口蹄疫病毒L~（pro）和3C~（pro）调控宿主抗病毒天然免疫反应的分子机制研究
|
摘要
天然免疫不仅是机体抵抗病原体(包括病毒、细菌等)侵袭的第一道防线,而且是激活获得性免疫的基础。作为一种重要的抗病毒因子,干扰素在天然免疫研究领域具有十分重要的地位。而在进化过程中,很多病毒具有了逃逸或抑制干扰素的能力。深入研究病毒如何调控干扰素产生是当前病毒学和免疫学研究热点。
目前,对人和小鼠天然免疫系统已经研究的比较清楚,而对猪天然免疫系统的了解还知之甚少。主要体现在大量的猪源天然免疫信号分子和效应分子没有被克隆和鉴定,以及效应分子启动子荧光素酶报告系统等高通量检测信号通路的工具缺乏,这在一定程度上阻碍了病毒与猪天然免疫系统相互作用的深入研究。鉴于此,本课题以猪天然免疫信号通路为切入点,克隆了16个重要的猪天然免疫信号通路相关分子,并构建了猪天然免疫信号通路效应分子启动子荧光素酶报告系统,初步建立了研究猪天然免疫信号通路的技术平台。在此基础上,进一步系统分析了口蹄疫病毒非结构蛋白Lpro和3Cpro抑制干扰素产生的作用机制和分子细节。具体内容如下：
1.猪IFN-β启动子及其NF-κB结合位点荧光素酶报告系统的建立
为了建立检测猪β干扰素信号传导蛋白和基因的方法,在详细分析了猪IFN-β基因启动子区域后,采用PCR方法从猪基因组DNA中克隆了IFN-β基因的启动子片段,分别构建了含有猪IFN-p基因启动子的荧光素酶报告载体(pIFN-β-Luc)及含有4个重复的NF-κB结合位点序列的荧光素酶报告载体(4×NF-κB-Luc)。将荧光素酶报告载体转染PK-15细胞,在poly(I:C)或poly(dA:dT)的刺激下,荧光素酶的表达显著增加,说明荧光素酶报告载体构建正确。本研究为进一步开展猪β干扰素信号转导通路的研究奠定了基础。
2.猪RANTES启动子荧光素酶报告系统的建立
正常T细胞表达和分泌的活性调节蛋白(regulated upon activation, normal T-cells expressed and secreted, RANTES)是一种重要的趋化因子,在炎症以及免疫反应中发挥着重要作用。通过对本实验室克隆获得的猪RANTES基因启动子区域的分析,确定了其特征性激活转录元件的结合位点,并构建了包含启动子的一系列5’端缺失突变体的荧光素酶报告质粒,转染细胞发现猪RANTES基因启动子-220/+46的266bp核苷酸区域可以满足其在PK-15细胞中的基础转录活性。进一步研究发现,poly(I:C)或poly(dA:dT)能显著诱导猪RANTES启动子活性以及mRNA水平的表达,且呈时间和剂量依赖性。启动子缺失和突变实验发现,干扰素刺激应答元件对poly(I:C)或poly(dA:dT)诱导RANTES转录是必需的。此外,干扰素调节因子IRF-3和IRF-7在poly(I:C)或poly(dA:dT)诱导RANTES途径中也发挥了重要作用。
3.猪p-干扰素启动子刺激物1 (IPS-1)等天然免疫信号通路基因的克隆
RIG-I/MDA5是胞内识别dsRNA的重要模式识别受体,p干扰素启动子刺激物1 (IFN-βpromoter stimulator 1, IPS-1)(也称为MAVS/VISA/Cardif)作为RIG-I/MDA5的重要接头分子参与诱导Ⅰ型干扰素的产生。本研究运用RT-PCR和RACE-PCR从猪外周血单核细胞中克隆得到猪IPS-1的cDNA,序列分析发现,猪IPS-1基因开放读码框全长1575 bp,编码524个氨基酸；其编码蛋白N端为CARD区,中间是脯氨酸富集区,C端为跨膜区。该蛋白与小鼠、大鼠、猴、人和牛RIG-I相似物的同源性介于59-79%。半定量PCR显示猪IPS-1基因在多个不同的组织中均有表达,利用绿荧光蛋白作标记证实猪IPS-1主要定位于线粒体,且其C端的跨膜结构域对其线粒体定位是必需的。超表达猪IPS-1能显著激活转录因子IRF-3和NF-κB,并诱导IFN-β的产生。利用缺失突变体进一步分析发现IPS-1的CARD区和跨膜区在IPS-1诱导Ⅰ型干扰素的信号通路中都是必需的。此外,猪IPS-1的干扰分子能负调控poly(I:C)诱导IFN-β的能力,表明IPS-1是猪天然免疫信号通路中的一个重要调节因子。该研究为今后进一步探讨IPS-1在猪感染性疾病中的作用奠定了基础。
除了猪IPS-1基因外,本研究还相继克隆得到RIG-I、MDA5、TRAF6等15个猪天然免疫信号通路中的重要分子。这为今后研究猪天然免疫奠定基础,同时也为研究猪病原与宿主相互作用提供便利工具。
4. FMDV Lpro通过下调干扰素调节因子3/7的表达抑制dsRNA诱导的Ⅰ型干扰素的转录
已有研究证实口蹄疫病毒前导蛋白(FMDV Lpro)能通过抑制核转录因子NF-κB的活性负调控IFN-β的产生。本研究利用荧光素酶报告系统和荧光定量PCR证实Lpro也通过下调干扰素调节因子IRF-3/7的表达抑制dsRNA诱导的IFN-αl/β的表达。此外,超表达Lpro能显著降低包括2',5'-OAS、ISG54、IP-10和RANTES在内的多个IRF依赖的干扰素诱导基因的表达。Lpro突变体实验表明,Lpro抑制dsRNA诱导的IFN-αl/β启动子的激活以及降低IRF-3/7表达的能力不依赖于其切割eIF-4G的活性。这些结果说明FMDV能通过多种策略来抵抗宿主对病毒感染的应答。
5. FMDV Lpro作为病毒编码的去泛素化酶负调控Ⅰ型干扰素产生
本研究发现FMDV Lpro具有去泛素化蛋白酶活性。序列比对和生物信息学结构分析发现,Lpro第51位半胱氨酸(C51)和第148位组氨酸(H148)的催化活性位点在7个血清型的FMDV中均高度保守,并且其拓扑结构与已知的细胞内去泛素化酶USP14以及病毒编码的去泛素化酶SARS-CoV木瓜样蛋白酶(PLpro)高度同源。经纯化的或者体内表达的Lpro均可以将K48和K63连接形式的泛素从泛素化蛋白上去除。进一步实验证实,Lpro可以显著抑制RIG-I、TBK1、TRAF3和TRAF6的泛素化,这些分子的泛素化均参与Ⅰ型干扰素的激活。突变体实验发现,Lpro的催化活性以及SAP结构域对其去泛素化活性以及抑制Ⅰ型干扰素都是必需的。这些结果表明FMDV Lpro作为病毒编码的新型去泛素化蛋白酶参与抑制Ⅰ型干扰素的产生,揭示了FMDV抵抗宿主的抗病毒天然免疫反应的一种新的机制。
6. FMDV Lpro通过抑制λ1干扰素的转录负调控λ1干扰素的抗病毒作用
IFN-λ1是最近发现的一种新的Ⅱ型干扰素,具有广谱的抗病毒活性。本研究发现,经纯化的重组猪IFN-λ1处理IBRS-2细胞后,能显著的减少FMDV在IBRS-2细胞上的复制,且呈剂量依赖性。通过双荧光素酶以及荧光定量RT-PCR分析发现FMDV感染不能诱导IFN-λ1的产生,提示抑制IFN-λ1的产生是FMDV的另一种有效的免疫逃避策略。进一步研究发现FMDV Lpro抑制由poly(I:C)诱导的IFN-λ1启动子活性,说明FMDV Lpro参与调节IFN-λ1的表达。突变体实验表明Lpro催化活性以及SAP区域对其抑制poly(I:C)诱导IFN-λ1产生是必需的。这些结果表明IFN-λ1能抑制FMDV,但FMDV通过编码Lpro拮抗IFN-λ1的抗病毒作用。
7. FMDV Lpro抑制dsRNA诱导的RANTES转录的分子机制研究
趋化因子RANTES在炎症以及免疫反应中发挥着重要的作用。已有研究报道,与缺失Lpro的口蹄疫基因工程病毒相比,野生型FMDV能显著抑制RANTES的表达,但具体机制尚不清楚。本研究发现超表达FMDV Lpro能显著抑制poly(I:C)诱导的猪RANTES启动子活性以及mRNA水平的表达。此外,FMDV Lpro也能抑制IRF-3/7介导的RANTES启动子的激活。RANTES启动子的突变体实验发现Lpro是通过IRSE抑制poly(I:C)诱导的RANTES启动子的激活。Lpro突变体实验发现Lpro催化活性以及SAP区域对抑制poly(I:C)诱导RANTES产生是必需的。这一结果说明FMDV可能通过抑制RANTES调控宿主的炎症以及免疫反应。
8. FMDV 3Cpro蛋白酶抑制Ⅰ、Ⅲ型干扰素产生的分子机制初步研究
口蹄疫病毒3C蛋白(FMDV 3Cpro)是FMDV编码的重要蛋白酶之一,本研究发现3Cpro参与抑制Ⅰ型干扰素的产生,这说明FMDV通过编码多种蛋白来抵抗宿主对病毒感染的应答。进一步研究发现,3Cpro通过阻碍IRF-3/7的活化抑制IFN-α1/β启动子的激活。此外,超表达3Cpro能显著降低包括2',5'-OAS、ISG54、IP-10、RANTES和IFN-λ1在内的多个IRF依赖的细胞因子的表达。
总之,本研究初步建立了猪天然免疫信号通路研究的技术平台,利用该平台较为系统地分析口蹄疫病毒Lpro和3Cpro抑制干扰素和RANTES产生的作用机制和分子细节,揭示了口蹄疫病毒的免疫抑制特性和免疫逃逸策略,为今后开发更安全有效的新型口蹄疫疫苗奠定了理论基础。
Innate immunity is not only the first defensive line to pathogen (including viruses and bacteria etc.) but also the basis to activate acquired immunity. Act as an important anti-virus factor, interferon plays a fundamental role in innate immunity research. And many viruses have the capability to escape or inhibit the effect of interferon in their evolution. It is a hot point in present virological and immunological research to deeply study for virus how to modulate the production of interferon.
At present, the innate immunity of human and mice is relatively clear in researches, while little is known about the porcine innate immunity. A large amount of porcine signal molecules and effective molecules in innate immunity haven't been cloned and identified, and the lack of luciferase reporting system for effective molecule promoter partly impedes deeply study at the interaction between virus and porcine innate immunity. Since this project took the signal pathway of porcine innate immunity as entry point to clone 16 important molecules related to signal pathway in porcine innate immunity and constructed Iuciferase reporting system for effective molecule promoter in porcine innate immunity, preliminarily build up technological platform to study signal pathway of porcine innate immunity. On the basis, to systematically analyze the mechanism and molecular details in the production of interferon inhibited by non-structure protein Lpro and 3Cpro in FMDV. The main studies were as following:
1. Construction and identification of luciferase reporter gene vectors directed by porcine IFN-βpromoter and its NF-kB binding site
To establish a method for detection of porcine proteins and genes related to IFN-βsignal transduction, we analyzed the regulatory elements that regulate the transcrip tion of porcine IFN-βgene. The promoter region of porcine IFN-βgene and its four copies NF-kB (nuclear factor kB) binding site regions were amplified from porcine genomic DNA by PCR and were cloned into promoter-free plasmid pGL3-basic. Then these constructs were transiently transfected into PK-15 cells and luciferase activities were measured with or without the transfection of poly(I:C) or poly(dA:dT). Higher expression of luciferase was obviously detected in PK-15 cells transfected with poly(I:C) or poly(dA:dT). These reporter constructs are important tools for investigation of porcine IFN-βsignaling transduction pathways.
2. Molecular cloning of the porcine RANTES promoter:functional characterization of dsDNA/dsRNA response elements in PK-15 cells
The chemokine RANTES (regulated upon activation, normal T-cells expressed and secreted) plays an essential role in inflammation and immune response. In this study, we cloned the nucleotide sequence of the 5'-flanking region of the porcine RANTES (poRANTES) gene and characterized the regulatory elements that activate transcription. Analyses of a series of 5'deletion constructs demonstrated that a 266 bp region (-220/+46) that spanned the potential transcription start site of the poRANTES gene was sufficient to activate transcription in PK-15 cells. Furthermore, our results indicated that dsDNA/dsRNA significantly induced poRANTES promoter activity and expression of mRNA levels in a time-and dose-dependent manner. Promoter deletions and mutagenesis experiments indicated that an interferon-stimulated responsive element (ISRE) was critical for dsDNA/dsRNA-induced poRANTES transcription. In addition, porcine interferon regulatory factor 3 (IRF-3) and IRF-7 play important roles in dsDNA/dsRNA-induced poRANTES expression.
3. Molecular cloning and functional characterization of porcine IFN-βpromoter stimulator 1 (IPS-1)
The IFN-βpromoter stimulator 1 (IPS-1), also known as MAVS/VISA/Cardif, is an adaptor molecule for retinoic-acid-inducible protein I (RIG-I) or melanoma-differentiation-associated gene 5 (MDA5) that senses intracellular double-stranded RNA (dsRNA) and triggers a signal for producing type I IFN. In the present study, the porcine IPS-1 cDNA was cloned using RT-PCR coupled with rapid amplification of cDNA ends (RACE)-PCR from porcine peripheral blood monouclear cells. The open reading frame of porcine IPS-1 consists of 1575 bp encoding 524 amino acids. The putative porcine IPS-1 protein contains an N-terminal CARD-like domain, a proline-rich domain in the middle, a C-terminal transmembrane domain, and exhibits similarity to mouse, rat, monkey, human and cattle counterparts ranging from 59 to 79%. Semi-quantitative RT-PCR showed that porcine IPS-1 mRNA was widely expressed in different tissues. Porcine kidney (PK-15) cells transfected with a DNA construct encoding porcine IPS-1 could produce type I IFN, and activate IRF-3/7 (interferon regulatory factor 3/7) and NF-kB. Deletion mutant analyses further revealed that both the CARD-like domain and transmembrane domain are essential for these functions. In addition, poly(I:C)-induced porcine IFN-βpromoter activation in PK-15 cells could be significantly reduced by siRNA targeting IPS-1, indicating that IPS-1 is an important immunoregulator in porcine innate immune system. The availability of porcine IPS-1 and establishment of its function in type I IFN signaling pathway provides a useful molecule for defining its role during the course of pig infectious diseases.
Besides porcine IPS-1 gene, this research in succession cloned RIG-I、MDA5、TRAF6 etc 15 important molecules in signal pathway of porcine innate immunity. It laid basis on the research in porcine innate immunity in future and provided convenient tool to study the interaction between porcine pathogen and host.
4. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels
The leader proteinase (Lpro) of FMDV has been identified as an interferon-β(IFN-β) antagonist that disrupts the integrity of transcription factor nuclear factor kB (NF-kB). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-αl/βexpression caused by Lpro was also associated with a decrease of IRF-3/7 in protein levels, two critical transcription factors for activation of IFN-a/β. Furthermore, overexpression of Lpro significantly reduced the transcription ofro multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening Lpro mutants indicated that the ability to process eIF-4G of Lpro is not required for suppressing dsRNA-induced activation of the IFN-al/βpromoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-kB, Lpro also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.
5. The leader proteinase of foot-and-mouth disease virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase
Here, we demonstrate that FMDV Lpro has deubiquitinating activity. Sequence alignment and structural bioinformatics analyses revealed that the catalytic residues (Cys51 and His 148) are highly conserved in FMDV Lpro of all seven serotypes and the topology of FMDV Lpro is remarkably similar to that of ubiquitin-specific protease 14 (USP14), a cellular deubiquitylation enzyme (DUB), and that of severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a coronaviral deubiquitylation enzyme (DUB). Both purified Lpro protein and in vivo ectopically expressed Lpro removed ubiquitin (Ub) moieties from cellular substrates, acting on both lysine-48-and lysine-63-linked polyubiquitin chains. Furthermore, Lpro significantly inhibited ubiquitination of RIG-I TANK-binding kinase 1 (TBK1), TNF receptor-associated factor 6 (TRAF6) and TRAF3, key signaling molecules in activation of type I IFN response. Mutations in Lpro that ablate the catalytic activity (C51A or D163N/D164N) or disrupt the SAP (for SAF-A/B, Acinus, and PIAS) domain (I83A/L86A) abrogated the DUB activity of Lpro as well as its ability to block signaling to the IFN-βpromoter. Collectively, these results demonstrate that FMDV Lpro possesses DUB activity in addition to serving as a viral proteinase and describe a novel mechanism evolved by FMDV to counteract host innate antiviral responses.
