsp[4] on evading IFN-I responses remains to be further defined. This discovery suggests that nsp[4] contributes to HP-PRRSV pathogenesis through the inhibition of VISA-dependent signaling pathway

Methods

Results

Conclusion