Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1β Modulates Host Innate Immune Response by Antagonizing IRF3 Activation
Porcine Reproductive and Respiratory Syndrome Virus Nonstructural Protein 1β Modulates Host Innate Immune Response by Antagonizing IRF3 Activation
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DOI：
10.1128/jvi.01326-09
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发表时间：
2010-02-01
影响因子：
5.4
通讯作者：
Osorio, Fernando A.
中科院分区：
文献类型：
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作者：
Beura, Lalit K.;Sarkar, Saumendra N.;Osorio, Fernando A.
猪繁殖与呼吸综合征病毒(PRRSV)感染猪引起的一种以适应性免疫反应延迟和缺陷为特征的严重疾病。据推测，一种次优的先天免疫反应是该病发病的原因。在本文提出的研究中，我们验证了这一假设，并鉴定了几种由PRRS病毒基因组编码的具有先天免疫逃避特性的非结构蛋白(NSP)。在所有测试的10个PRRSV NSP中，有4个被发现对β-干扰素(IFN-β)启动子的激活具有强烈到中等的抑制作用。抑制作用以NSP1最强，其次是NSP2、NSP11和NSP4。我们重点研究了NSP1α和NSP1β(NSP1在病毒感染过程中的自我切割产物)和NSP11，这三个具有很强抑制活性的NSP1。当这三种蛋白在细胞系中稳定表达时，都强烈抑制双链RNA(DsRNA)信号通路。研究发现，NSP1β可抑制双链RNA和仙台病毒对干扰素调节因子3(IRF3)和核因子-kappa B依赖的基因诱导。从机制上讲，NSP1β对dsRNA诱导的IRF3的磷酸化和核转位有明显的抑制作用。此外，当在猪骨髓单核细胞系中进行测试时，NSP1β抑制了仙台病毒介导的猪干扰素-β启动子活性的激活。我们认为这种NSP1β介导的宿主天然免疫应答的颠覆在PRRSV的致病过程中起着重要的作用。
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 NSP1 alpha and NSP1 beta (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. NSP1 beta was found to inhibit both IFN regulatory factor 3 (IRF3)- and NF-kappa B-dependent gene induction by dsRNA and Sendai virus. Mechanistically, the dsRNA-induced phosphorylation and nuclear translocation of IRF3 were strongly inhibited by NSP1 beta. Moreover, when tested in a porcine myelomonocytic cell line, NSP1 beta inhibited Sendai virus-mediated activation of porcine IFN-beta promoter activity. We propose that this NSP1 beta-mediated subversion of the host innate immune response plays an important role in PRRSV pathogenesis.