6. FMDV could be inhibited by interferon-Iambda 1 and had mechanisms to block this action
FMDV causes an economically important disease in swine-producing area, and interferon lambda 1 (IFN-λ1), a newly identified type III interferon, has antiviral activity against a broad spectrum of viruses. In this study, we found that replication of FMDV in IBRS-2 cells was significantly reduced following treatment with the purified recombinant porcine IFN-λ1 in a dose-dependent manner. However, FMDV could not activate IFN-λ1 promoter in IBRS-2 cells, and the activity of IFN-λ1 promoter was much lower than that triggered by poly(I:C). Furthermore, we found that the leader proteinase (Lpro) of FMDV is involved in IFN-λ1 regulation. The obtained results showed that FMDV Lpro inhibited poly(I:C)-induced IFN-λ1 promoter activity. Screening Lpro mutants indicated that the catalytic activity and a SAP (for SAF-A/B, Acinus, and PIAS) domain of Lpro were required for suppressing dsRNA-induced IFN-λ1 production. In conclusion, our results suggested that FMDV could be inhibited by IFN-λ1 and had mechanisms to inhibit this action.
7. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced RANTES transcription in PK-15 cells
The chemokine RANTES plays an essential role in inflammation and immune response. Previous study has been demonstrated that infection with wild-type (WT) foot-and-mouth disease virus inhibits the expression of RANTES compared to infection with a genetically engineered mutant lacking the leader protein (Lpro) coding region in PK-15 cells. However, a complete analysis of the promoter cis-regulatory elements and nuclear factors involved in this inhibition of RANTES gene transcription has not been fully elucidated. In this study, we showed that transfection of PK-15 cells with Lpro of FMDV expression plasmid, in the absence of other FMDV proteins, inhibited dsRNA-induced RANTES in luciferase activity and mRNA transcription. Promoter mutagenesis experiments indicate that interferon-stimulated responsive element (ISRE) was important for the ability of Lpro to inhibit dsRNA-induced the RANTES promoter. Furthermore, the overexpression of Lpro also inhibited IRF-3/7-mediated activation of the RANTES promoter. Screening Lpr0 mutants indicated that the catalytic activity and a SAP (for SAF-A/B, Acinus, and PIAS) domain of Lpro were required for suppressing dsRNA-induced RANTES production. These findings reveal one of the important mechanisms underlying the innate immune evasion by FMDV during infection.
8. Foot-and-mouth disease virus 3C proteinase inhibits type IIFN transcription The 3C proteinase (Lpro) of FMDV has proteinase activity and is involved in processing the viral polyprotein. In this study, our results show that 3Cpro is involved in the inhibition of type I IFN response, suggesting multiple proteins used by FMDV to counteract the immune response to viral infection. FMDV 3Cpro negatively regulates IFN-al/βexpression by disrupting activation of IRF-3/7. Furthermore, overexpression of 3Cpro significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, RANTES, and IFN-λ1.
In a word, this project preliminarily build up technological platform to study signal pathway of porcine innate immunity and systematically analyzed the mechanism and molecular details in the production of interferon inhibited by non-structure protein Lpro and 3Cpro in FMDV, proclaimed the immune inhibitory characteristic and immune escaping strategy, which established theoretical basis to exploit safer and more effective vaccine of FMD from now on.
目前,对人和小鼠天然免疫系统已经研究的比较清楚,而对猪天然免疫系统的了解还知之甚少。主要体现在大量的猪源天然免疫信号分子和效应分子没有被克隆和鉴定,以及效应分子启动子荧光素酶报告系统等高通量检测信号通路的工具缺乏,这在一定程度上阻碍了病毒与猪天然免疫系统相互作用的深入研究。鉴于此,本课题以猪天然免疫信号通路为切入点,克隆了16个重要的猪天然免疫信号通路相关分子,并构建了猪天然免疫信号通路效应分子启动子荧光素酶报告系统,初步建立了研究猪天然免疫信号通路的技术平台。在此基础上,进一步系统分析了口蹄疫病毒非结构蛋白Lpro和3Cpro抑制干扰素产生的作用机制和分子细节。具体内容如下：
1.猪IFN-β启动子及其NF-κB结合位点荧光素酶报告系统的建立
为了建立检测猪β干扰素信号传导蛋白和基因的方法,在详细分析了猪IFN-β基因启动子区域后,采用PCR方法从猪基因组DNA中克隆了IFN-β基因的启动子片段,分别构建了含有猪IFN-p基因启动子的荧光素酶报告载体(pIFN-β-Luc)及含有4个重复的NF-κB结合位点序列的荧光素酶报告载体(4×NF-κB-Luc)。将荧光素酶报告载体转染PK-15细胞,在poly(I:C)或poly(dA:dT)的刺激下,荧光素酶的表达显著增加,说明荧光素酶报告载体构建正确。本研究为进一步开展猪β干扰素信号转导通路的研究奠定了基础。
2.猪RANTES启动子荧光素酶报告系统的建立
正常T细胞表达和分泌的活性调节蛋白(regulated upon activation, normal T-cells expressed and secreted, RANTES)是一种重要的趋化因子,在炎症以及免疫反应中发挥着重要作用。通过对本实验室克隆获得的猪RANTES基因启动子区域的分析,确定了其特征性激活转录元件的结合位点,并构建了包含启动子的一系列5’端缺失突变体的荧光素酶报告质粒,转染细胞发现猪RANTES基因启动子-220/+46的266bp核苷酸区域可以满足其在PK-15细胞中的基础转录活性。进一步研究发现,poly(I:C)或poly(dA:dT)能显著诱导猪RANTES启动子活性以及mRNA水平的表达,且呈时间和剂量依赖性。启动子缺失和突变实验发现,干扰素刺激应答元件对poly(I:C)或poly(dA:dT)诱导RANTES转录是必需的。此外,干扰素调节因子IRF-3和IRF-7在poly(I:C)或poly(dA:dT)诱导RANTES途径中也发挥了重要作用。
3.猪p-干扰素启动子刺激物1 (IPS-1)等天然免疫信号通路基因的克隆
RIG-I/MDA5是胞内识别dsRNA的重要模式识别受体,p干扰素启动子刺激物1 (IFN-βpromoter stimulator 1, IPS-1)(也称为MAVS/VISA/Cardif)作为RIG-I/MDA5的重要接头分子参与诱导Ⅰ型干扰素的产生。本研究运用RT-PCR和RACE-PCR从猪外周血单核细胞中克隆得到猪IPS-1的cDNA,序列分析发现,猪IPS-1基因开放读码框全长1575 bp,编码524个氨基酸；其编码蛋白N端为CARD区,中间是脯氨酸富集区,C端为跨膜区。该蛋白与小鼠、大鼠、猴、人和牛RIG-I相似物的同源性介于59-79%。半定量PCR显示猪IPS-1基因在多个不同的组织中均有表达,利用绿荧光蛋白作标记证实猪IPS-1主要定位于线粒体,且其C端的跨膜结构域对其线粒体定位是必需的。超表达猪IPS-1能显著激活转录因子IRF-3和NF-κB,并诱导IFN-β的产生。利用缺失突变体进一步分析发现IPS-1的CARD区和跨膜区在IPS-1诱导Ⅰ型干扰素的信号通路中都是必需的。此外,猪IPS-1的干扰分子能负调控poly(I:C)诱导IFN-β的能力,表明IPS-1是猪天然免疫信号通路中的一个重要调节因子。该研究为今后进一步探讨IPS-1在猪感染性疾病中的作用奠定了基础。
除了猪IPS-1基因外,本研究还相继克隆得到RIG-I、MDA5、TRAF6等15个猪天然免疫信号通路中的重要分子。这为今后研究猪天然免疫奠定基础,同时也为研究猪病原与宿主相互作用提供便利工具。
4. FMDV Lpro通过下调干扰素调节因子3/7的表达抑制dsRNA诱导的Ⅰ型干扰素的转录
已有研究证实口蹄疫病毒前导蛋白(FMDV Lpro)能通过抑制核转录因子NF-κB的活性负调控IFN-β的产生。本研究利用荧光素酶报告系统和荧光定量PCR证实Lpro也通过下调干扰素调节因子IRF-3/7的表达抑制dsRNA诱导的IFN-αl/β的表达。此外,超表达Lpro能显著降低包括2',5'-OAS、ISG54、IP-10和RANTES在内的多个IRF依赖的干扰素诱导基因的表达。Lpro突变体实验表明,Lpro抑制dsRNA诱导的IFN-αl/β启动子的激活以及降低IRF-3/7表达的能力不依赖于其切割eIF-4G的活性。这些结果说明FMDV能通过多种策略来抵抗宿主对病毒感染的应答。
5. FMDV Lpro作为病毒编码的去泛素化酶负调控Ⅰ型干扰素产生
本研究发现FMDV Lpro具有去泛素化蛋白酶活性。序列比对和生物信息学结构分析发现,Lpro第51位半胱氨酸(C51)和第148位组氨酸(H148)的催化活性位点在7个血清型的FMDV中均高度保守,并且其拓扑结构与已知的细胞内去泛素化酶USP14以及病毒编码的去泛素化酶SARS-CoV木瓜样蛋白酶(PLpro)高度同源。经纯化的或者体内表达的Lpro均可以将K48和K63连接形式的泛素从泛素化蛋白上去除。进一步实验证实,Lpro可以显著抑制RIG-I、TBK1、TRAF3和TRAF6的泛素化,这些分子的泛素化均参与Ⅰ型干扰素的激活。突变体实验发现,Lpro的催化活性以及SAP结构域对其去泛素化活性以及抑制Ⅰ型干扰素都是必需的。这些结果表明FMDV Lpro作为病毒编码的新型去泛素化蛋白酶参与抑制Ⅰ型干扰素的产生,揭示了FMDV抵抗宿主的抗病毒天然免疫反应的一种新的机制。
6. FMDV Lpro通过抑制λ1干扰素的转录负调控λ1干扰素的抗病毒作用
IFN-λ1是最近发现的一种新的Ⅱ型干扰素,具有广谱的抗病毒活性。本研究发现,经纯化的重组猪IFN-λ1处理IBRS-2细胞后,能显著的减少FMDV在IBRS-2细胞上的复制,且呈剂量依赖性。通过双荧光素酶以及荧光定量RT-PCR分析发现FMDV感染不能诱导IFN-λ1的产生,提示抑制IFN-λ1的产生是FMDV的另一种有效的免疫逃避策略。进一步研究发现FMDV Lpro抑制由poly(I:C)诱导的IFN-λ1启动子活性,说明FMDV Lpro参与调节IFN-λ1的表达。突变体实验表明Lpro催化活性以及SAP区域对其抑制poly(I:C)诱导IFN-λ1产生是必需的。这些结果表明IFN-λ1能抑制FMDV,但FMDV通过编码Lpro拮抗IFN-λ1的抗病毒作用。
7. FMDV Lpro抑制dsRNA诱导的RANTES转录的分子机制研究
趋化因子RANTES在炎症以及免疫反应中发挥着重要的作用。已有研究报道,与缺失Lpro的口蹄疫基因工程病毒相比,野生型FMDV能显著抑制RANTES的表达,但具体机制尚不清楚。本研究发现超表达FMDV Lpro能显著抑制poly(I:C)诱导的猪RANTES启动子活性以及mRNA水平的表达。此外,FMDV Lpro也能抑制IRF-3/7介导的RANTES启动子的激活。RANTES启动子的突变体实验发现Lpro是通过IRSE抑制poly(I:C)诱导的RANTES启动子的激活。Lpro突变体实验发现Lpro催化活性以及SAP区域对抑制poly(I:C)诱导RANTES产生是必需的。这一结果说明FMDV可能通过抑制RANTES调控宿主的炎症以及免疫反应。
8. FMDV 3Cpro蛋白酶抑制Ⅰ、Ⅲ型干扰素产生的分子机制初步研究
口蹄疫病毒3C蛋白(FMDV 3Cpro)是FMDV编码的重要蛋白酶之一,本研究发现3Cpro参与抑制Ⅰ型干扰素的产生,这说明FMDV通过编码多种蛋白来抵抗宿主对病毒感染的应答。进一步研究发现,3Cpro通过阻碍IRF-3/7的活化抑制IFN-α1/β启动子的激活。此外,超表达3Cpro能显著降低包括2',5'-OAS、ISG54、IP-10、RANTES和IFN-λ1在内的多个IRF依赖的细胞因子的表达。
总之,本研究初步建立了猪天然免疫信号通路研究的技术平台,利用该平台较为系统地分析口蹄疫病毒Lpro和3Cpro抑制干扰素和RANTES产生的作用机制和分子细节,揭示了口蹄疫病毒的免疫抑制特性和免疫逃逸策略,为今后开发更安全有效的新型口蹄疫疫苗奠定了理论基础。
Innate immunity is not only the first defensive line to pathogen (including viruses and bacteria etc.) but also the basis to activate acquired immunity. Act as an important anti-virus factor, interferon plays a fundamental role in innate immunity research. And many viruses have the capability to escape or inhibit the effect of interferon in their evolution. It is a hot point in present virological and immunological research to deeply study for virus how to modulate the production of interferon.
At present, the innate immunity of human and mice is relatively clear in researches, while little is known about the porcine innate immunity. A large amount of porcine signal molecules and effective molecules in innate immunity haven't been cloned and identified, and the lack of luciferase reporting system for effective molecule promoter partly impedes deeply study at the interaction between virus and porcine innate immunity. Since this project took the signal pathway of porcine innate immunity as entry point to clone 16 important molecules related to signal pathway in porcine innate immunity and constructed Iuciferase reporting system for effective molecule promoter in porcine innate immunity, preliminarily build up technological platform to study signal pathway of porcine innate immunity. On the basis, to systematically analyze the mechanism and molecular details in the production of interferon inhibited by non-structure protein Lpro and 3Cpro in FMDV. The main studies were as following:
1. Construction and identification of luciferase reporter gene vectors directed by porcine IFN-βpromoter and its NF-kB binding site
To establish a method for detection of porcine proteins and genes related to IFN-βsignal transduction, we analyzed the regulatory elements that regulate the transcrip tion of porcine IFN-βgene. The promoter region of porcine IFN-βgene and its four copies NF-kB (nuclear factor kB) binding site regions were amplified from porcine genomic DNA by PCR and were cloned into promoter-free plasmid pGL3-basic. Then these constructs were transiently transfected into PK-15 cells and luciferase activities were measured with or without the transfection of poly(I:C) or poly(dA:dT). Higher expression of luciferase was obviously detected in PK-15 cells transfected with poly(I:C) or poly(dA:dT). These reporter constructs are important tools for investigation of porcine IFN-βsignaling transduction pathways.
2. Molecular cloning of the porcine RANTES promoter:functional characterization of dsDNA/dsRNA response elements in PK-15 cells
The chemokine RANTES (regulated upon activation, normal T-cells expressed and secreted) plays an essential role in inflammation and immune response. In this study, we cloned the nucleotide sequence of the 5'-flanking region of the porcine RANTES (poRANTES) gene and characterized the regulatory elements that activate transcription. Analyses of a series of 5'deletion constructs demonstrated that a 266 bp region (-220/+46) that spanned the potential transcription start site of the poRANTES gene was sufficient to activate transcription in PK-15 cells. Furthermore, our results indicated that dsDNA/dsRNA significantly induced poRANTES promoter activity and expression of mRNA levels in a time-and dose-dependent manner. Promoter deletions and mutagenesis experiments indicated that an interferon-stimulated responsive element (ISRE) was critical for dsDNA/dsRNA-induced poRANTES transcription. In addition, porcine interferon regulatory factor 3 (IRF-3) and IRF-7 play important roles in dsDNA/dsRNA-induced poRANTES expression.
3. Molecular cloning and functional characterization of porcine IFN-βpromoter stimulator 1 (IPS-1)
The IFN-βpromoter stimulator 1 (IPS-1), also known as MAVS/VISA/Cardif, is an adaptor molecule for retinoic-acid-inducible protein I (RIG-I) or melanoma-differentiation-associated gene 5 (MDA5) that senses intracellular double-stranded RNA (dsRNA) and triggers a signal for producing type I IFN. In the present study, the porcine IPS-1 cDNA was cloned using RT-PCR coupled with rapid amplification of cDNA ends (RACE)-PCR from porcine peripheral blood monouclear cells. The open reading frame of porcine IPS-1 consists of 1575 bp encoding 524 amino acids. The putative porcine IPS-1 protein contains an N-terminal CARD-like domain, a proline-rich domain in the middle, a C-terminal transmembrane domain, and exhibits similarity to mouse, rat, monkey, human and cattle counterparts ranging from 59 to 79%. Semi-quantitative RT-PCR showed that porcine IPS-1 mRNA was widely expressed in different tissues. Porcine kidney (PK-15) cells transfected with a DNA construct encoding porcine IPS-1 could produce type I IFN, and activate IRF-3/7 (interferon regulatory factor 3/7) and NF-kB. Deletion mutant analyses further revealed that both the CARD-like domain and transmembrane domain are essential for these functions. In addition, poly(I:C)-induced porcine IFN-βpromoter activation in PK-15 cells could be significantly reduced by siRNA targeting IPS-1, indicating that IPS-1 is an important immunoregulator in porcine innate immune system. The availability of porcine IPS-1 and establishment of its function in type I IFN signaling pathway provides a useful molecule for defining its role during the course of pig infectious diseases.
