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Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus - PubMed

Review

Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus

Yan Sun et al. Viruses. 2012 Apr.

Abstract

Innate immunity is the first line of defense against viral infection, and in turn, viruses have evolved to evade host immune surveillance. As a result, viruses may persist in host and develop chronic infections. Type I interferons (IFN-α/β) are among the most potent antiviral cytokines triggered by viral infections. Porcine reproductive and respiratory syndrome (PRRS) is a disease of pigs that is characterized by negligible induction of type I IFNs and viral persistence for an extended period. For IFN production, RIG-I/MDA5 and JAK-STAT pathways are two major signaling pathways, and recent studies indicate that PRRS virus is armed to modulate type I IFN responses during infection. This review describes the viral strategies for modulation of type I IFN responses. At least three non-structural proteins (Nsp1, Nsp2, and Nsp11) and a structural protein (N nucleocapsid protein) have been identified and characterized to play roles in the IFN suppression and NF-κB pathways. Nsp's are early proteins while N is a late protein, suggesting that additional signaling pathways may be involved in addition to the IFN pathway. The understanding of molecular bases for virus-mediated modulation of host innate immune signaling will help us design new generation vaccines and control PRRS.

Keywords: JAK-STAT; MDA5; NF-κB; Nsp; PRRS; PRRSV; RIG-I; arterivirus; interferon; non-structural proteins; nucleocapsid.

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Figures

Figure 1
Figure 1

Signal pathways for type I IFN production and IFN stimulated gene expressions. Double-stranded RNA, single-stranded RNA, and CpG DNA are recognized by TLR3, TLR7/8, and TLR9, respectively, in the endosomes, which leads to the dimerization of receptors and recruitment of TRIF or MyD88. The stimulation results in the assembly of signaling complexes and initiation of signaling cascades leading to the phosphorylation and activation of IRF3/IRF7, NF-κB, and AP-1. Once activated, these transcription factors translocate to the nucleus, and together with CBP, induce the transcription of IFN-α and IFN-β. Activation of RIG-I/MDA5 by viral RNA may be inhibited by LGP2. Both RIG-I and MDA5 activates IPS-1 through the CARD domain. IPS-1 then induces signaling pathways resulting in the activation of IRF3, IRF7, and NF-κB through different adaptors and kinases. IPS-1 signaling also likely involves the MAP kinase cascade for activation of AP-1. The nuclear signal of IRF3/IRF7, NF-κB, and AP-1 is similar to that of TLR. Once IFN-α and IFN-β are secreted extracellularly outside the cell after production, they bind to IFN receptors on itself (autocrine) or neighbor cells (paracrine), the receptor associated JAK1 kinase is phosphorylated and activated to recruit STAT1 and STAT2 through their SH2 domain for phosphorylation. The phosphorylated STAT1 and STAT2 are detached from the IFN receptors and associated each other to form ISGF3 complexes along with IRF9. ISGF3 then undergoes nuclear translocation and binds to ISRE to induce the transcription of hundreds of ISGs. Five major kinds of ISGs are listed here; MxA, OAS–1/RNaseL, RIG-I/MDA5, ISG15, and PKR. For their modes of action, see the text. Grey circle indicates the lysine-48-linked ubiquitin chain which leads to the degradation of proteins. Yellow circle indicates phosphorylation.

Figure 2
Figure 2

The modulation of type I IFN production by PRRSV. PRRSV has been shown to reduce the expression of TLR3 and IRF7 in pDCs. While Nsp1 has the ability to degrade CBP in the nucleus, Nsp1α subunit inhibits the IκB phosphorylation in the cytoplasm. Nsp2 inhibits IFN production by blocking the ubiquitinylation of phosphorylated IκB and phosphorylation of IRF3 through the OTU domain. Nsp11 suppresses IFN-β production through degradation of IPS-1 mRNA. For the second wave of IFN signaling, PRRSV Nsp1β blocks the phosphorylation of STATs and inhibits the nuclear translocation of ISGF3 complex. Nsp1 interacts with PIAS. Since PIAS is a multi-functional protein, Nsp1 interaction may also modulate pathways other than the JAK-STAT pathway. PKR is redistributed during PRRSV infection. Nsp2 has the potential to deconjugate ISGylation. The GP5 protein induces apoptosis. Since Nsp1 is cotranslationally processed to Nsp1α and Nsp1β in PRRSV-infected cells, the uncleaved form of Nsp1 is unlikely to exist in virus-infected cells. It is unknown which subunit of Nsp1 interacts with PIAS and degrades CBP.

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