Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1 Modulates Host Innate Immune Response by Antagonizing IRF3 Activation

Nebraska Center for Virology and School of Veterinary and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska 68583, USA.
Journal of Virology (Impact Factor: 4.44). 11/2009; 84(3):1574-84. DOI: 10.1128/JVI.01326-09
Source: PubMed


Porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine leads to a serious disease characterized by a delayed and defective adaptive immune response. It is hypothesized that a suboptimal innate immune response is responsible for the disease pathogenesis. In the study presented here we tested this hypothesis and identified several nonstructural proteins (NSPs) with innate immune evasion properties encoded by the PRRS viral genome. Four of the total ten PRRSV NSPs tested were found to have strong to moderate inhibitory effects on beta interferon (IFN-beta) promoter activation. The strongest inhibitory effect was exhibited by NSP1 followed by, NSP2, NSP11, and NSP4. We focused on NSP1alpha and NSP1beta (self-cleavage products of NSP1 during virus infection) and NSP11, three NSPs with strong inhibitory activity. All of three proteins, when expressed stably in cell lines, strongly inhibited double-stranded RNA (dsRNA) signaling pathways. NSP1beta was found to inhibit both IFN regulatory factor 3 (IRF3)- and NF-kappaB-dependent gene induction by dsRNA and Sendai virus. Mechanistically, the dsRNA-induced phosphorylation and nuclear translocation of IRF3 were strongly inhibited by NSP1beta. Moreover, when tested in a porcine myelomonocytic cell line, NSP1beta inhibited Sendai virus-mediated activation of porcine IFN-beta promoter activity. We propose that this NSP1beta-mediated subversion of the host innate immune response plays an important role in PRRSV pathogenesis.

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    • "et al., 2010; Chen et al., 2010) and TNF-to evade the host innate immune response. The Nsp11 of PRRSV also participates in the inhibition of TNF-production and antagonizes type I interferons (Beura et al., 2010), although it does not acts as an great extent as Nsp1. Recent studies have revealed that Nsp11 may degrade IPS-1 mRNA by its endoribonulease activity to inhibit interferons production (Sun et al., 2012). "
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    ABSTRACT: Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized to be one of the most important pathogens severely affecting global swine industry. An increasingly number of studies has paid much attention to the diverse roles of its nonstructural proteins (Nsps) in regulating the innate immune response of host upon PRRSV infection. In the present study, we first discovered that highly pathogenic PRRSV (HP-PRRSV) and low pathogenic PRRSV (LP-PRRSV) infection exhibited a differential TNF-α expression in pulmonary alveolar macrophages (PAMs), showing that HP-PRRSV infection induces lower TNF-α production at protein level in PAMs, compared with LP-PRRSV. Next, HP-PRRSV was confirmed to strongly suppress TNF-α production by inhibiting ERK signaling pathway. Finally, both Nsp1β and Nsp11 were demonstrated to be responsible for the inhibitory effect on TNF-α production induced by HP-PRRSV and the differential TNF-α production in PAMs. These findings contribute to the understanding of the pathogenesis of the Chinese HP-PRRSV. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · Virus Research
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    • "The process is independent of the PCP activity of nsp1 [30]. Beura et al. showed that nsp1β interfered with IRF3 signaling pathway by inhibiting dsRNA-induced IRF3 phosphorylation and nuclear translocation [31]. The discrepancy is possibly because an nsp1β that is 27-residue longer than its authentic form was used in Beura's study. "
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    ABSTRACT: Interferons (IFNs) are important components in innate immunity involved in the first line of defense to protect host against viral infection. Porcine reproductive and respiratory syndrome virus (PRRSV) leads to severe economic losses for swine industry since being first identified in early 1990s. PRRSV interplays with host IFN production and IFN-activated signaling, which may contribute to the delayed onset and low level of neutralizing antibodies, as well as weak cell-mediated immune response in infected pigs. PRRSV encodes several proteins that act as antagonists for the IFN signaling. In this review, we summarized the various strategies used by PRRSV to antagonize IFN production and thwart IFN-activated antiviral signaling, as well as the variable interference with IFN-mediated immune response by different PRRSV strains. Thorough understanding of the interaction between PRRSV and host innate immune response will facilitate elucidation of PRRSV pathogenesis and development of a better strategy to control PRRS.
    Full-text · Article · Jul 2014 · BioMed Research International
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    • "Our results are not completely consistent with the previous report (Beura et al., 2010), in which NSP3, and NSP5 showed no inhibitory effect. The obvious disagreement might be due to the differences of PRRSV strains or method, in which performed CAT assays to evaluate IFN-␤ activation by co-transfected with IRF3 in HeLa cells (Beura et al., 2010). On the strength of previous reports and pertinent phenomena observed in this study, it is self-evident that NSP4 can strikingly influence the production of IFN-␤. "
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    ABSTRACT: Type I interferons (IFNs), predominantly IFN-α and β, play important roles in both innate and adaptive immune responses against viral infections. Porcine reproductive and respiratory syndrome virus (PRRSV) has been recognized to be able to down-regulate the IFN response during in vivo and in vitro infection. In this study, we first analyzed inhibitory effect of each NSP of low pathogenic PRRSV HB-1/3.9 on IFN-β transcription in MARC-145 cells, and the results showed that the IFN-β promoter activation could be suppressed by NSP1α, NSP2, NSP1β, NSP3, NSP4, NSP5 and NSP11. We next confirmed that the inhibitory effect of NSP4 was mainly mediated through suppressing NF-κB activation, whereas not hindering NF-κB phosphorylation and nuclear translocation, and nuclear-localized NSP4 was responsible for inhibiting IFN-β activation. We further found that the NSP4 of different pathogenic PRRSV strains exhibited differential inhibitory effect on IFN-β, NF-κB, and IRF3 transcription, and the NSP4 of highly pathogenic (HP)-PRRSV could display more strong inhibitory effect. Finally, we determined that the amino acid at residue 155 in NSP4 contributed to its inhibitory effect for IFN-β transcription in vitro by altering its subcellular distribution. Our findings suggest that the nucleus-localized NSP4 of PRRSV participates in the modulation of the host type I IFNs system, and also provide novel insight for understanding the pathogenesis of the Chinese HP-PRRSV.
    Full-text · Article · Jun 2014 · Virus Research
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