Besides porcine IPS-1 gene, this research in succession cloned RIG-I、MDA5、TRAF6 etc 15 important molecules in signal pathway of porcine innate immunity. It laid basis on the research in porcine innate immunity in future and provided convenient tool to study the interaction between porcine pathogen and host.
4. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced type I interferon transcription by decreasing interferon regulatory factor 3/7 in protein levels
The leader proteinase (Lpro) of FMDV has been identified as an interferon-β(IFN-β) antagonist that disrupts the integrity of transcription factor nuclear factor kB (NF-kB). In this study, we showed that the reduction of double stranded RNA (dsRNA)-induced IFN-αl/βexpression caused by Lpro was also associated with a decrease of IRF-3/7 in protein levels, two critical transcription factors for activation of IFN-a/β. Furthermore, overexpression of Lpro significantly reduced the transcription ofro multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, and RANTES. Screening Lpro mutants indicated that the ability to process eIF-4G of Lpro is not required for suppressing dsRNA-induced activation of the IFN-al/βpromoter and decreasing IRF-3/7 expression. Taken together, our results demonstrate that, in addition to disrupting NF-kB, Lpro also decreases IRF-3/7 expression to suppress dsRNA-induced type I IFN production, suggesting multiple strategies used by FMDV to counteract the immune response to viral infection.
5. The leader proteinase of foot-and-mouth disease virus negatively regulates type I interferon pathway by acting as a viral deubiquitinase
Here, we demonstrate that FMDV Lpro has deubiquitinating activity. Sequence alignment and structural bioinformatics analyses revealed that the catalytic residues (Cys51 and His 148) are highly conserved in FMDV Lpro of all seven serotypes and the topology of FMDV Lpro is remarkably similar to that of ubiquitin-specific protease 14 (USP14), a cellular deubiquitylation enzyme (DUB), and that of severe acute respiratory syndrome coronavirus (SARS-CoV) papain-like protease (PLpro), a coronaviral deubiquitylation enzyme (DUB). Both purified Lpro protein and in vivo ectopically expressed Lpro removed ubiquitin (Ub) moieties from cellular substrates, acting on both lysine-48-and lysine-63-linked polyubiquitin chains. Furthermore, Lpro significantly inhibited ubiquitination of RIG-I TANK-binding kinase 1 (TBK1), TNF receptor-associated factor 6 (TRAF6) and TRAF3, key signaling molecules in activation of type I IFN response. Mutations in Lpro that ablate the catalytic activity (C51A or D163N/D164N) or disrupt the SAP (for SAF-A/B, Acinus, and PIAS) domain (I83A/L86A) abrogated the DUB activity of Lpro as well as its ability to block signaling to the IFN-βpromoter. Collectively, these results demonstrate that FMDV Lpro possesses DUB activity in addition to serving as a viral proteinase and describe a novel mechanism evolved by FMDV to counteract host innate antiviral responses.
6. FMDV could be inhibited by interferon-Iambda 1 and had mechanisms to block this action
FMDV causes an economically important disease in swine-producing area, and interferon lambda 1 (IFN-λ1), a newly identified type III interferon, has antiviral activity against a broad spectrum of viruses. In this study, we found that replication of FMDV in IBRS-2 cells was significantly reduced following treatment with the purified recombinant porcine IFN-λ1 in a dose-dependent manner. However, FMDV could not activate IFN-λ1 promoter in IBRS-2 cells, and the activity of IFN-λ1 promoter was much lower than that triggered by poly(I:C). Furthermore, we found that the leader proteinase (Lpro) of FMDV is involved in IFN-λ1 regulation. The obtained results showed that FMDV Lpro inhibited poly(I:C)-induced IFN-λ1 promoter activity. Screening Lpro mutants indicated that the catalytic activity and a SAP (for SAF-A/B, Acinus, and PIAS) domain of Lpro were required for suppressing dsRNA-induced IFN-λ1 production. In conclusion, our results suggested that FMDV could be inhibited by IFN-λ1 and had mechanisms to inhibit this action.
7. Foot-and-mouth disease virus leader proteinase inhibits dsRNA-induced RANTES transcription in PK-15 cells
The chemokine RANTES plays an essential role in inflammation and immune response. Previous study has been demonstrated that infection with wild-type (WT) foot-and-mouth disease virus inhibits the expression of RANTES compared to infection with a genetically engineered mutant lacking the leader protein (Lpro) coding region in PK-15 cells. However, a complete analysis of the promoter cis-regulatory elements and nuclear factors involved in this inhibition of RANTES gene transcription has not been fully elucidated. In this study, we showed that transfection of PK-15 cells with Lpro of FMDV expression plasmid, in the absence of other FMDV proteins, inhibited dsRNA-induced RANTES in luciferase activity and mRNA transcription. Promoter mutagenesis experiments indicate that interferon-stimulated responsive element (ISRE) was important for the ability of Lpro to inhibit dsRNA-induced the RANTES promoter. Furthermore, the overexpression of Lpro also inhibited IRF-3/7-mediated activation of the RANTES promoter. Screening Lpr0 mutants indicated that the catalytic activity and a SAP (for SAF-A/B, Acinus, and PIAS) domain of Lpro were required for suppressing dsRNA-induced RANTES production. These findings reveal one of the important mechanisms underlying the innate immune evasion by FMDV during infection.
8. Foot-and-mouth disease virus 3C proteinase inhibits type IIFN transcription The 3C proteinase (Lpro) of FMDV has proteinase activity and is involved in processing the viral polyprotein. In this study, our results show that 3Cpro is involved in the inhibition of type I IFN response, suggesting multiple proteins used by FMDV to counteract the immune response to viral infection. FMDV 3Cpro negatively regulates IFN-al/βexpression by disrupting activation of IRF-3/7. Furthermore, overexpression of 3Cpro significantly reduced the transcription of multiple IRF-responsive genes including 2',5'-OAS, ISG54, IP-10, RANTES, and IFN-λ1.
In a word, this project preliminarily build up technological platform to study signal pathway of porcine innate immunity and systematically analyzed the mechanism and molecular details in the production of interferon inhibited by non-structure protein Lpro and 3Cpro in FMDV, proclaimed the immune inhibitory characteristic and immune escaping strategy, which established theoretical basis to exploit safer and more effective vaccine of FMD from now on.
引文
1. J.莎姆布鲁克.分子克隆实验指南第三版(上、下册).北京：科学出版社,2005.
2. 李军,曾芸.病毒诱导Ⅰ型干扰素产生的机制.生命的化学,2006,26：395-398.
3. 李婷婷.猪源VISA基因及其突变体的克隆与真核表达.[学士学位论文].武汉：华中农业大学图书馆,2007.
4. 李臻,张远强.p趋化性细胞因子RANTES的研究进展.生理科学进展,2006,37：79-82.
5. 秦成峰,秦鄂德.RIG-I样受体与RNA病毒识别.微生物学报,2008,48：1418-1423
6. 舒红兵.抗病毒天然免疫.北京：科学出版社,2009.
7. 王素霞,刘媛,吴慧娟等.去泛素化酶的研究及其进展.临床与实验病理学杂志,2008,24：734-737.
8. 吴学宝.猪瘟病毒影响RANTES产生分子机制的研究.[硕士学位论文].武汉：华中农业大学图书馆,2010.
9. 殷震,刘景华.动物病毒学.北京：科学出版社,1997.
10.赵付伟.猪Ⅲ型干扰素IFN-λ1的克隆、表达和抗病毒活性研究[硕士学位论文].武汉：华中农业大学图书馆,2010.
11. Abe T, Hemmi H, Miyamoto H, et al. Involvement of the Toll-like receptor 9 signaling pathway in the induction of innate immunity by baculovirus. J Virol,2005,79:2847-2858.
12. Abe T, Takahashi H, Hamazaki H, et al. Baculovirus induces an innate immune response and confers protection from lethal influenza virus infection in mice. J Immunol,2003,171: 1133-1139.
13. Akira S. Pathogen recognition by innate immunity and its signaling. Proc Jpn Acad Ser B Phys Biol Sci,2009,85:143-156.
14. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol,2004,4:499-511.
15. Alvarez B, Revilla C, Chamorro S, et al. Molecular cloning, characterization and tissue expression of porcine Toll-like receptor 4. Dev Comp Immunol,2006,30:345-355.
16. Alves M P, Neuhaus V, Guzylack-Piriou L, et al. Toll-like receptor 7 and MyD88 knockdown by lentivirus-mediated RNA interference to porcine dendritic cell subsets. Gene Ther,2007,14: 836-844.
17. Amanatidou V, Sourvinos G, Apostolakis S, et al. RANTES promoter gene polymorphisms and susceptibility to severe respiratory syncytial virus-induced bronchiolitis. Pediatr Infect Dis J, 2008,27:38-42.
18. Andersen J, VanScoy S, Cheng T F, et al. IRF-3-dependent and augmented target genes during viral infection. Genes Immun,2008,9:168-175.
19. Andrejeva J, Childs K S, Young D F, et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA,2004,101:17264-17269.
20. Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol,2006a,80:4501-4509.
21. Ank N, West H, Paludan S R. IFN-lambda:novel antiviral cytokines. J Interferon Cytokine Res, 2006b,26:373-379.
22. Arimoto K, Takahashi H, Hishiki T, et al. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci USA,2007,104:7500-7505.
23. Aust G, Brylla E, Lehmann I, et al. Cloning of bovine RANTES mRNA and its expression and regulation in ovaries in the periovulatory period. FEBS Lett,1999,463:160-164.
24. Balakirev M Y, Jaquinod M, Haas A L, et al. Deubiquitinating function of adenovirus proteinase. J Virol,2002,76:6323-6331.
25. Bao X, Liu T, Shan Y, et al. Human metapneumovirus glycoprotein G inhibits innate immune responses. PLoS Pathog,2008,4:e1000077.
26. Barral P M, Morrison J M, Drahos J, et al. MDA-5 is cleaved in poliovirus-infected cells. J Virol, 2007,81:3677-3684.
27. Barral P M, Sarkar D, Fisher P B, et al. RIG-I is cleaved during picornavirus infection. Virology, 2009,391:171-176.
28. Barretto N, Jukneliene D, Ratia K, et al. The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol,2005,79:15189-15198.
29. Barro M, Patton J T. Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3,1RF5, and IRF7. J Virol,2007,81:4473-4481.
30. Bauer S, Pigisch S, Hangel D, et al. Recognition of nucleic acid and nucleic acid analogs by Toll-like receptors 7,8 and 9. Immunobiology,2008,213:315-328.
31. Bautista E M, Ferman G S, Golde W T. Induction of lymphopenia and inhibition of T cell function during acute infection of swine with foot and mouth disease virus (FMDV). Vet Immunol Immunopathol,2003,92:61-73.
32. Bautista E M, Ferman G S, Gregg D, et al. Constitutive expression of alpha interferon by skin dendritic cells confers resistance to infection by foot-and-mouth disease virus. J Virol,2005,79: 4838-4847.
33. Bautista E M, Gregg D, Golde W T. Characterization and functional analysis of skin-derived dendritic cells from swine without a requirement for in vitro propagation. Vet Immunol Immunopathol,2002,88:131-148.
34. Bautista E M, Nfon C, Ferman G S, et al. IL-13 replaces IL-4 in development of monocyte derived dendritic cells (MoDC) of swine. Vet Immunol Immunopathol,2007,115:56-67.
35. Baxt B, Mason P W. Foot-and-mouth disease virus undergoes restricted replication in macrophage cell cultures following Fc receptor-mediated adsorption. Virology,1995,207: 503-509.
36. Belsham G J, Brangwyn J K. A region of the 5'noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells:involvement with the role of L protease in translational control. J Virol,1990,64:5389-5395.
37. Belsham G J, Mclnerney G M, Ross-Smith N. Foot-and-mouth disease virus 3C protease induces cleavage of translation initiation factors eIF4A and eIF4G within infected cells.J Virol,2000,74: 272-280.
38. Bhoj V G, Chen Z J. Ubiquitylation in innate and adaptive immunity. Nature,2009,458: 430-437.
39. Biacchesi S, Skiadopoulos M H, Yang L, et al. Recombinant human Metapneumovirus lacking the small hydrophobic SH and/or attachment G glycoprotein:deletion of G yields a promising vaccine candidate. J Virol,2004,78:12877-12887.
40. Bless N M, Huber-Lang M, Guo R F, et al. Role of CC chemokines (macrophage inflammatory protein-1 beta, monocyte chemoattractant protein-1, RANTES) in acute lung injury in rats. J Immunol,2000,164:2650-2659.
41. Boger C A, Fischereder M, Deinzer M, et al. RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients. Atherosclerosis,2005, 183:121-129.
42. Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol,2004,25:280-288.
43. Borca M V, Gudmundsdottir I, Fernandez-Sainz I J, et al. Patterns of cellular gene expression in swine macrophages infected with highly virulent classical swine fever virus strain Brescia. Virus Res,2008,138:89-96.
44. Brand S, Beigel F, Olszak T, et al. IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. Am JPhysiol Gastrointest Liver Physiol,2005,289:G960-968.
45. Brown C C, Piccone M E, Mason P W, et al. Pathogenesis of wild-type and leaderless foot-and-mouth disease virus in cattle. J Virol,1996,70:5638-5641.
46. Capozzo A V, Burke D J, Fox J W, et al. Expression of foot and mouth disease virus non-structural polypeptide 3ABC induces histone H3 cleavage in BHK21 cells. Virus Res,2002, 90:91-99.
47. Carrasco C P, Rigden R C, Schaffner R, et al. Porcine dendritic cells generated in vitro: morphological, phenotypic and functional properties. Immunology,2001,104:175-184.
48. Casola A, Garofalo R P, Haeberle H, et al. Multiple cis regulatory elements control RANTES promoter activity in alveolar epithelial cells infected with respiratory syncytial virus. J Virol, 2001,75:6428-6439.
49. Casola A, Henderson A, Liu T, et al. Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation. Am J Physiol Lung Cell Mol Physiol,2002,283: L1280-1290.
50. Castaldello A, Sgarbanti M, Marsili G, et al. Interferon regulatory factor-1 acts as a powerful adjuvant in tat DNA based vaccination. J Cell Physiol,224:702-709.
51. Centi S, Negrisolo S, Stefanic A, et al. Upper urinary tract infections are associated with RANTES promoter polymorphism. JPediatr,157:1038-1040 e1031.
52. Chen C J, Chen J H, Chen S Y, et al. Upregulation of RANTES gene expression in neuroglia by Japanese encephalitis virus infection. J Virol,2004,78:12107-12119.
53. Chen Z, Rijnbrand R, Jangra R K, et al. Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. Virology,2007a,366:277-292.
54. Chen Z, Wang Y, Ratia K, et al. Proteolytic processing and deubiquitinating activity of papain-like proteases of human coronavirus NL63. J Virol,2007b,81:6007-6018.
55. Cheng G, Zhong J, Chung J, et al. Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells. Proc Natl Acad Sci USA,2007,104: 9035-9040.
56. Childs K, Stock N, Ross C, et al. mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology,2007,359:190-200.
57. Chinsangaram J, Koster M, Grubman M J. Inhibition of L-deleted foot-and-mouth disease virus replication by alpha/beta interferon involves double-stranded RNA-dependent protein kinase. J Virol,2001,75:5498-5503.
58. Chinsangaram J, Mason P W, Grubman M J. Protection of swine by live and inactivated vaccines prepared from a leader proteinase-deficient serotype A12 foot-and-mouth disease virus. Vaccine, 1998,16:1516-1522.
59. Chinsangaram J, Piccone M E, Grubman M J. Ability of foot-and-mouth disease virus to form plaques in cell culture is associated with suppression of alpha/beta interferon. J Virol,1999,73: 9891-9898.
60. Clarke B E, Sangar D V, Burroughs J N, et al. Two initiation sites for foot-and-mouth disease virus polyprotein in vivo. J Gen Virol,1985,66 (Pt 12):2615-2626.
61. Clementz M A, Chen Z, Banach B S, et al. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases. J Virol,2010,84:4619-4629.
62. Coffman R L, Sher A, Seder R A. Vaccine adjuvants:putting innate immunity to work. Immunity, 2010,33:492-503.
63. Dai X, Sayama K, Tohyama M, et al. The NF-kappaB, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes. Int Immunol,2008,20:901-909.
