The Insufficient Activation of RIG-I-Like Signaling Pathway Contributes to Highly Efficient Replication of Porcine Picornaviruses in IBRS-2 Cells.
The Insufficient Activation of RIG-I-Like Signaling Pathway Contributes to Highly Efficient Replication of Porcine Picornaviruses in IBRS-2 Cells.
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DOI：
10.1016/j.mcpro.2021.100147
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Zhang X;Yang F;Li K;Cao W;Ru Y;Chen S;Li S;Liu X;Zhu Z;Zheng H
塞内卡谷病毒（SVV）或通常称为塞内卡病毒A，是与猪群中的水泡病和新生儿死亡相关的小核糖核酸病毒之一。我们以前的研究发现SVV在猪Instituto Biologico-Rim Suino-2（IBRS-2）细胞中的复制速度比在猪肾-15（PK-15）细胞中的复制速度快得多。然而，其潜在机制仍不清楚。在本研究中，我们全面比较了IBRS-2细胞和PK-15细胞在SVV感染后的表达特征。我们发现，在SVV感染期间，PK-15细胞中的先天免疫应答相关途径被有效激活，但IBRS-2细胞中没有。在PK-15细胞中诱导了大量干扰素（IFN）刺激的基因。相反，在IBRS-2细胞中没有诱导IFN刺激的基因。此外，我们在另一种猪小核糖核酸病毒口蹄疫病毒感染的两种细胞系中也检测到类似的结果。进一步研究表明，Janus激酶信号转导子和转录激活子信号通路在IBRS-2和PK-15细胞中均正常发挥作用。系统的筛选研究表明，IBRS-2细胞中维甲酸诱导基因I样受体信号通路中TANK结合激酶1到IFN调节因子3的异常信号转导是导致两种细胞株天然免疫反应表现和病毒复制速率不同的根本原因。总之，我们的研究结果确定了IBRS-2和PK-15细胞系的不同特征，这将有助于阐明SVV的发病机制。此外，潜在机制的鉴定将提供新的靶点，并为降低病毒清除率提供新的见解，并可能提高SVV在癌细胞中的溶瘤作用。SVV在IBRS-2和PK-15细胞中引发了不同的先天性免疫应答。SVV在PK-15细胞中比在IBRS-2细胞中诱导更高水平的I型IFN。IBRS-2细胞系具有异常的RLR途径，但具有完整的I型IFN途径。TBK 1介导的抗病毒信号转导在IBRS-2细胞中功能失调。IBRS-2和PK-15细胞已被广泛用于猪小核糖核酸病毒的研究。然而，该病毒在IBRS-2细胞中的复制速度比PK-15细胞更快，并且引起更严重的CPE，并且潜在的机制仍然未知。蛋白质组学分析表明，RLR途径在IBRS-2细胞中处于功能失调状态。我们最终确定IBRS-2细胞中TBK 1到IRF 3的信号转导功能障碍是猪小核糖核酸病毒感染过程中RLR通路功能障碍的根本原因。
Seneca Valley virus (SVV) or commonly known as senecavirus A, is one of the picornavirus that is associated with vesicular disease and neonatal mortality in swine herds. Our previous study found that SVV replicates extremely faster in porcine Instituto Biologico-Rim Suino-2 (IBRS-2) cells than that in porcine kidney-15 (PK-15) cells. However, the underlying mechanism remains unknown. In this study, we comprehensively compared the expression features between IBRS-2 cells and PK-15 cells in response to SVV infection by an unbiased high-throughput quantitative proteomic analysis. We found that the innate immune response–related pathways were efficiently activated in PK-15 cells but not in IBRS-2 cells during SVV infection. A large amount of interferon (IFN)-stimulated genes were induced in PK-15 cells. In contrast, no IFN-stimulated genes were induced in IBRS-2 cells. Besides, we determined similar results in the two cell lines infected by another porcine picornavirus foot-and-mouth disease virus. Further study demonstrated that the Janus kinase signal transducer and activator of transcription signaling pathway was functioning properly in both IBRS-2 and PK-15 cells. A systematic screening study revealed that the aberrant signal transduction from TANK-binding kinase 1 to IFN regulatory factor 3 in the retinoic acid–inducible gene I–like receptor signaling pathway in IBRS-2 cells was the fundamental cause of the different innate immune response manifestation and different viral replication rate in the two cell lines. Together, our findings determined the different features of IBRS-2 and PK-15 cell lines, which will help for clarification of the pathogenesis of SVV. Besides, identification of the underlying mechanisms will provide new targets and an insight for decreasing the viral clearance rate and probably improve the oncolytic effect by SVV in cancer cells. Divergent innate immune responses were triggered by SVV in IBRS-2 and PK-15 cells. SVV induced higher levels of type I IFN in PK-15 cells than in IBRS-2 cells. IBRS-2 cell line has an aberrant RLR pathway but an intact type I IFN pathway. TBK1-mediated antiviral signal transduction was dysfunctional in IBRS-2 cells. Both IBRS-2 and PK-15 cells have been widely used for porcine picornavirus research. However, the virus replicates faster and causes severer CPE in IBRS-2 cells than in PK-15 cells, and the underlying mechanism remains unknown. Proteomic analyses suggested that the RLR pathway was in a dysfunctional state in IBRS-2 cells. We finally determined that the disabled signal transduction from TBK1 to IRF3 in IBRS-2 cells was the fundamental cause of dysfunction of the RLR pathway during porcine picornavirus infection.
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