64. Danoff T M, Lalley P A, Chang Y S, et al. Cloning, genomic organization, and chromosomal localization of the Scya5 gene encoding the murine chemokine RANTES. J Immunol,1994,152: 1182-1189.
65. Dauber B, Schneider J, Wolff T. Double-stranded RNA binding of influenza B virus nonstructural NS1 protein inhibits protein kinase R but is not essential to antagonize production of alpha/beta interferon. J Virol,2006,80:11667-11677.
66. de Los Santos T, de Avila Botton S, Weiblen R, et al. The leader proteinase of foot-and-mouth disease virus inhibits the induction of beta interferon mRNA and blocks the host innate immune response. J Virol,2006,80:1906-1914.
67. de Los Santos T, Diaz-San Segundo F, Grubman M J. Degradation of nuclear factor kappa B during foot-and-mouth disease virus infection. J Virol,2007,81:12803-12815.
68. de los Santos T, Segundo F D, Zhu J, et al. A conserved domain in the leader proteinase of foot-and-mouth disease virus is required for proper subcellular localization and function. J Virol, 2009,83:1800-1810.
69. Delhaye S, van Pesch V, Michiels T. The leader protein of Theiler's virus interferes with nucleocytoplasmic trafficking of cellular proteins. J Virol,2004,78:4357-4362.
70. Deng L, Wang C, Spencer E, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell,2000, 103:351-361.
71. Devaney M A, Vakharia V N, Lloyd R E, et al. Leader protein of foot-and-mouth disease virus is required for cleavage of the p220 component of the cap-binding protein complex. J Virol,1988, 62:4407-4409.
72. Devaraj S G, Wang N, Chen Z, et al. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J Biol Chem, 2007,282:32208-32221.
73. Diao F, Li S, Tian Y, et al. Negative regulation of MDA5-but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase. Proc Natl Acad Sci USA,2007,104: 11706-11711.
74. Dias C C, Moraes M P, Segundo F D, et al. Porcine type I interferon rapidly protects swine against challenge with multiple serotypes of foot-and-mouth disease virus. J Interferon Cytokine Res,2011,31:227-236.
75. Diaz-San Segundo F, Salguero F J, de Avila A, et al. Selective lymphocyte depletion during the early stage of the immune response to foot-and-mouth disease virus infection in swine. J Virol, 2006,80:2369-2379.
76. Donelan N R, Basler C F, Garcia-Sastre A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol,2003,77:13257-13266.
77. Elliott M B, Tebbey P W, Pryharski K S, et al. Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5). JMed Virol,2004,73:300-308.
78. Etchison D, Milburn S C, Edery I, et al. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J Biol Chem,1982,257: 14806-14810.
79. Falk M M, Grigera P R, Bergmann I E, et al. Foot-and-mouth disease virus protease 3C induces specific proteolytic cleavage of host cell histone H3. J Virol,1990,64:748-756.
80. Fan L, Briese T, Lipkin W I. Z proteins of New World arenaviruses bind RIG-I and interfere with type I interferon induction. J Virol,2010,84:1785-1791.
81. Fang Q, Wang F, Zhao D. Association between regulated upon activation, normal T cells expressed and secreted (RANTES)-28C/G polymorphism and asthma risk--a meta-analysis. Int J Med Sci,2010,7:55-61.
82. Fernandes-Alnemri T, Yu J W, Datta P, et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature,2009,458:509-513.
83. Finberg R W, Wang J P, Kurt-Jones E A. Toll like receptors and viruses. Rev Med Virol,2007,17: 35-43.
84. Finlay B B, McFadden G. Anti-immunology:evasion of the host immune system by bacterial and viral pathogens. Cell,2006,124:767-782.
85. Foeger N, Glaser W, Skern T. Recognition of eukaryotic initiation factor 4G isoforms by picornaviral proteinases. J Biol Chem,2002,277:44300-44309.
86. Fredericksen B L, Keller B C, Fornek J, et al. Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1. J Virol,2008,82:609-616.
87. Frias-Staheli N, Giannakopoulos N V, Kikkert M, et al. Ovarian tumor domain-containing viral proteases evade ubiquitin-and ISG15-dependent innate immune responses. Cell Host Microbe, 2007,2:404-416.
88. Friedman C S, O'Donnell M A, Legarda-Addison D, et al. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep,2008,9:930-936.
89. Frieman M, Ratia K, Johnston R E, et al. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol,2009,83:6689-6705.
90. Gack M U, Nistal-Villan E, Inn K S, et al. Phosphorylation-mediated negative regulation of RIG-I antiviral activity. J Virol,2010,84:3220-3229.
91. Gack M U, Shin Y C, Joo C H, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature,2007,446:916-920.
92. Gad H H, Dellgren C, Hamming O J, et al. Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family. JBiol Chem,2009,284:20869-20875.
93. Garcia-Briones M, Rosas M F, Gonzalez-Magaldi M, et al. Differential distribution of non-structural proteins of foot-and-mouth disease virus in BHK-21 cells. Virology,2006,349: 409-421.
94. Gatot J S, Gioia R, Chau T L, et al. Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. J Biol Chem,2007,282:31131-31146.
95. Geiss G, Jin G, Guo J, et al. A comprehensive view of regulation of gene expression by double-stranded RNA-mediated cell signaling. J Biol Chem,2001,276:30178-30182.
96. Genin P, Algarte M, Roof P, et al. Regulation of RANTES chemokine gene expression requires cooperativity between NF-kappa B and IFN-regulatory factor transcription factors. J Immunol, 2000,164:5352-5361.
97. Genin P, Vaccaro A, Civas A. The role of differential expression of human interferon--a genes in antiviral immunity. Cytokine Growth Factor Rev,2009,20:283-295.
98. Gilliet M, Cao W, Liu Y J. Plasmacytoid dendritic cells:sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol,2008,8:594-606.
99. Gitlin L, Barchet W, Gilfillan S, et al. Essential role of mda-5 in type Ⅰ IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picomavirus. Proc Natl Acad Sci USA,2006,103:8459-8464.
100. Golde W T, Nfon C K, Toka F N. Immune evasion during foot-and-mouth disease virus infection of swine. Immunol Rev,2008,225:85-95.
101. Gorbalenya A E, Koonin E V, Lai M M. Putative papain-related thiol proteases of positive-strand RNA viruses. Identification of rubi- and aphthovirus proteases and delineation of a novel conserved domain associated with proteases of rubi-, alpha-and coronaviruses. FEBS Lett,1991, 288:201-205.
102. Graff J W, Ettayebi K, Hardy M E. Rotavirus NSP1 inhibits NFkappaB activation by inducing proteasome-dependent degradation of beta-TrCP:a novel mechanism of IFN antagonism. PLoS Pathog,2009,5:el000280.
103. Gregg D A, Schlafer D H, Mebus C A. African swine fever virus infection of skin-derived dendritic cells in vitro causes interference with subsequent foot-and-mouth disease virus infection. J Vet Diagn Invest,1995,7:44-51.
104. Grigera P R, Tisminetzky S G. Histone H3 modification in BHK cells infected with foot-and-mouth disease virus. Virology,1984,136:10-19.
105. Grubman M J, Baxt B. Foot-and-mouth disease. Clin Microbiol Rev,2004,17:465-493.
106. Grubman M J, Moraes M P, Diaz-San Segundo F, et al. Evading the host immune response:how foot-and-mouth disease virus has become an effective pathogen. FEMS Immunol Med Microbiol, 2008,53:8-17.
107. Guo Z, Chen L M, Zeng H, et al. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I.Am JRespir Cell Mol Biol,2007,36:263-269.
108. Guzylack-Piriou L, Balmelli C, McCullough K C, et al. Type-A CpG oligonucleotides activate exclusively porcine natural interferon-producing cells to secrete interferon-alpha, tumour necrosis factor-alpha and interleukin-12. Immunology,2004,112:28-37.
109. Guzylack-Piriou L, Bergamin F, Gerber M, et al. Plasmacytoid dendritic cell activation by foot-and-mouth disease virus requires immune complexes. Eur J Immunol,2006,36:1674-1683.
110. Habjan M, Andersson I, Klingstrom J, et al. Processing of genome 5'termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction. PLoS One,2008,3: e2032.
111. Hartman Z C, Appledorn D M, Amalfitano A. Adenovirus vector induced innate immune responses:impact upon efficacy and toxicity in gene therapy and vaccine applications. Virus Res, 2008,132:1-14.
112. Hato S V, Ricour C, Schulte B M, et al. The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3. Cell Microbiol,2007,9:2921-2930.
113. Hayden M S, Ghosh S. Shared principles in NF-kappaB signaling. Cell,2008,132:344-362.
114. Hayden M S, Ghosh S. Signaling to NF-kappaB. Genes Dev,2004,18:2195-2224.
115. Hervas-Stubbs S, Rueda P, Lopez L, et al. Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN. J Immunol,2007,178:2361-2369.
116. Hilton L, Moganeradj K, Zhang G, et al. The NPro product of bovine viral diarrhea virus inhibits DNA binding by interferon regulatory factor 3 and targets it for proteasomal degradation. J Virol, 2006,80:11723-11732.
117. Hiscott J. Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. Cytokine Growth Factor Rev,2007a,18:483-490.
118. Hiscott J. Triggering the innate antiviral response through IRF-3 activation. JBiol Chem,2007b, 282:15325-15329.
119. Hiura T S, Kempiak S J, Nel A E. Activation of the human RANTES gene promoter in a macrophage cell line by lipopolysaccharide is dependent on stress-activated protein kinases and the IkappaB kinase cascade:implications for exacerbation of allergic inflammation by environmental pollutants. Clin Immunol,1999,90:287-301.
120. Honda K, Yanai H, Takaoka A, et al. Regulation of the type I IFN induction:a current view. Int Immunol,2005,17:1367-1378.
121. Hong S W, Kim S, Lee D K. The role of Bach2 in nucleic acid-triggered antiviral innate immune responses. Biochem Biophys Res Commun,2008,365:426-432.
122. Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature,2009,458:514-518.
123. Hornung V, Ellegast J, Kim S, et al.5'-Triphosphate RNA is the ligand for RIG-I. Science,2006, 314:994-997.
124. Hou W, Wang X, Ye L, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol,2009,83:3834-3842.
125. Hu M, Li P, Song L, et al. Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. Embo J,2005,24:3747-3756.
126. Isaacson M K, Ploegh H L. Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe,2009,5:559-570.
127. Ishii K J, Kawagoe T, Koyama S, et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature,2008,451:725-729.
128. Jiang D, Guo H, Xu C, et al. Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J Virol,2008,82:1665-1678.
129. Jin M S, Lee J O. Structures of the toll-like receptor family and its ligand complexes. Immunity, 2008,29:182-191.
130. Johansson E, Domeika K, Berg M, et al. Characterisation of porcine monocyte-derived dendritic cells according to their cytokine profile. Vet Immunol Immunopathol,2003,91:183-197.
131.Jounai N, Takeshita F, Kobiyama K, et al. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA,2007,104:14050-14055.
132. Kato H, Sato S, Yoneyama M, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity,2005,23:19-28.
133. Kato H, Takeuchi O, Mikamo-Satoh E, et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.J Exp Med,2008,205:1601-1610.
134. Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature,2006,441:101-105.
135. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol,2006,7:131-137.
136. Kawai T, Akira S. SnapShot: Pattern-recognition receptors. Cell,2007,129:1024.
137. Kawai T, Takahashi K, Sato S, et al. IPS-1, an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction. Nat Immunol,2005,6:981-988.
138. Kayagaki N, Phung Q, Chan S, et al. DUBA:a deubiquitinase that regulates type I interferon production. Science,2007,318:1628-1632.
139. Kim E T, Oh S E, Lee Y O, et al. Cleavage specificity of the UL48 deubiquitinating protease activity of human cytomegalovirus and the growth of an active-site mutant virus in cultured cells. J Virol,2009,83:12046-12056.
140. Kim T K, Maniatis T. The mechanism of transcriptional synergy of an in vitro assembled interferon-beta enhanceosome. Mol Cell,1997,1:119-129.
141. Kirchweger R, Ziegler E, Lamphear B J, et al. Foot-and-mouth disease virus leader proteinase: purification of the Lb form and determination of its cleavage site on eIF-4 gamma. J Virol,1994, 68:5677-5684.
142. Kleina L G, Grubman M J. Antiviral effects of a thiol protease inhibitor on foot-and-mouth disease virus. J Virol,1992,66:7168-7175.
143. Kobiyama K, Takeshita F, Ishii K J, et al. A signaling polypeptide derived from an innate immune adaptor molecule can be harnessed as a new class of vaccine adjuvant. J Immunol,2009, 182:1593-1601.
144. Kojima-Shibata C, Shinkai H, Morozumi T, et al. Differences in distribution of single nucleotide polymorphisms among intracellular pattern recognition receptors in pigs. Immunogenetics,2009, 61:153-160.
145. Komuro A, Bamming D, Horvath C M. Negative regulation of cytoplasmic RNA-mediated antiviral signaling. Cytokine,2008,43:350-358.
146. Kotenko S V, Gallagher G, Baurin V V, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol,2003,4:69-77.
147. Koyama S, Ishii K J, Coban C, et al. Innate immune response to viral infection. Cytokine,2008, 43:336-341.
148. Krieg A M. The toll of too much TLR7. Immunity,2007,27:695-697.
149. Kudo T, Lu H, Wu J Y, et al. Regulation of RANTES promoter activation in gastric epithelial cells infected with Helicobacter pylori. Infect Immun,2005,73:7602-7612.
150. Kuhn R, Luz N, Beck E. Functional analysis of the internal translation initiation site of foot-and-mouth disease virus.J Virol,1990,64:4625-4631.
151. La Rocca S A, Herbert R J, Crooke H, et al. Loss of interferon regulatory factor 3 in cells infected with classical swine fever virus involves the N-terminal protease, Npro. J Virol,2005, 79:7239-7247.
152. Larsen K C, Spencer A J, Goodman A L, et al. Expression of takl and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines. Vaccine,2009,27:5589-5598.
153. Lastra J M, Galindo R C, Gortazar C, et al. Expression of immunoregulatory genes in peripheral blood mononuclear cells of European wild boar immunized with BCG. Vet Microbiol,2009,134: 334-339.
154. Leforban Y. Prevention measures against foot-and-mouth disease in Europe in recent years. Vaccine,1999,17:1755-1759.
155. Lefort S, Soucy-Faulkner A, Grandvaux N, et al. Binding of Kaposi's sarcoma-associated herpesvirus K-bZIP to interferon-responsive factor 3 elements modulates antiviral gene expression. J Virol,2007,81:10950-10960.
156. Lei X, Liu X, Ma Y, et al. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol,2010, 84:8051-8061.
157. Li H, Ma G, Gui D, et al. Characterization of the porcine p65 subunit of NF-kappaB and its association with virus antibody levels. Mol Immunol,2011,48:914-923.
158. Li M C, Wang H Y, Wang H Y, et al. Liposome-mediated IL-28 and IL-29 expression in A549 cells and anti-viral effect of IL-28 and IL-29 on WISH cells. Acta Pharmacol Sin,2006,27: 453-459.
159. Lin R, Genin P, Mamane Y, et al. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene,2001,20: 800-811.
160. Lin R, Heylbroeck C, Genin P, et al. Essential role of interferon regulatory factor 3 in direct activation of RANTES chemokine transcription. Mol Cell Biol,1999,19:959-966.
161. Lin R, Noyce R S, Collins S E, et al. The herpes simplex virus ICPO RING finger domain inhibits IRF3-and IRF7-mediated activation of interferon-stimulated genes. J Virol,2004,78: 1675-1684.
162. Lin R, Yang L, Nakhaei P, et al. Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. J Biol Chem,2006,281: 2095-2103.
163. Lindner H A, Fotouhi-Ardakani N, Lytvyn V, et al. The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J Virol,2005,79: 15199-15208.
164. Lindner H A, Lytvyn V, Qi H, et al. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys,2007,466:8-14.
165. Lisnic V J, Krmpotic A, Jonjic S. Modulation of natural killer cell activity by viruses. Curr Opin Microbiol,2010,13:530-539.
166. Lladser A, Mougiakakos D, Tufvesson H, et al. DAI (DLM-1/ZBP1) as a Genetic Adjuvant for DNA Vaccines That Promotes Effective Antitumor CTL Immunity. Mol Ther,2011,19:594-601.
167. Lokuta M A, Maher J, Noe K H, et al. Mechanisms of murine RANTES chemokine gene induction by Newcastle disease virus. JBiol Chem,1996,271:13731-13738.
168. Longhi M P, Trumpfheller C, Idoyaga J, et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+Thl immunity with poly IC as adjuvant. J Exp Med,2009, 206:1589-1602.
169. Loo Y M, Fornek J, Crochet N, et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol,2008,82:335-345.
170. Luo M, Qu X, Pan R, et al. The virus-induced signaling adaptor molecule enhances DNA-raised immune protection against H5N1 influenza virus infection in mice. Vaccine,2011,29: 2561-2567.
171. Luo R, Xiao S, Jiang Y, et al. Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon-beta production by interfering with the RIG-I signaling pathway. Mol Immunol,2008,45:2839-2846.
172. Ma D, Jiang D, Qing M, et al. Antiviral effect of interferon lambda against West Nile virus. Antiviral Res,2009,83:53-60.
173. Mao A P, Li S, Zhong B, et al. Virus-triggered ubiquitination of TRAF3/6 by cIAPl/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J Biol Chem,2010, 285:9470-9476.
174. Mason P W, Grubman M J, Baxt B. Molecular basis of pathogenesis of FMDV. Virus Res,2003, 91:9-32.
175. Mason P W, Piccone M E, McKenna T S, et al. Evaluation of a live-attenuated foot-and-mouth disease virus as a vaccine candidate. Virology,1997,227:96-102.
176. Matsukura S, Kokubu F, Kurokawa M, et al. Synthetic double-stranded RNA induces multiple genes related to inflammation through Toll-like receptor 3 depending on NF-kappaB and/or IRF-3 in airway epithelial cells. Clin Exp Allergy,2006,36:1049-1062.
177. Medina M, Domingo E, Brangwyn J K, et al. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology,1993,194: 355-359.
178. Melchjorsen J, Paludan S R. Induction of RANTES/CCL5 by herpes simplex virus is regulated by nuclear factor kappa B and interferon regulatory factor 3. J Gen Virol,2003,84:2491-2495.
179. Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature,2005,437:1167-1172.
180. Mibayashi M, Martinez-Sobrido L, Loo Y M, et al. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol,2007,81: 514-524.
181. Miyamoto N G, Medberry P S, Hesselgesser J, et al. Interleukin-lbeta induction of the chemokine RANTES promoter in the human astrocytoma line CH235 requires both constitutive and inducible transcription factors. JNeuroimmunol,2000,105:78-90.
182. Moffat K, Howell G, Knox C, et al. Effects of foot-and-mouth disease virus nonstructural proteins on the structure and function of the early secretory pathway:2BC but not 3A blocks endoplasmic reticulum-to-Golgi transport. J Virol,2005,79:4382-4395.
183. Moffat K, Knox C, Howell G, et al. Inhibition of the secretory pathway by foot-and-mouth disease virus 2BC protein is reproduced by coexpression of 2B with 2C, and the site of inhibition is determined by the subcellular location of 2C. J Virol,2007,81:1129-1139.
184. Moraes M P, de Los Santos T, Koster M, et al. Enhanced antiviral activity against foot-and-mouth disease virus by a combination of type Ⅰ and Ⅱ porcine interferons. J Virol,2007, 81:7124-7135.
185. Mordstein M, Kochs G, Dumoutier L, et al. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog,2008,4: e1000151.
186. Moriuchi H, Moriuchi M, Fauci A S. Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection. J Immunol,1997,158:3483-3491.
187. Muneta Y, Uenishi H, Kikuma R, et al. Porcine TLR2 and TLR6:identification and their involvement in Mycoplasma hyopneumoniae infection. J Interferon Cytokine Res,2003,23: 583-590.
188. Nakhaei P, Genin P, Civas A, et al. RIG-I-like receptors:sensing and responding to RNA virus infection. Semin Immunol,2009,21:215-222.
189. Nardese V, Longhi R, Polo S, et al. Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES. Nat Struct Biol,2001,8:611-615.
190. Nelson P J, Kim H T, Manning W C, et al. Genomic organization and transcriptional regulation of the RANTES chemokine gene. J Immunol,1993,151:2601-2612.
191.Nfon C K, Dawson H, Toka F N, et al. Langerhans cells in porcine skin. Vet Immunol Immunopathol,2008a,126:236-247.
192. Nfon C K, Ferman G S, Toka F N, et al. Interferon-alpha production by swine dendritic cells is inhibited during acute infection with foot-and-mouth disease virus. Viral Immunol,2008b,21: 68-77.
193.Nijman S M, Luna-Vargas M P, Velds A, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell,2005,123:773-786.
194. Nistal-Villan E, Gack M U, Martinez-Delgado G, et al. Negative role of RIG-I serine 8 phosphorylation in the regulation of interferon-beta production. J Biol Chem,2010,285: 20252-20261.
195. O'Neill L A. The interleukin-1 receptor/Toll-like receptor superfamily:10 years of progress. Immunol Rev,2008,226:10-18.
196. Oganesyan G, Saha S K, Guo B, et al. Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response. Nature,2006,439:208-211.
197. Okumura A, Alce T, Lubyova B, et al. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. Virology,2008,373:85-97.
198. Onoguchi K, Yoneyama M, Takemura A, et al. Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem,2007,282:7576-7581.
199. Opitz B, Rejaibi A, Dauber B, et al. IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol,2007,9:930-938.
200. Oshiumi H, Matsumoto M, Hatakeyama S, et al. Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. J Biol Chem,2009,284:807-817.
201. Oshiumi H, Miyashita M, Inoue N, et al. The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. Cell Host Microbe,2010,8: 496-509.
202. Papon L, Oteiza A, Imaizumi T, et al. The viral RNA recognition sensor RIG-I is degraded during encephalomyocarditis virus (EMCV) infection. Virology,2009,393:311-318.
203. Pashine A, Valiante N M, Ulmer J B. Targeting the innate immune response with improved vaccine adjuvants. Nat Med,2005,11:S63-68.
204. Pestka S, Krause C D, Sarkar D, et al. Interleukin-10 and related cytokines and receptors. Annu Rev Immunol,2004,22:929-979.
205. Piccone M E, Rieder E, Mason P W, et al. The foot-and-mouth disease virus leader proteinase gene is not required for viral replication. J Virol,1995,69:5376-5382.
206. Pichlmair A, Schulz O, Tan C P, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science,2006,314:997-1001.
207. Pickart C M, Eddins M J. Ubiquitin:structures, functions, mechanisms. Biochim Biophys Acta, 2004a,1695:55-72.
208. Pickart C M, Fushman D. Polyubiquitin chains:polymeric protein signals. Curr Opin Chem Biol, 2004b,8:610-616.
209. Pintaric M, Gerner W, Saalmuller A. Synergistic effects of IL-2, IL-12 and IL-18 on cytolytic activity, perforin expression and IFN-gamma production of porcine natural killer cells. Vet Immunol Immunopathol,2008,121:68-82.
210. Plumet S, Herschke F, Bourhis J M, et al. Cytosolic 5'-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response. PLoS One,2007,2: e279.
211. Rabinowitz J D, White E. Autophagy and metabolism. Science,2010,330:1344-1348.
212. Randall R E, Goodbourn S. Interferons and viruses:an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol,2008,89:1-47.
213. Ratia K, Saikatendu K S, Santarsiero B D, et al. Severe acute respiratory syndrome coronavirus papain-like protease:structure of a viral deubiquitinating enzyme. Proc Natl Acad Sci USA, 2006,103:5717-5722.
214. Rhee E G, Blattman J N, Kasturi S P, et al. Multiple innate immune pathways contribute to the immunogenicity of recombinant adenovirus vaccine vectors. J Virol,2011,85:315-323.
215.Robek M D, Boyd B S, Chisari F V. Lambda interferon inhibits hepatitis B and C virus replication. JVirol,2005,79:3851-3854.
216. Roberts P J, Belsham G J. Identification of critical amino acids within the foot-and-mouth disease virus leader protein, a cysteine protease. Virology,1995,213:140-146.
217. Rodrigues L, Filipe J, Seldon M P, et al. Termination of NF-kappaB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase. Embo J,2009,28: 1283-1295.
218. Rosenstiel P, Till A, Schreiber S. NOD-like receptors and human diseases. Microbes Infect,2007, 9:648-657.
219. Rueckert R R, Wimmer E. Systematic nomenclature of picornavirus proteins. J Virol,1984,50: 957-959.
220. Ruggieri A, Franco M, Gatto I, et al. Modulation of RANTES expression by HCV core protein in liver derived cell lines. BMC Gastroenterol,2007,7:21.
221. Ryals J, Dierks P, Ragg H, et al. A 46-nucleotide promoter segment from an IFN-alpha gene renders an unrelated promoter inducible by virus. Cell,1985,41:497-507.
222. Sadler A J, Williams B R. Interferon-inducible antiviral effectors. Nat Rev Immunol,2008,8: 559-568.
223. Saito T, Hirai R, Loo Y M, et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci USA,2007,104:582-587.
224. Saitoh T, Yamamoto M, Miyagishi M, et al. A20 is a negative regulator of IFN regulatory factor 3 signaling. J Immunol,2005,174:1507-1512.
225. Sanchez-Castanon M, Baquero I C, Sanchez-Velasco P, et al. Polymorphisms in CCL5 promoter are associated with pulmonary tuberculosis in northern Spain. Int J Tuberc Lung Dis,2009,13: 480-485.
226. Schlick P, Kronovetr J, Hampoelz B, et al. Modulation of the electrostatic charge at the active site of foot-and-mouth-disease-virus leader proteinase, an unusual papain-like enzyme. Biochem J,2002,363:493-501.
227. Schlieker C, Korbel G A, Kattenhorn L M, et al. A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae. J Virol,2005,79:15582-15585.
228. Scudamore J M, Harris D M. Control of foot and mouth disease:lessons from the experience of the outbreak in Great Britain in 2001. Rev Sci Tech,2002,21:699-710.
229. Seth R B, Sun L, Ea C K, et al. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell,2005,122:669-682.
230. Sheppard P, Kindsvogel W, Xu W, et al.IL-28, IL-29 and their class Ⅱ cytokine receptor IL-28R. Nat Immunol,2003,4:63-68.
231. Shimosato T, Tohno M, Kitazawa H, et al. Toll-like receptor 9 is expressed on follicle-associated epithelia containing M cells in swine Peyer's patches. Immunol Lett,2005,98:83-89.
232. Shinkai H, Tanaka M, Morozumi T, et al. Biased distribution of single nucleotide polymorphisms (SNPs) in porcine Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR5, and TLR6 genes. Immunogenetics,2006,58:324-330.
233. Skern T, Fita I, Guarne A. A structural model of picornavirus leader proteinases based on papain and bleomycin hydrolase. J Gen Virol,1998,79 (Pt 2):301-307.
234. Solis M, Goubau D, Hiscott J. RIG-I has guts:identification of a role for RIG-I in colitis development. Cell Res,2007,17:974-975.
235. Solis M, Nakhaei P, Jalalirad M, et al. RIG-1-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I. J Virol,2011,85:1224-1236.
236. Stahl-Hennig C, Eisenblatter M, Jasny E, et al. Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques. PLoS Pathog,2009,5:el000373.
237. Stancato L F, David M, Carter-Su C, et al. Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation. JBiol Chem,1996,271:4134-4137.
238. Stark G R, Kerr I M, Williams B R, et al. How cells respond to interferons. Annu Rev Biochem, 1998,67:227-264.
239. Stetson D B, Medzhitov R. Type I interferons in host defense. Immunity,2006,25:373-381.
240. Strebel K, Beck E. A second protease of foot-and-mouth disease virus. J Virol,1986,58: 893-899.
241. Summerfield A, Knotig S M, McCullough K C. Lymphocyte apoptosis during classical swine fever:implication of activation-induced cell death. J Virol,1998,72:1853-1861.
242. Sun S C. Deubiquitylation and regulation of the immune response. Nat Rev Immunol,2008,8: 501-511.
243. Sun Z, Chen Z, Lawson S R, et al. The cysteine protease domain of porcine reproductive and respiratory syndrome virus nonstructural protein 2 possesses deubiquitinating and interferon antagonism functions. J Virol,2010,84:7832-7846.
244. Sun Z, Ren H, Liu Y, et al. Phosphorylation of RIG-I by casein kinase Ⅱ inhibits its antiviral response. J Virol,2011,85:1036-1047.
245. Sweet C R, Conlon J, Golenbock D T, et al. YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction. Cell Microbiol,2007,9:2700-2715.
246. Tahara T, Arisawa T, Shibata T, et al. Effect of RANTES promoter genotype on the severity of intestinal metaplasia in Helicobacter pylori-infected Japanese subjects. Dig Dis Sci,2009,54: 1247-1252.
247. Tait S W, Reid E B, Greaves DR,et al. Mechanism of inactivation of NF-kappa B by a viral homologue of I kappa b alpha. Signal-induced release of i kappa b alpha results in binding of the viral homologue to NF-kappa B. J Biol Chem,2000,275:34656-34664.
248. Takahashi K, Kawai T, Kumar H, et al. Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA. J Immunol,2006,176:4520-4524.
249. Takahasi K, Yoneyama M, Nishihori T, et al. Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell,2008,29:428-440.
250. Takaoka A, Taniguchi T. Cytosolic DNA recognition for triggering innate immune responses. Adv Drug Deliv Rev,2008,60:847-857.
251. Takaoka A, Yanai H. Interferon signalling network in innate defence. Cell Microbiol,2006,8: 907-922.
252. Takeshita F, Tanaka T, Matsuda T, et al. Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity. J Virol,2006,80:6218-6224.
253. Talon J, Horvath C M, Polley R, et al. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol,2000,74:7989-7996.
254. Tang X, Gao J S, Guan Y J, et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell,2007,131:93-105.
255.Tenoever B R, Ng S L, Chua M A, et al. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science,2007,315:1274-1278.
256. Tesar M, Marquardt O. Foot-and-mouth disease virus protease 3C inhibits cellular transcription and mediates cleavage of histone H3. Virology,1990,174:364-374.
257. Thanos D, Maniatis T. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell,1995,83:1091-1100.
258. Thomas A V, Broers A D, Vandegaart H F, et al. Genomic structure, promoter analysis and expression of the porcine (Sus scrofa) TLR4 gene. Mol Immunol,2006,43:653-659.
259. Thompson D, Muriel P, Russell D, et al. Economic costs of the foot and mouth disease outbreak in the United Kingdom in 2001. Rev Sci Tech,2002,21:675-687.
260. Tian M, Liu F, Wen G Y, et al. Effect of variation in RANTES promoter on serum RANTES levels and risk of recurrent wheezing after RSV bronchiolitis in children from Han, Southern China. Eur J Pediatr,2009,168:963-967.
261. Ting J P, Willingham S B, Bergstralh D T. NLRs at the intersection of cell death and immunity. Nat Rev Immunol,2008,8:372-379.
262. Toka F N, Nfon C, Dawson H, et al. Natural killer cell dysfunction during acute infection with foot-and-mouth disease virus. Clin Vaccine Immunol,2009,16:1738-1749.
263. Tohno M, Shimosato T, Kitazawa H, et al. Toll-like receptor 2 is expressed on the intestinal M cells in swine. Biochem Biophys Res Commun,2005,330:547-554.
264. Tohno M, Ueda W, Azuma Y, et al. Molecular cloning and functional characterization of porcine nucleotide-binding oligomerization domain-2 (NOD2). Mol Immunol,2008,45:194-203.
265. Trumpfheller C, Caskey M, Nchinda G, et al. The microbial mimic poly IC induces durable and protective CD4+T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci USA,2008,105:2574-2579.
266. Uematsu S, Akira S. Toll-like receptors and Type I interferons. J Biol Chem,2007,282: 15319-15323.
267. van Pesch V, van Eyll O, Michiels T. The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production. J Virol,2001,75:7811-7817.
268. Vilcek J. Novel interferons. Nat Immunol,2003,4:8-9.
269. Viswanathan K, Fruh K, DeFilippis V. Viral hijacking of the host ubiquitin system to evade interferon responses. Curr Opin Microbiol,2010,13:517-523.
270. Wang C, Chen T, Zhang J, et al. The E3 ubiquitin ligase Nrdpl'preferentially'promotes TLR-mediated production of type I interferon. Nat Immunol,2009,10:744-752.
271. Wang Y, Zhang H X, Sun Y P, et al. Rig-I-/-mice develop colitis associated with downregulation of G alpha i2. Cell Res,2007,17:858-868.
272. Wang Y Y, Li L, Han K J, et al. A20 is a potent inhibitor of TLR3 - and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter. FEBS Lett,2004,576:86-90.
273. Wertz I E, O'Rourke K M, Zhou H, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature,2004,430:694-699.
274. Wilkinson K D, Tashayev V L, O'Connor L B, et al. Metabolism of the polyubiquitin degradation signal:structure, mechanism, and role of isopeptidase T. Biochemistry,1995,34:14535-14546.
275. Xiong Y, Lin M, Yuan B, et al. Expression of exogenous IFN-alpha by bypassing the translation block protects cells against FMDV infection. Antiviral Res,2009,84:60-66.
276. Xu L G, Wang Y Y, Han K J, et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell,2005,19:727-740.
277. Yang P C, Chu R M, Chung W B, et al. Epidemiological characteristics and financial costs of the 1997 foot-and-mouth disease epidemic in Taiwan. Vet Rec,1999,145:731-734.
278. Yang Y, Liang Y, Qu L, et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci U S A,2007,104:7253-7258.
279. Yao Q, Huang Q, Cao Y, et al. Porcine interferon-gamma protects swine from foot-and-mouth disease virus (FMDV). Vet Immunol Immunopathol,2008,122:309-311.
280. Yao T C, Tsai Y C, Huang J L. Association of RANTES promoter polymorphism with juvenile rheumatoid arthritis. Arthritis Rheum,2009,60:1173-1178.
281. Yie J, Senger K, Thanos D. Mechanism by which the IFN-beta enhanceosome activates transcription. Proc Natl Acad Sci USA,1999,96:13108-13113.
282. Yoneyama M, Fujita T. RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev,2009,227:54-65.
283. Yoneyama M, Fujita T. Structural mechanism of RNA recognition by the RIG-I-like receptors. Immunity,2008,29:178-181.
284. Yoneyama M, Kikuchi M, Matsumoto K, et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol,2005,175: 2851-2858.
285. Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol,2004,5:730-737.
286. Zhang M, Wu X, Lee A J, et al. Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem,2008a,283:18621-18626.
287. Zhang N N, Shen S H, Jiang L J, et al. RIG-1 plays a critical role in negatively regulating granulocytic proliferation. Proc Natl Acad Sci U S A,2008b,105:10553-10558.
288. Zheng D, Chen G, Guo B, et al. PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production. Cell Res,2008,18:1105-1113.
289. Ziegler E, Borman A M, Kirchweger R, et al. Foot-and-mouth disease virus Lb proteinase can stimulate rhinovirus and enterovirus IRES-driven translation and cleave several proteins of cellular and viral origin. J Virol,1995,69:3465-3474.
290. Zoll J, Melchers W J, Galama J M, et al. The mengovirus leader protein suppresses alpha/beta interferon production by inhibition of the iron/ferritin-mediated activation of NF-kappa B. J Virol, 2002,76:9664-9672.
2. 李军,曾芸.病毒诱导Ⅰ型干扰素产生的机制.生命的化学,2006,26：395-398.
3. 李婷婷.猪源VISA基因及其突变体的克隆与真核表达.[学士学位论文].武汉：华中农业大学图书馆,2007.
4. 李臻,张远强.p趋化性细胞因子RANTES的研究进展.生理科学进展,2006,37：79-82.
5. 秦成峰,秦鄂德.RIG-I样受体与RNA病毒识别.微生物学报,2008,48：1418-1423
6. 舒红兵.抗病毒天然免疫.北京：科学出版社,2009.
7. 王素霞,刘媛,吴慧娟等.去泛素化酶的研究及其进展.临床与实验病理学杂志,2008,24：734-737.
8. 吴学宝.猪瘟病毒影响RANTES产生分子机制的研究.[硕士学位论文].武汉：华中农业大学图书馆,2010.
9. 殷震,刘景华.动物病毒学.北京：科学出版社,1997.
10.赵付伟.猪Ⅲ型干扰素IFN-λ1的克隆、表达和抗病毒活性研究[硕士学位论文].武汉：华中农业大学图书馆,2010.
11. Abe T, Hemmi H, Miyamoto H, et al. Involvement of the Toll-like receptor 9 signaling pathway in the induction of innate immunity by baculovirus. J Virol,2005,79:2847-2858.
12. Abe T, Takahashi H, Hamazaki H, et al. Baculovirus induces an innate immune response and confers protection from lethal influenza virus infection in mice. J Immunol,2003,171: 1133-1139.
13. Akira S. Pathogen recognition by innate immunity and its signaling. Proc Jpn Acad Ser B Phys Biol Sci,2009,85:143-156.
14. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol,2004,4:499-511.
15. Alvarez B, Revilla C, Chamorro S, et al. Molecular cloning, characterization and tissue expression of porcine Toll-like receptor 4. Dev Comp Immunol,2006,30:345-355.
16. Alves M P, Neuhaus V, Guzylack-Piriou L, et al. Toll-like receptor 7 and MyD88 knockdown by lentivirus-mediated RNA interference to porcine dendritic cell subsets. Gene Ther,2007,14: 836-844.
17. Amanatidou V, Sourvinos G, Apostolakis S, et al. RANTES promoter gene polymorphisms and susceptibility to severe respiratory syncytial virus-induced bronchiolitis. Pediatr Infect Dis J, 2008,27:38-42.
18. Andersen J, VanScoy S, Cheng T F, et al. IRF-3-dependent and augmented target genes during viral infection. Genes Immun,2008,9:168-175.
19. Andrejeva J, Childs K S, Young D F, et al. The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter. Proc Natl Acad Sci USA,2004,101:17264-17269.
20. Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol,2006a,80:4501-4509.
21. Ank N, West H, Paludan S R. IFN-lambda:novel antiviral cytokines. J Interferon Cytokine Res, 2006b,26:373-379.
22. Arimoto K, Takahashi H, Hishiki T, et al. Negative regulation of the RIG-I signaling by the ubiquitin ligase RNF125. Proc Natl Acad Sci USA,2007,104:7500-7505.
23. Aust G, Brylla E, Lehmann I, et al. Cloning of bovine RANTES mRNA and its expression and regulation in ovaries in the periovulatory period. FEBS Lett,1999,463:160-164.
24. Balakirev M Y, Jaquinod M, Haas A L, et al. Deubiquitinating function of adenovirus proteinase. J Virol,2002,76:6323-6331.
25. Bao X, Liu T, Shan Y, et al. Human metapneumovirus glycoprotein G inhibits innate immune responses. PLoS Pathog,2008,4:e1000077.
26. Barral P M, Morrison J M, Drahos J, et al. MDA-5 is cleaved in poliovirus-infected cells. J Virol, 2007,81:3677-3684.
27. Barral P M, Sarkar D, Fisher P B, et al. RIG-I is cleaved during picornavirus infection. Virology, 2009,391:171-176.
28. Barretto N, Jukneliene D, Ratia K, et al. The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol,2005,79:15189-15198.
29. Barro M, Patton J T. Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3,1RF5, and IRF7. J Virol,2007,81:4473-4481.
30. Bauer S, Pigisch S, Hangel D, et al. Recognition of nucleic acid and nucleic acid analogs by Toll-like receptors 7,8 and 9. Immunobiology,2008,213:315-328.
31. Bautista E M, Ferman G S, Golde W T. Induction of lymphopenia and inhibition of T cell function during acute infection of swine with foot and mouth disease virus (FMDV). Vet Immunol Immunopathol,2003,92:61-73.
32. Bautista E M, Ferman G S, Gregg D, et al. Constitutive expression of alpha interferon by skin dendritic cells confers resistance to infection by foot-and-mouth disease virus. J Virol,2005,79: 4838-4847.
33. Bautista E M, Gregg D, Golde W T. Characterization and functional analysis of skin-derived dendritic cells from swine without a requirement for in vitro propagation. Vet Immunol Immunopathol,2002,88:131-148.
34. Bautista E M, Nfon C, Ferman G S, et al. IL-13 replaces IL-4 in development of monocyte derived dendritic cells (MoDC) of swine. Vet Immunol Immunopathol,2007,115:56-67.
35. Baxt B, Mason P W. Foot-and-mouth disease virus undergoes restricted replication in macrophage cell cultures following Fc receptor-mediated adsorption. Virology,1995,207: 503-509.
36. Belsham G J, Brangwyn J K. A region of the 5'noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells:involvement with the role of L protease in translational control. J Virol,1990,64:5389-5395.
37. Belsham G J, Mclnerney G M, Ross-Smith N. Foot-and-mouth disease virus 3C protease induces cleavage of translation initiation factors eIF4A and eIF4G within infected cells.J Virol,2000,74: 272-280.
38. Bhoj V G, Chen Z J. Ubiquitylation in innate and adaptive immunity. Nature,2009,458: 430-437.
39. Biacchesi S, Skiadopoulos M H, Yang L, et al. Recombinant human Metapneumovirus lacking the small hydrophobic SH and/or attachment G glycoprotein:deletion of G yields a promising vaccine candidate. J Virol,2004,78:12877-12887.
40. Bless N M, Huber-Lang M, Guo R F, et al. Role of CC chemokines (macrophage inflammatory protein-1 beta, monocyte chemoattractant protein-1, RANTES) in acute lung injury in rats. J Immunol,2000,164:2650-2659.
41. Boger C A, Fischereder M, Deinzer M, et al. RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients. Atherosclerosis,2005, 183:121-129.
42. Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol,2004,25:280-288.
43. Borca M V, Gudmundsdottir I, Fernandez-Sainz I J, et al. Patterns of cellular gene expression in swine macrophages infected with highly virulent classical swine fever virus strain Brescia. Virus Res,2008,138:89-96.
44. Brand S, Beigel F, Olszak T, et al. IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. Am JPhysiol Gastrointest Liver Physiol,2005,289:G960-968.
45. Brown C C, Piccone M E, Mason P W, et al. Pathogenesis of wild-type and leaderless foot-and-mouth disease virus in cattle. J Virol,1996,70:5638-5641.
46. Capozzo A V, Burke D J, Fox J W, et al. Expression of foot and mouth disease virus non-structural polypeptide 3ABC induces histone H3 cleavage in BHK21 cells. Virus Res,2002, 90:91-99.
47. Carrasco C P, Rigden R C, Schaffner R, et al. Porcine dendritic cells generated in vitro: morphological, phenotypic and functional properties. Immunology,2001,104:175-184.
48. Casola A, Garofalo R P, Haeberle H, et al. Multiple cis regulatory elements control RANTES promoter activity in alveolar epithelial cells infected with respiratory syncytial virus. J Virol, 2001,75:6428-6439.
49. Casola A, Henderson A, Liu T, et al. Regulation of RANTES promoter activation in alveolar epithelial cells after cytokine stimulation. Am J Physiol Lung Cell Mol Physiol,2002,283: L1280-1290.
50. Castaldello A, Sgarbanti M, Marsili G, et al. Interferon regulatory factor-1 acts as a powerful adjuvant in tat DNA based vaccination. J Cell Physiol,224:702-709.
51. Centi S, Negrisolo S, Stefanic A, et al. Upper urinary tract infections are associated with RANTES promoter polymorphism. JPediatr,157:1038-1040 e1031.
52. Chen C J, Chen J H, Chen S Y, et al. Upregulation of RANTES gene expression in neuroglia by Japanese encephalitis virus infection. J Virol,2004,78:12107-12119.
53. Chen Z, Rijnbrand R, Jangra R K, et al. Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. Virology,2007a,366:277-292.
54. Chen Z, Wang Y, Ratia K, et al. Proteolytic processing and deubiquitinating activity of papain-like proteases of human coronavirus NL63. J Virol,2007b,81:6007-6018.
55. Cheng G, Zhong J, Chung J, et al. Double-stranded DNA and double-stranded RNA induce a common antiviral signaling pathway in human cells. Proc Natl Acad Sci USA,2007,104: 9035-9040.
56. Childs K, Stock N, Ross C, et al. mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology,2007,359:190-200.
57. Chinsangaram J, Koster M, Grubman M J. Inhibition of L-deleted foot-and-mouth disease virus replication by alpha/beta interferon involves double-stranded RNA-dependent protein kinase. J Virol,2001,75:5498-5503.
58. Chinsangaram J, Mason P W, Grubman M J. Protection of swine by live and inactivated vaccines prepared from a leader proteinase-deficient serotype A12 foot-and-mouth disease virus. Vaccine, 1998,16:1516-1522.
59. Chinsangaram J, Piccone M E, Grubman M J. Ability of foot-and-mouth disease virus to form plaques in cell culture is associated with suppression of alpha/beta interferon. J Virol,1999,73: 9891-9898.
60. Clarke B E, Sangar D V, Burroughs J N, et al. Two initiation sites for foot-and-mouth disease virus polyprotein in vivo. J Gen Virol,1985,66 (Pt 12):2615-2626.
61. Clementz M A, Chen Z, Banach B S, et al. Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases. J Virol,2010,84:4619-4629.
62. Coffman R L, Sher A, Seder R A. Vaccine adjuvants:putting innate immunity to work. Immunity, 2010,33:492-503.
63. Dai X, Sayama K, Tohyama M, et al. The NF-kappaB, p38 MAPK and STAT1 pathways differentially regulate the dsRNA-mediated innate immune responses of epidermal keratinocytes. Int Immunol,2008,20:901-909.
64. Danoff T M, Lalley P A, Chang Y S, et al. Cloning, genomic organization, and chromosomal localization of the Scya5 gene encoding the murine chemokine RANTES. J Immunol,1994,152: 1182-1189.
65. Dauber B, Schneider J, Wolff T. Double-stranded RNA binding of influenza B virus nonstructural NS1 protein inhibits protein kinase R but is not essential to antagonize production of alpha/beta interferon. J Virol,2006,80:11667-11677.
66. de Los Santos T, de Avila Botton S, Weiblen R, et al. The leader proteinase of foot-and-mouth disease virus inhibits the induction of beta interferon mRNA and blocks the host innate immune response. J Virol,2006,80:1906-1914.
67. de Los Santos T, Diaz-San Segundo F, Grubman M J. Degradation of nuclear factor kappa B during foot-and-mouth disease virus infection. J Virol,2007,81:12803-12815.
68. de los Santos T, Segundo F D, Zhu J, et al. A conserved domain in the leader proteinase of foot-and-mouth disease virus is required for proper subcellular localization and function. J Virol, 2009,83:1800-1810.
69. Delhaye S, van Pesch V, Michiels T. The leader protein of Theiler's virus interferes with nucleocytoplasmic trafficking of cellular proteins. J Virol,2004,78:4357-4362.
70. Deng L, Wang C, Spencer E, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell,2000, 103:351-361.
71. Devaney M A, Vakharia V N, Lloyd R E, et al. Leader protein of foot-and-mouth disease virus is required for cleavage of the p220 component of the cap-binding protein complex. J Virol,1988, 62:4407-4409.
72. Devaraj S G, Wang N, Chen Z, et al. Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J Biol Chem, 2007,282:32208-32221.
73. Diao F, Li S, Tian Y, et al. Negative regulation of MDA5-but not RIG-I-mediated innate antiviral signaling by the dihydroxyacetone kinase. Proc Natl Acad Sci USA,2007,104: 11706-11711.
74. Dias C C, Moraes M P, Segundo F D, et al. Porcine type I interferon rapidly protects swine against challenge with multiple serotypes of foot-and-mouth disease virus. J Interferon Cytokine Res,2011,31:227-236.
75. Diaz-San Segundo F, Salguero F J, de Avila A, et al. Selective lymphocyte depletion during the early stage of the immune response to foot-and-mouth disease virus infection in swine. J Virol, 2006,80:2369-2379.
76. Donelan N R, Basler C F, Garcia-Sastre A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J Virol,2003,77:13257-13266.
77. Elliott M B, Tebbey P W, Pryharski K S, et al. Inhibition of respiratory syncytial virus infection with the CC chemokine RANTES (CCL5). JMed Virol,2004,73:300-308.
78. Etchison D, Milburn S C, Edery I, et al. Inhibition of HeLa cell protein synthesis following poliovirus infection correlates with the proteolysis of a 220,000-dalton polypeptide associated with eucaryotic initiation factor 3 and a cap binding protein complex. J Biol Chem,1982,257: 14806-14810.
79. Falk M M, Grigera P R, Bergmann I E, et al. Foot-and-mouth disease virus protease 3C induces specific proteolytic cleavage of host cell histone H3. J Virol,1990,64:748-756.
80. Fan L, Briese T, Lipkin W I. Z proteins of New World arenaviruses bind RIG-I and interfere with type I interferon induction. J Virol,2010,84:1785-1791.
81. Fang Q, Wang F, Zhao D. Association between regulated upon activation, normal T cells expressed and secreted (RANTES)-28C/G polymorphism and asthma risk--a meta-analysis. Int J Med Sci,2010,7:55-61.
82. Fernandes-Alnemri T, Yu J W, Datta P, et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature,2009,458:509-513.
83. Finberg R W, Wang J P, Kurt-Jones E A. Toll like receptors and viruses. Rev Med Virol,2007,17: 35-43.
84. Finlay B B, McFadden G. Anti-immunology:evasion of the host immune system by bacterial and viral pathogens. Cell,2006,124:767-782.
85. Foeger N, Glaser W, Skern T. Recognition of eukaryotic initiation factor 4G isoforms by picornaviral proteinases. J Biol Chem,2002,277:44300-44309.
86. Fredericksen B L, Keller B C, Fornek J, et al. Establishment and maintenance of the innate antiviral response to West Nile Virus involves both RIG-I and MDA5 signaling through IPS-1. J Virol,2008,82:609-616.
87. Frias-Staheli N, Giannakopoulos N V, Kikkert M, et al. Ovarian tumor domain-containing viral proteases evade ubiquitin-and ISG15-dependent innate immune responses. Cell Host Microbe, 2007,2:404-416.
88. Friedman C S, O'Donnell M A, Legarda-Addison D, et al. The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response. EMBO Rep,2008,9:930-936.
89. Frieman M, Ratia K, Johnston R E, et al. Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling. J Virol,2009,83:6689-6705.
90. Gack M U, Nistal-Villan E, Inn K S, et al. Phosphorylation-mediated negative regulation of RIG-I antiviral activity. J Virol,2010,84:3220-3229.
91. Gack M U, Shin Y C, Joo C H, et al. TRIM25 RING-finger E3 ubiquitin ligase is essential for RIG-I-mediated antiviral activity. Nature,2007,446:916-920.
92. Gad H H, Dellgren C, Hamming O J, et al. Interferon-lambda is functionally an interferon but structurally related to the interleukin-10 family. JBiol Chem,2009,284:20869-20875.
93. Garcia-Briones M, Rosas M F, Gonzalez-Magaldi M, et al. Differential distribution of non-structural proteins of foot-and-mouth disease virus in BHK-21 cells. Virology,2006,349: 409-421.
94. Gatot J S, Gioia R, Chau T L, et al. Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. J Biol Chem,2007,282:31131-31146.
95. Geiss G, Jin G, Guo J, et al. A comprehensive view of regulation of gene expression by double-stranded RNA-mediated cell signaling. J Biol Chem,2001,276:30178-30182.
96. Genin P, Algarte M, Roof P, et al. Regulation of RANTES chemokine gene expression requires cooperativity between NF-kappa B and IFN-regulatory factor transcription factors. J Immunol, 2000,164:5352-5361.
97. Genin P, Vaccaro A, Civas A. The role of differential expression of human interferon--a genes in antiviral immunity. Cytokine Growth Factor Rev,2009,20:283-295.
98. Gilliet M, Cao W, Liu Y J. Plasmacytoid dendritic cells:sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol,2008,8:594-606.
99. Gitlin L, Barchet W, Gilfillan S, et al. Essential role of mda-5 in type Ⅰ IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picomavirus. Proc Natl Acad Sci USA,2006,103:8459-8464.
100. Golde W T, Nfon C K, Toka F N. Immune evasion during foot-and-mouth disease virus infection of swine. Immunol Rev,2008,225:85-95.
101. Gorbalenya A E, Koonin E V, Lai M M. Putative papain-related thiol proteases of positive-strand RNA viruses. Identification of rubi- and aphthovirus proteases and delineation of a novel conserved domain associated with proteases of rubi-, alpha-and coronaviruses. FEBS Lett,1991, 288:201-205.
102. Graff J W, Ettayebi K, Hardy M E. Rotavirus NSP1 inhibits NFkappaB activation by inducing proteasome-dependent degradation of beta-TrCP:a novel mechanism of IFN antagonism. PLoS Pathog,2009,5:el000280.
103. Gregg D A, Schlafer D H, Mebus C A. African swine fever virus infection of skin-derived dendritic cells in vitro causes interference with subsequent foot-and-mouth disease virus infection. J Vet Diagn Invest,1995,7:44-51.
104. Grigera P R, Tisminetzky S G. Histone H3 modification in BHK cells infected with foot-and-mouth disease virus. Virology,1984,136:10-19.
105. Grubman M J, Baxt B. Foot-and-mouth disease. Clin Microbiol Rev,2004,17:465-493.
106. Grubman M J, Moraes M P, Diaz-San Segundo F, et al. Evading the host immune response:how foot-and-mouth disease virus has become an effective pathogen. FEMS Immunol Med Microbiol, 2008,53:8-17.
107. Guo Z, Chen L M, Zeng H, et al. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I.Am JRespir Cell Mol Biol,2007,36:263-269.
108. Guzylack-Piriou L, Balmelli C, McCullough K C, et al. Type-A CpG oligonucleotides activate exclusively porcine natural interferon-producing cells to secrete interferon-alpha, tumour necrosis factor-alpha and interleukin-12. Immunology,2004,112:28-37.
109. Guzylack-Piriou L, Bergamin F, Gerber M, et al. Plasmacytoid dendritic cell activation by foot-and-mouth disease virus requires immune complexes. Eur J Immunol,2006,36:1674-1683.
110. Habjan M, Andersson I, Klingstrom J, et al. Processing of genome 5'termini as a strategy of negative-strand RNA viruses to avoid RIG-I-dependent interferon induction. PLoS One,2008,3: e2032.
111. Hartman Z C, Appledorn D M, Amalfitano A. Adenovirus vector induced innate immune responses:impact upon efficacy and toxicity in gene therapy and vaccine applications. Virus Res, 2008,132:1-14.
112. Hato S V, Ricour C, Schulte B M, et al. The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3. Cell Microbiol,2007,9:2921-2930.
113. Hayden M S, Ghosh S. Shared principles in NF-kappaB signaling. Cell,2008,132:344-362.
114. Hayden M S, Ghosh S. Signaling to NF-kappaB. Genes Dev,2004,18:2195-2224.
115. Hervas-Stubbs S, Rueda P, Lopez L, et al. Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN. J Immunol,2007,178:2361-2369.
116. Hilton L, Moganeradj K, Zhang G, et al. The NPro product of bovine viral diarrhea virus inhibits DNA binding by interferon regulatory factor 3 and targets it for proteasomal degradation. J Virol, 2006,80:11723-11732.
117. Hiscott J. Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. Cytokine Growth Factor Rev,2007a,18:483-490.
118. Hiscott J. Triggering the innate antiviral response through IRF-3 activation. JBiol Chem,2007b, 282:15325-15329.
119. Hiura T S, Kempiak S J, Nel A E. Activation of the human RANTES gene promoter in a macrophage cell line by lipopolysaccharide is dependent on stress-activated protein kinases and the IkappaB kinase cascade:implications for exacerbation of allergic inflammation by environmental pollutants. Clin Immunol,1999,90:287-301.
120. Honda K, Yanai H, Takaoka A, et al. Regulation of the type I IFN induction:a current view. Int Immunol,2005,17:1367-1378.
121. Hong S W, Kim S, Lee D K. The role of Bach2 in nucleic acid-triggered antiviral innate immune responses. Biochem Biophys Res Commun,2008,365:426-432.
122. Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature,2009,458:514-518.
123. Hornung V, Ellegast J, Kim S, et al.5'-Triphosphate RNA is the ligand for RIG-I. Science,2006, 314:994-997.
124. Hou W, Wang X, Ye L, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol,2009,83:3834-3842.
125. Hu M, Li P, Song L, et al. Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. Embo J,2005,24:3747-3756.
126. Isaacson M K, Ploegh H L. Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe,2009,5:559-570.
127. Ishii K J, Kawagoe T, Koyama S, et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature,2008,451:725-729.
128. Jiang D, Guo H, Xu C, et al. Identification of three interferon-inducible cellular enzymes that inhibit the replication of hepatitis C virus. J Virol,2008,82:1665-1678.
129. Jin M S, Lee J O. Structures of the toll-like receptor family and its ligand complexes. Immunity, 2008,29:182-191.
130. Johansson E, Domeika K, Berg M, et al. Characterisation of porcine monocyte-derived dendritic cells according to their cytokine profile. Vet Immunol Immunopathol,2003,91:183-197.
131.Jounai N, Takeshita F, Kobiyama K, et al. The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci USA,2007,104:14050-14055.
132. Kato H, Sato S, Yoneyama M, et al. Cell type-specific involvement of RIG-I in antiviral response. Immunity,2005,23:19-28.
133. Kato H, Takeuchi O, Mikamo-Satoh E, et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.J Exp Med,2008,205:1601-1610.
134. Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature,2006,441:101-105.
135. Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol,2006,7:131-137.
136. Kawai T, Akira S. SnapShot: Pattern-recognition receptors. Cell,2007,129:1024.
137. Kawai T, Takahashi K, Sato S, et al. IPS-1, an adaptor triggering RIG-I-and Mda5-mediated type I interferon induction. Nat Immunol,2005,6:981-988.
138. Kayagaki N, Phung Q, Chan S, et al. DUBA:a deubiquitinase that regulates type I interferon production. Science,2007,318:1628-1632.
139. Kim E T, Oh S E, Lee Y O, et al. Cleavage specificity of the UL48 deubiquitinating protease activity of human cytomegalovirus and the growth of an active-site mutant virus in cultured cells. J Virol,2009,83:12046-12056.
140. Kim T K, Maniatis T. The mechanism of transcriptional synergy of an in vitro assembled interferon-beta enhanceosome. Mol Cell,1997,1:119-129.
141. Kirchweger R, Ziegler E, Lamphear B J, et al. Foot-and-mouth disease virus leader proteinase: purification of the Lb form and determination of its cleavage site on eIF-4 gamma. J Virol,1994, 68:5677-5684.
142. Kleina L G, Grubman M J. Antiviral effects of a thiol protease inhibitor on foot-and-mouth disease virus. J Virol,1992,66:7168-7175.
143. Kobiyama K, Takeshita F, Ishii K J, et al. A signaling polypeptide derived from an innate immune adaptor molecule can be harnessed as a new class of vaccine adjuvant. J Immunol,2009, 182:1593-1601.
144. Kojima-Shibata C, Shinkai H, Morozumi T, et al. Differences in distribution of single nucleotide polymorphisms among intracellular pattern recognition receptors in pigs. Immunogenetics,2009, 61:153-160.
145. Komuro A, Bamming D, Horvath C M. Negative regulation of cytoplasmic RNA-mediated antiviral signaling. Cytokine,2008,43:350-358.
146. Kotenko S V, Gallagher G, Baurin V V, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol,2003,4:69-77.
147. Koyama S, Ishii K J, Coban C, et al. Innate immune response to viral infection. Cytokine,2008, 43:336-341.
148. Krieg A M. The toll of too much TLR7. Immunity,2007,27:695-697.
149. Kudo T, Lu H, Wu J Y, et al. Regulation of RANTES promoter activation in gastric epithelial cells infected with Helicobacter pylori. Infect Immun,2005,73:7602-7612.
150. Kuhn R, Luz N, Beck E. Functional analysis of the internal translation initiation site of foot-and-mouth disease virus.J Virol,1990,64:4625-4631.
151. La Rocca S A, Herbert R J, Crooke H, et al. Loss of interferon regulatory factor 3 in cells infected with classical swine fever virus involves the N-terminal protease, Npro. J Virol,2005, 79:7239-7247.
152. Larsen K C, Spencer A J, Goodman A L, et al. Expression of takl and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines. Vaccine,2009,27:5589-5598.
153. Lastra J M, Galindo R C, Gortazar C, et al. Expression of immunoregulatory genes in peripheral blood mononuclear cells of European wild boar immunized with BCG. Vet Microbiol,2009,134: 334-339.
154. Leforban Y. Prevention measures against foot-and-mouth disease in Europe in recent years. Vaccine,1999,17:1755-1759.
155. Lefort S, Soucy-Faulkner A, Grandvaux N, et al. Binding of Kaposi's sarcoma-associated herpesvirus K-bZIP to interferon-responsive factor 3 elements modulates antiviral gene expression. J Virol,2007,81:10950-10960.
156. Lei X, Liu X, Ma Y, et al. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol,2010, 84:8051-8061.
157. Li H, Ma G, Gui D, et al. Characterization of the porcine p65 subunit of NF-kappaB and its association with virus antibody levels. Mol Immunol,2011,48:914-923.
158. Li M C, Wang H Y, Wang H Y, et al. Liposome-mediated IL-28 and IL-29 expression in A549 cells and anti-viral effect of IL-28 and IL-29 on WISH cells. Acta Pharmacol Sin,2006,27: 453-459.
159. Lin R, Genin P, Mamane Y, et al. HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene,2001,20: 800-811.
160. Lin R, Heylbroeck C, Genin P, et al. Essential role of interferon regulatory factor 3 in direct activation of RANTES chemokine transcription. Mol Cell Biol,1999,19:959-966.
161. Lin R, Noyce R S, Collins S E, et al. The herpes simplex virus ICPO RING finger domain inhibits IRF3-and IRF7-mediated activation of interferon-stimulated genes. J Virol,2004,78: 1675-1684.
162. Lin R, Yang L, Nakhaei P, et al. Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. J Biol Chem,2006,281: 2095-2103.
163. Lindner H A, Fotouhi-Ardakani N, Lytvyn V, et al. The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J Virol,2005,79: 15199-15208.
164. Lindner H A, Lytvyn V, Qi H, et al. Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys,2007,466:8-14.
165. Lisnic V J, Krmpotic A, Jonjic S. Modulation of natural killer cell activity by viruses. Curr Opin Microbiol,2010,13:530-539.
166. Lladser A, Mougiakakos D, Tufvesson H, et al. DAI (DLM-1/ZBP1) as a Genetic Adjuvant for DNA Vaccines That Promotes Effective Antitumor CTL Immunity. Mol Ther,2011,19:594-601.
167. Lokuta M A, Maher J, Noe K H, et al. Mechanisms of murine RANTES chemokine gene induction by Newcastle disease virus. JBiol Chem,1996,271:13731-13738.
168. Longhi M P, Trumpfheller C, Idoyaga J, et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+Thl immunity with poly IC as adjuvant. J Exp Med,2009, 206:1589-1602.
169. Loo Y M, Fornek J, Crochet N, et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. J Virol,2008,82:335-345.
170. Luo M, Qu X, Pan R, et al. The virus-induced signaling adaptor molecule enhances DNA-raised immune protection against H5N1 influenza virus infection in mice. Vaccine,2011,29: 2561-2567.
171. Luo R, Xiao S, Jiang Y, et al. Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon-beta production by interfering with the RIG-I signaling pathway. Mol Immunol,2008,45:2839-2846.
172. Ma D, Jiang D, Qing M, et al. Antiviral effect of interferon lambda against West Nile virus. Antiviral Res,2009,83:53-60.
173. Mao A P, Li S, Zhong B, et al. Virus-triggered ubiquitination of TRAF3/6 by cIAPl/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J Biol Chem,2010, 285:9470-9476.
174. Mason P W, Grubman M J, Baxt B. Molecular basis of pathogenesis of FMDV. Virus Res,2003, 91:9-32.
175. Mason P W, Piccone M E, McKenna T S, et al. Evaluation of a live-attenuated foot-and-mouth disease virus as a vaccine candidate. Virology,1997,227:96-102.
176. Matsukura S, Kokubu F, Kurokawa M, et al. Synthetic double-stranded RNA induces multiple genes related to inflammation through Toll-like receptor 3 depending on NF-kappaB and/or IRF-3 in airway epithelial cells. Clin Exp Allergy,2006,36:1049-1062.
177. Medina M, Domingo E, Brangwyn J K, et al. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology,1993,194: 355-359.
178. Melchjorsen J, Paludan S R. Induction of RANTES/CCL5 by herpes simplex virus is regulated by nuclear factor kappa B and interferon regulatory factor 3. J Gen Virol,2003,84:2491-2495.
179. Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature,2005,437:1167-1172.
180. Mibayashi M, Martinez-Sobrido L, Loo Y M, et al. Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol,2007,81: 514-524.
181. Miyamoto N G, Medberry P S, Hesselgesser J, et al. Interleukin-lbeta induction of the chemokine RANTES promoter in the human astrocytoma line CH235 requires both constitutive and inducible transcription factors. JNeuroimmunol,2000,105:78-90.
182. Moffat K, Howell G, Knox C, et al. Effects of foot-and-mouth disease virus nonstructural proteins on the structure and function of the early secretory pathway:2BC but not 3A blocks endoplasmic reticulum-to-Golgi transport. J Virol,2005,79:4382-4395.
183. Moffat K, Knox C, Howell G, et al. Inhibition of the secretory pathway by foot-and-mouth disease virus 2BC protein is reproduced by coexpression of 2B with 2C, and the site of inhibition is determined by the subcellular location of 2C. J Virol,2007,81:1129-1139.
184. Moraes M P, de Los Santos T, Koster M, et al. Enhanced antiviral activity against foot-and-mouth disease virus by a combination of type Ⅰ and Ⅱ porcine interferons. J Virol,2007, 81:7124-7135.
185. Mordstein M, Kochs G, Dumoutier L, et al. Interferon-lambda contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLoS Pathog,2008,4: e1000151.
186. Moriuchi H, Moriuchi M, Fauci A S. Nuclear factor-kappa B potently up-regulates the promoter activity of RANTES, a chemokine that blocks HIV infection. J Immunol,1997,158:3483-3491.
187. Muneta Y, Uenishi H, Kikuma R, et al. Porcine TLR2 and TLR6:identification and their involvement in Mycoplasma hyopneumoniae infection. J Interferon Cytokine Res,2003,23: 583-590.
188. Nakhaei P, Genin P, Civas A, et al. RIG-I-like receptors:sensing and responding to RNA virus infection. Semin Immunol,2009,21:215-222.
189. Nardese V, Longhi R, Polo S, et al. Structural determinants of CCR5 recognition and HIV-1 blockade in RANTES. Nat Struct Biol,2001,8:611-615.
190. Nelson P J, Kim H T, Manning W C, et al. Genomic organization and transcriptional regulation of the RANTES chemokine gene. J Immunol,1993,151:2601-2612.
191.Nfon C K, Dawson H, Toka F N, et al. Langerhans cells in porcine skin. Vet Immunol Immunopathol,2008a,126:236-247.
192. Nfon C K, Ferman G S, Toka F N, et al. Interferon-alpha production by swine dendritic cells is inhibited during acute infection with foot-and-mouth disease virus. Viral Immunol,2008b,21: 68-77.
193.Nijman S M, Luna-Vargas M P, Velds A, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell,2005,123:773-786.
194. Nistal-Villan E, Gack M U, Martinez-Delgado G, et al. Negative role of RIG-I serine 8 phosphorylation in the regulation of interferon-beta production. J Biol Chem,2010,285: 20252-20261.
195. O'Neill L A. The interleukin-1 receptor/Toll-like receptor superfamily:10 years of progress. Immunol Rev,2008,226:10-18.
196. Oganesyan G, Saha S K, Guo B, et al. Critical role of TRAF3 in the Toll-like receptor-dependent and-independent antiviral response. Nature,2006,439:208-211.
197. Okumura A, Alce T, Lubyova B, et al. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. Virology,2008,373:85-97.
198. Onoguchi K, Yoneyama M, Takemura A, et al. Viral infections activate types I and III interferon genes through a common mechanism. J Biol Chem,2007,282:7576-7581.
199. Opitz B, Rejaibi A, Dauber B, et al. IFNbeta induction by influenza A virus is mediated by RIG-I which is regulated by the viral NS1 protein. Cell Microbiol,2007,9:930-938.
200. Oshiumi H, Matsumoto M, Hatakeyama S, et al. Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. J Biol Chem,2009,284:807-817.
201. Oshiumi H, Miyashita M, Inoue N, et al. The ubiquitin ligase Riplet is essential for RIG-I-dependent innate immune responses to RNA virus infection. Cell Host Microbe,2010,8: 496-509.
202. Papon L, Oteiza A, Imaizumi T, et al. The viral RNA recognition sensor RIG-I is degraded during encephalomyocarditis virus (EMCV) infection. Virology,2009,393:311-318.
203. Pashine A, Valiante N M, Ulmer J B. Targeting the innate immune response with improved vaccine adjuvants. Nat Med,2005,11:S63-68.
204. Pestka S, Krause C D, Sarkar D, et al. Interleukin-10 and related cytokines and receptors. Annu Rev Immunol,2004,22:929-979.
205. Piccone M E, Rieder E, Mason P W, et al. The foot-and-mouth disease virus leader proteinase gene is not required for viral replication. J Virol,1995,69:5376-5382.
206. Pichlmair A, Schulz O, Tan C P, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science,2006,314:997-1001.
207. Pickart C M, Eddins M J. Ubiquitin:structures, functions, mechanisms. Biochim Biophys Acta, 2004a,1695:55-72.
208. Pickart C M, Fushman D. Polyubiquitin chains:polymeric protein signals. Curr Opin Chem Biol, 2004b,8:610-616.
209. Pintaric M, Gerner W, Saalmuller A. Synergistic effects of IL-2, IL-12 and IL-18 on cytolytic activity, perforin expression and IFN-gamma production of porcine natural killer cells. Vet Immunol Immunopathol,2008,121:68-82.
210. Plumet S, Herschke F, Bourhis J M, et al. Cytosolic 5'-triphosphate ended viral leader transcript of measles virus as activator of the RIG I-mediated interferon response. PLoS One,2007,2: e279.
211. Rabinowitz J D, White E. Autophagy and metabolism. Science,2010,330:1344-1348.
212. Randall R E, Goodbourn S. Interferons and viruses:an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol,2008,89:1-47.
213. Ratia K, Saikatendu K S, Santarsiero B D, et al. Severe acute respiratory syndrome coronavirus papain-like protease:structure of a viral deubiquitinating enzyme. Proc Natl Acad Sci USA, 2006,103:5717-5722.
214. Rhee E G, Blattman J N, Kasturi S P, et al. Multiple innate immune pathways contribute to the immunogenicity of recombinant adenovirus vaccine vectors. J Virol,2011,85:315-323.
215.Robek M D, Boyd B S, Chisari F V. Lambda interferon inhibits hepatitis B and C virus replication. JVirol,2005,79:3851-3854.
216. Roberts P J, Belsham G J. Identification of critical amino acids within the foot-and-mouth disease virus leader protein, a cysteine protease. Virology,1995,213:140-146.
217. Rodrigues L, Filipe J, Seldon M P, et al. Termination of NF-kappaB activity through a gammaherpesvirus protein that assembles an EC5S ubiquitin-ligase. Embo J,2009,28: 1283-1295.
218. Rosenstiel P, Till A, Schreiber S. NOD-like receptors and human diseases. Microbes Infect,2007, 9:648-657.
219. Rueckert R R, Wimmer E. Systematic nomenclature of picornavirus proteins. J Virol,1984,50: 957-959.
220. Ruggieri A, Franco M, Gatto I, et al. Modulation of RANTES expression by HCV core protein in liver derived cell lines. BMC Gastroenterol,2007,7:21.
221. Ryals J, Dierks P, Ragg H, et al. A 46-nucleotide promoter segment from an IFN-alpha gene renders an unrelated promoter inducible by virus. Cell,1985,41:497-507.
222. Sadler A J, Williams B R. Interferon-inducible antiviral effectors. Nat Rev Immunol,2008,8: 559-568.
223. Saito T, Hirai R, Loo Y M, et al. Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci USA,2007,104:582-587.
224. Saitoh T, Yamamoto M, Miyagishi M, et al. A20 is a negative regulator of IFN regulatory factor 3 signaling. J Immunol,2005,174:1507-1512.
225. Sanchez-Castanon M, Baquero I C, Sanchez-Velasco P, et al. Polymorphisms in CCL5 promoter are associated with pulmonary tuberculosis in northern Spain. Int J Tuberc Lung Dis,2009,13: 480-485.
226. Schlick P, Kronovetr J, Hampoelz B, et al. Modulation of the electrostatic charge at the active site of foot-and-mouth-disease-virus leader proteinase, an unusual papain-like enzyme. Biochem J,2002,363:493-501.
227. Schlieker C, Korbel G A, Kattenhorn L M, et al. A deubiquitinating activity is conserved in the large tegument protein of the herpesviridae. J Virol,2005,79:15582-15585.
228. Scudamore J M, Harris D M. Control of foot and mouth disease:lessons from the experience of the outbreak in Great Britain in 2001. Rev Sci Tech,2002,21:699-710.
229. Seth R B, Sun L, Ea C K, et al. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell,2005,122:669-682.
230. Sheppard P, Kindsvogel W, Xu W, et al.IL-28, IL-29 and their class Ⅱ cytokine receptor IL-28R. Nat Immunol,2003,4:63-68.
231. Shimosato T, Tohno M, Kitazawa H, et al. Toll-like receptor 9 is expressed on follicle-associated epithelia containing M cells in swine Peyer's patches. Immunol Lett,2005,98:83-89.
232. Shinkai H, Tanaka M, Morozumi T, et al. Biased distribution of single nucleotide polymorphisms (SNPs) in porcine Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR5, and TLR6 genes. Immunogenetics,2006,58:324-330.
233. Skern T, Fita I, Guarne A. A structural model of picornavirus leader proteinases based on papain and bleomycin hydrolase. J Gen Virol,1998,79 (Pt 2):301-307.
234. Solis M, Goubau D, Hiscott J. RIG-I has guts:identification of a role for RIG-I in colitis development. Cell Res,2007,17:974-975.
235. Solis M, Nakhaei P, Jalalirad M, et al. RIG-1-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I. J Virol,2011,85:1224-1236.
236. Stahl-Hennig C, Eisenblatter M, Jasny E, et al. Synthetic double-stranded RNAs are adjuvants for the induction of T helper 1 and humoral immune responses to human papillomavirus in rhesus macaques. PLoS Pathog,2009,5:el000373.
237. Stancato L F, David M, Carter-Su C, et al. Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation. JBiol Chem,1996,271:4134-4137.
238. Stark G R, Kerr I M, Williams B R, et al. How cells respond to interferons. Annu Rev Biochem, 1998,67:227-264.
239. Stetson D B, Medzhitov R. Type I interferons in host defense. Immunity,2006,25:373-381.
240. Strebel K, Beck E. A second protease of foot-and-mouth disease virus. J Virol,1986,58: 893-899.
241. Summerfield A, Knotig S M, McCullough K C. Lymphocyte apoptosis during classical swine fever:implication of activation-induced cell death. J Virol,1998,72:1853-1861.
242. Sun S C. Deubiquitylation and regulation of the immune response. Nat Rev Immunol,2008,8: 501-511.
243. Sun Z, Chen Z, Lawson S R, et al. The cysteine protease domain of porcine reproductive and respiratory syndrome virus nonstructural protein 2 possesses deubiquitinating and interferon antagonism functions. J Virol,2010,84:7832-7846.
244. Sun Z, Ren H, Liu Y, et al. Phosphorylation of RIG-I by casein kinase Ⅱ inhibits its antiviral response. J Virol,2011,85:1036-1047.
245. Sweet C R, Conlon J, Golenbock D T, et al. YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction. Cell Microbiol,2007,9:2700-2715.
246. Tahara T, Arisawa T, Shibata T, et al. Effect of RANTES promoter genotype on the severity of intestinal metaplasia in Helicobacter pylori-infected Japanese subjects. Dig Dis Sci,2009,54: 1247-1252.
247. Tait S W, Reid E B, Greaves DR,et al. Mechanism of inactivation of NF-kappa B by a viral homologue of I kappa b alpha. Signal-induced release of i kappa b alpha results in binding of the viral homologue to NF-kappa B. J Biol Chem,2000,275:34656-34664.
248. Takahashi K, Kawai T, Kumar H, et al. Roles of caspase-8 and caspase-10 in innate immune responses to double-stranded RNA. J Immunol,2006,176:4520-4524.
249. Takahasi K, Yoneyama M, Nishihori T, et al. Nonself RNA-sensing mechanism of RIG-I helicase and activation of antiviral immune responses. Mol Cell,2008,29:428-440.
250. Takaoka A, Taniguchi T. Cytosolic DNA recognition for triggering innate immune responses. Adv Drug Deliv Rev,2008,60:847-857.
251. Takaoka A, Yanai H. Interferon signalling network in innate defence. Cell Microbiol,2006,8: 907-922.
252. Takeshita F, Tanaka T, Matsuda T, et al. Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity. J Virol,2006,80:6218-6224.
253. Talon J, Horvath C M, Polley R, et al. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein. J Virol,2000,74:7989-7996.
254. Tang X, Gao J S, Guan Y J, et al. Acetylation-dependent signal transduction for type I interferon receptor. Cell,2007,131:93-105.
255.Tenoever B R, Ng S L, Chua M A, et al. Multiple functions of the IKK-related kinase IKKepsilon in interferon-mediated antiviral immunity. Science,2007,315:1274-1278.
256. Tesar M, Marquardt O. Foot-and-mouth disease virus protease 3C inhibits cellular transcription and mediates cleavage of histone H3. Virology,1990,174:364-374.
257. Thanos D, Maniatis T. Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell,1995,83:1091-1100.
258. Thomas A V, Broers A D, Vandegaart H F, et al. Genomic structure, promoter analysis and expression of the porcine (Sus scrofa) TLR4 gene. Mol Immunol,2006,43:653-659.
259. Thompson D, Muriel P, Russell D, et al. Economic costs of the foot and mouth disease outbreak in the United Kingdom in 2001. Rev Sci Tech,2002,21:675-687.
260. Tian M, Liu F, Wen G Y, et al. Effect of variation in RANTES promoter on serum RANTES levels and risk of recurrent wheezing after RSV bronchiolitis in children from Han, Southern China. Eur J Pediatr,2009,168:963-967.
261. Ting J P, Willingham S B, Bergstralh D T. NLRs at the intersection of cell death and immunity. Nat Rev Immunol,2008,8:372-379.
262. Toka F N, Nfon C, Dawson H, et al. Natural killer cell dysfunction during acute infection with foot-and-mouth disease virus. Clin Vaccine Immunol,2009,16:1738-1749.
263. Tohno M, Shimosato T, Kitazawa H, et al. Toll-like receptor 2 is expressed on the intestinal M cells in swine. Biochem Biophys Res Commun,2005,330:547-554.
264. Tohno M, Ueda W, Azuma Y, et al. Molecular cloning and functional characterization of porcine nucleotide-binding oligomerization domain-2 (NOD2). Mol Immunol,2008,45:194-203.
265. Trumpfheller C, Caskey M, Nchinda G, et al. The microbial mimic poly IC induces durable and protective CD4+T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci USA,2008,105:2574-2579.
266. Uematsu S, Akira S. Toll-like receptors and Type I interferons. J Biol Chem,2007,282: 15319-15323.
267. van Pesch V, van Eyll O, Michiels T. The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production. J Virol,2001,75:7811-7817.
268. Vilcek J. Novel interferons. Nat Immunol,2003,4:8-9.
269. Viswanathan K, Fruh K, DeFilippis V. Viral hijacking of the host ubiquitin system to evade interferon responses. Curr Opin Microbiol,2010,13:517-523.
270. Wang C, Chen T, Zhang J, et al. The E3 ubiquitin ligase Nrdpl'preferentially'promotes TLR-mediated production of type I interferon. Nat Immunol,2009,10:744-752.
271. Wang Y, Zhang H X, Sun Y P, et al. Rig-I-/-mice develop colitis associated with downregulation of G alpha i2. Cell Res,2007,17:858-868.
272. Wang Y Y, Li L, Han K J, et al. A20 is a potent inhibitor of TLR3 - and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter. FEBS Lett,2004,576:86-90.
273. Wertz I E, O'Rourke K M, Zhou H, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature,2004,430:694-699.
274. Wilkinson K D, Tashayev V L, O'Connor L B, et al. Metabolism of the polyubiquitin degradation signal:structure, mechanism, and role of isopeptidase T. Biochemistry,1995,34:14535-14546.
275. Xiong Y, Lin M, Yuan B, et al. Expression of exogenous IFN-alpha by bypassing the translation block protects cells against FMDV infection. Antiviral Res,2009,84:60-66.
276. Xu L G, Wang Y Y, Han K J, et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell,2005,19:727-740.
277. Yang P C, Chu R M, Chung W B, et al. Epidemiological characteristics and financial costs of the 1997 foot-and-mouth disease epidemic in Taiwan. Vet Rec,1999,145:731-734.
278. Yang Y, Liang Y, Qu L, et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci U S A,2007,104:7253-7258.
279. Yao Q, Huang Q, Cao Y, et al. Porcine interferon-gamma protects swine from foot-and-mouth disease virus (FMDV). Vet Immunol Immunopathol,2008,122:309-311.
280. Yao T C, Tsai Y C, Huang J L. Association of RANTES promoter polymorphism with juvenile rheumatoid arthritis. Arthritis Rheum,2009,60:1173-1178.
281. Yie J, Senger K, Thanos D. Mechanism by which the IFN-beta enhanceosome activates transcription. Proc Natl Acad Sci USA,1999,96:13108-13113.
282. Yoneyama M, Fujita T. RNA recognition and signal transduction by RIG-I-like receptors. Immunol Rev,2009,227:54-65.
283. Yoneyama M, Fujita T. Structural mechanism of RNA recognition by the RIG-I-like receptors. Immunity,2008,29:178-181.
284. Yoneyama M, Kikuchi M, Matsumoto K, et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol,2005,175: 2851-2858.
285. Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol,2004,5:730-737.
286. Zhang M, Wu X, Lee A J, et al. Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. J Biol Chem,2008a,283:18621-18626.
287. Zhang N N, Shen S H, Jiang L J, et al. RIG-1 plays a critical role in negatively regulating granulocytic proliferation. Proc Natl Acad Sci U S A,2008b,105:10553-10558.
288. Zheng D, Chen G, Guo B, et al. PLP2, a potent deubiquitinase from murine hepatitis virus, strongly inhibits cellular type I interferon production. Cell Res,2008,18:1105-1113.
289. Ziegler E, Borman A M, Kirchweger R, et al. Foot-and-mouth disease virus Lb proteinase can stimulate rhinovirus and enterovirus IRES-driven translation and cleave several proteins of cellular and viral origin. J Virol,1995,69:3465-3474.
290. Zoll J, Melchers W J, Galama J M, et al. The mengovirus leader protein suppresses alpha/beta interferon production by inhibition of the iron/ferritin-mediated activation of NF-kappa B. J Virol, 2002,76:9664-9672.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |