PRRSV诱导炎症反应及其调控机制
|
摘要
猪繁殖与呼吸综合征(PRRS)是由猪繁殖与呼吸综合征病毒(PRRSV)引起的一种严重危害养猪业的病毒性传染病,主要表现为母猪严重的繁殖障碍及仔猪的呼吸系统疾病和生长受阻。PRRSV为单股正链RNA病毒,自20世纪80年代末爆发以来,PRRSV已经严重威胁到了全球养猪业的发展,并且造成了巨大的经济损失。自1995年我国报道发生该病以来,该病己成为困扰我国养猪生产中最重要的病毒性传染病之一。特别是2006年在我国出现的高致病性蓝耳病,导致全国各地大批生猪死亡,给我国养猪业造成了巨大的经济损失。PRRSV感染猪可以引起强烈的间质性肺炎,提示我们炎症反应在PRRSV感染和致病性方面扮演着十分重要的角色。然而,目前对这种毒株感染后引起宿主细胞的信号转导机制知之甚少。针对这种新的PRRSV,本文开展了对其诱导宿主细胞产生炎症反应信号转导机制的研究,为阐明PRRSV的致病机理以及其新型疫苗的研制提供理论依据。具体研究内容包括：
1.高致病性PRRSV感染激活IL-1β的分子机制及其生物学意义的研究
IL-1β是一种主要由单核细胞、巨噬细胞和淋巴细胞产生的促炎性细胞因子,是机体调节免疫和炎症反应的中心介质,能介导多种炎症反应,诱导致炎性细胞因子的基因表达及分泌,在炎性疾病的致病中扮演着十分重要的角色。以前的研究已经发现,PRRSV能够诱导高水平的IL-1β。但其诱导的分子机制仍未阐明。本研究利用PRRSV感染猪体内的宿主细胞-PAM细胞,发现PRRSV激活IL-1β mRNA的表达和蛋白分泌,同时也分析了几种模式识别受体及其接头分子,发现TLR4/MyD88信号级联及其下游的信号通路NF-κB, ERK1/2和p38MAPK均参与PRRSV激活IL-1β。通过siRNA干扰和特异性抑制剂发现NLRP3炎症小体参与PRRSV诱导IL-1p的分泌,但不影响其激活IL-1β mRNA水平的表达；能够诱导NLRP3炎症小体形成的ROS和心外流也参与PRRSV诱导IL-1β的分泌。我们同时还发现TLR4/MyD88/NF-KB信号通路参与PRRSV诱导NLRP3炎症小体组成元件的表达。此外,本研究还分析了PRRSV诱导IL-1β产生的生物学意义。通过IL-1β纯化蛋白及其中和性抗体处理PAM细胞后发现,IL-1β对PRRSV的增殖无明显影响,但其中和性抗体能够抑伟PRRSV激活其它的促炎性因子(IL-6,IL-8)的表达,说明IL-1β在PRRSV诱导炎症反应中处于主导地位。
2.高致病性PRRSV感染激活IL-6的分子机制的研究
IL-6是一种多效的细胞因子,调节多种生物进程,包括神经系统、造血系统、应激反应、炎症与免疫应答。通常情况下,连同与促炎性细胞因子TNF-αt和IL-1β一起产生。IL-6通常在机体急性反应的情况下被诱导,主要被用来维持细胞动态平衡,也参与调节炎症反应,主要是细胞因子和组织炎症反应。作为一种促炎性细胞因子,IL-6在病毒感染中扮演着十分重要的角色。PRRSV感染也能够激活IL-6的表达,但其具体分子机制仍不清楚。本研究发现,PRRSV能够诱导高水平的IL-6产生,无论是mRNA还是蛋白水平。同时还发现TLR4/MyD88信号级联及其下游信号通路NF-κB, ERK1/2和p38MAPK均参与PRRSV激活IL-6。通过siRNA干扰和特异性抑制剂发现NLRP3炎症小体参与PRRSV诱导IL-6的表达,同时ROS和疋外流也参与PRRSV诱导IL-6的分泌。阐明了PRRSV感染激活IL-6的分子机制。此外,我们还分析了IL-6对PRRSV增殖的影响,通过IL-6纯化蛋白处理PAM细胞后发现,IL-6对PRRSV的增殖无明显影响。
3.高致病性PRRSV感染激活1I,-8的分子机制的研究
IL-8,或称为CXCL8,是一种促炎性CXC家族的趋化因子。IL-8的产生主要受到NF-r.B调控,同时NF-IL-6转录结合位点也参与调控IL-8启动子活性。多种刺激例如炎症反应信号(IL-1p和TNF-a的产生)、化学和环境压力(化疗和缺氧)以及类固醇激素能够产生IL-8。IL-8作为一种促炎性趋化因子在炎症反应中扮演着十分重要的角色。PRRSV在不同组织均能诱导高水平的IL-8产生。通过PRRSV感染PAM细胞分析了PRRSV感染激活IL-8的分子机制。研究发现,PRRSV能够诱导高水平的IL-8产生,无论是mRNA还是蛋白水平。我们还发现TLR4/MyD88信号级联及其下游的信号通路NF-κB, ERK1/2和p38MAPK均参与PRRSV激活IL-8。通过siRNA干扰和特异性抑制剂发现NLRP3炎症小体参与PRRSV诱导IL-8的表达,同时ROS和K+外流也参与PRRSV诱导IL-8的分泌。同时还分析了IL-8对PRRSV增殖的影响,通过IL-8纯化蛋白处理PAM细胞后发现,IL-8对PRRSV的增殖无明显影响。
Porcine reproductive and respiratory syndrome (PRRS) is a viral infection disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), has a serious hazard to the swine industry, mainly represents a serious sow reproductive failure and respiratory system disease and growth stagnatim of piglets. PRRSV is a single-stranded RNA virus, since the outbreak in the late1980s, PRRSV has been a serious threat to the global development of pig industry, and caused huge economic losses. Since China reported the disease at1995, it has become one of the most important viral diseases in swine production in China. Especially in China at2006, the appearance of highly pathogenic PRRS, resulting in a large number of pigs were killed across the country, causing huge economic losses to the swine industry in our country. PRRSV can cause a strong interstitial pneumonia in infected pigs, suggesting that the inflammatory response plays a very important role in PRRSV infection and pathogenicity, however, it is poorly understood. For this new PRRSV, we analyzed the signal transduction mechanism of inflammatory response in PRRSV-infected host cell to provide a theoretical basis in order to clarify the pathogenesis of PRRSV. The specific studies include:
1. The molecular mechanism of highly pathogenic PRRSV infection activate IL-ip and its biological significance
IL-1β is a pro inflammatory cytokines primarily produced by monocytes, macrophages and lymphocytes, the center medium of body regulating immune and inflammatory responses, can mediate a variety of inflammatory reactions, induces other inflammatory cytokines expression and secretion, plays a very important role in the pathogenesis of inflammatory diseases. Previous studies have found out that PRRSV can induce high levels of IL-1β, but the molecular mechanisms are not yet elucidated. In this study, we used PAMs, the target cells of PRRSV-infected pigs, found PRRSV activates IL-1β both at mRNA expression and protein secretion level. We also analyzed several pattern recognition receptor and its adapter molecule, found out that TLR4/MyD88signal cascade and its downstream signaling pathways including NF-κB, ERK1/2and p38MAPK are involved in the the PRRSV activation of IL-1β. The siRNA interference and specific inhibitor treatment indicated that NLRP3inflammasome involved in PRRSV-induced IL-1β secretion, but didn't affect the activation of the expression of IL-1β mRNA levels. We also found that the activator to induce NLRP3inflammasome formation-ROS and K+efflux is also involved in PRRSV-induced IL-1β secretion. We also found TLR4/MyD88/NF-KB signaling pathway involved in PRRSV-induced NLRP3inflammasome component expression. In addition, we also analyzed the biological significance of PRRSV-induced IL-1β. Treatment of purified IL-1β protein and its neutralizing antibody on PAMs had no significant effect on the proliferation of PRRSV, but IL-1β neutralizing antibodies can inhibit the the PRRSV activation of other proinflammatory (IL-6, IL-8), indicating the centrol role of IL-1β in PRRSV-induced inflammatory response.
2. The molecular mechanism of highly pathogenic PRRSV infection activate IL-6
IL-6is a pleiotropic cytokine regulating a variety of biological processes, including the nervous system, the hematopoietic system, stress response, inflammation and immune response. Usually, produced together with the pro-inflammatory cytokines TNF-a and IL-1, IL-6is usually induced in the case of the body in acute reaction, is primarily be used to maintain cell homeostasis, and is also involved in the regulation of inflammation, cytokines and tissue inflammation reaction. As a pro-inflammatory cytokines, IL-6plays a very important role in viral infection. PRRSV infection is also capable of activating the expression of IL-6, but its specific molecular mechanisms are still unclear. Our study found that, PRRSV can induce high levels of IL-6, either on the mRNA or protein levels. We also found that TLR4/MyD88signaling cascade and its downstream signaling pathway of NF-κB, ERK1/2and p38MAPK are involved in PRRSV-induced IL-6. The siRNA interference and specific inhibitor treatment indicated that NLRP3inflammasome involved in PRRSV-induced IL-6production. We also found that ROS and K+efflux is also involved in PRRSV-induced IL-6secretion. In addition, we also analyzed the impact of IL-6on PRRSV proliferation. Treatment of purified IL-6protein on PAMs had no significant effect on the proliferation of PRRSV.
3. The molecular mechanism of highly pathogenic PRRSV infection activate IL-8
IL-8, or referred to CXCL8, is a CXC family pro-inflammatory chemokine. IL-8production mainly regulated by NF-κB, meanwhile NF-IL-6transcription binding sites is also involved in the regulation of the activity of the IL-8promoter. A variety of stimuli such as inflammatory response signal (IL-1(3and TNF-a generation), chemical and environmental stress (chemotherapy and hypoxia) and steroids can produce IL-8. As a pro-inflammatory chemokine IL-8plays a very important role in the inflammatory response summary. PRRSV is able to induce high level of IL-8in different organization. We used the PAMs, the target cells of PRRSV-infected pigs, to analyze the molecular mechanism of PRRSV infection activats IL-8. Our study found that, PRRSV can induce high levels of IL-8, either the mRNA or protein levels. We also found that TLR4/MyD88 signaling cascade and its downstream signaling pathway of NF-κB, ERK1/2and p38MAPK are involved in PRRSV-induced IL-8. The siRNA interference and specific inhibitor treatment indicated that NLRP3inflammasome involved in PRRSV-induced IL-8production. We also found that ROS and K+efflux is also involved in PRRSV-induced IL-8secretion. In addition, we also analyzed the impact of IL-8on PRRSV proliferation. Treatment of purified IL-8protein on PAMs had no significant effect on the proliferation of PRRSV.
1.高致病性PRRSV感染激活IL-1β的分子机制及其生物学意义的研究
IL-1β是一种主要由单核细胞、巨噬细胞和淋巴细胞产生的促炎性细胞因子,是机体调节免疫和炎症反应的中心介质,能介导多种炎症反应,诱导致炎性细胞因子的基因表达及分泌,在炎性疾病的致病中扮演着十分重要的角色。以前的研究已经发现,PRRSV能够诱导高水平的IL-1β。但其诱导的分子机制仍未阐明。本研究利用PRRSV感染猪体内的宿主细胞-PAM细胞,发现PRRSV激活IL-1β mRNA的表达和蛋白分泌,同时也分析了几种模式识别受体及其接头分子,发现TLR4/MyD88信号级联及其下游的信号通路NF-κB, ERK1/2和p38MAPK均参与PRRSV激活IL-1β。通过siRNA干扰和特异性抑制剂发现NLRP3炎症小体参与PRRSV诱导IL-1p的分泌,但不影响其激活IL-1β mRNA水平的表达；能够诱导NLRP3炎症小体形成的ROS和心外流也参与PRRSV诱导IL-1β的分泌。我们同时还发现TLR4/MyD88/NF-KB信号通路参与PRRSV诱导NLRP3炎症小体组成元件的表达。此外,本研究还分析了PRRSV诱导IL-1β产生的生物学意义。通过IL-1β纯化蛋白及其中和性抗体处理PAM细胞后发现,IL-1β对PRRSV的增殖无明显影响,但其中和性抗体能够抑伟PRRSV激活其它的促炎性因子(IL-6,IL-8)的表达,说明IL-1β在PRRSV诱导炎症反应中处于主导地位。
2.高致病性PRRSV感染激活IL-6的分子机制的研究
IL-6是一种多效的细胞因子,调节多种生物进程,包括神经系统、造血系统、应激反应、炎症与免疫应答。通常情况下,连同与促炎性细胞因子TNF-αt和IL-1β一起产生。IL-6通常在机体急性反应的情况下被诱导,主要被用来维持细胞动态平衡,也参与调节炎症反应,主要是细胞因子和组织炎症反应。作为一种促炎性细胞因子,IL-6在病毒感染中扮演着十分重要的角色。PRRSV感染也能够激活IL-6的表达,但其具体分子机制仍不清楚。本研究发现,PRRSV能够诱导高水平的IL-6产生,无论是mRNA还是蛋白水平。同时还发现TLR4/MyD88信号级联及其下游信号通路NF-κB, ERK1/2和p38MAPK均参与PRRSV激活IL-6。通过siRNA干扰和特异性抑制剂发现NLRP3炎症小体参与PRRSV诱导IL-6的表达,同时ROS和疋外流也参与PRRSV诱导IL-6的分泌。阐明了PRRSV感染激活IL-6的分子机制。此外,我们还分析了IL-6对PRRSV增殖的影响,通过IL-6纯化蛋白处理PAM细胞后发现,IL-6对PRRSV的增殖无明显影响。
3.高致病性PRRSV感染激活1I,-8的分子机制的研究
IL-8,或称为CXCL8,是一种促炎性CXC家族的趋化因子。IL-8的产生主要受到NF-r.B调控,同时NF-IL-6转录结合位点也参与调控IL-8启动子活性。多种刺激例如炎症反应信号(IL-1p和TNF-a的产生)、化学和环境压力(化疗和缺氧)以及类固醇激素能够产生IL-8。IL-8作为一种促炎性趋化因子在炎症反应中扮演着十分重要的角色。PRRSV在不同组织均能诱导高水平的IL-8产生。通过PRRSV感染PAM细胞分析了PRRSV感染激活IL-8的分子机制。研究发现,PRRSV能够诱导高水平的IL-8产生,无论是mRNA还是蛋白水平。我们还发现TLR4/MyD88信号级联及其下游的信号通路NF-κB, ERK1/2和p38MAPK均参与PRRSV激活IL-8。通过siRNA干扰和特异性抑制剂发现NLRP3炎症小体参与PRRSV诱导IL-8的表达,同时ROS和K+外流也参与PRRSV诱导IL-8的分泌。同时还分析了IL-8对PRRSV增殖的影响,通过IL-8纯化蛋白处理PAM细胞后发现,IL-8对PRRSV的增殖无明显影响。
Porcine reproductive and respiratory syndrome (PRRS) is a viral infection disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), has a serious hazard to the swine industry, mainly represents a serious sow reproductive failure and respiratory system disease and growth stagnatim of piglets. PRRSV is a single-stranded RNA virus, since the outbreak in the late1980s, PRRSV has been a serious threat to the global development of pig industry, and caused huge economic losses. Since China reported the disease at1995, it has become one of the most important viral diseases in swine production in China. Especially in China at2006, the appearance of highly pathogenic PRRS, resulting in a large number of pigs were killed across the country, causing huge economic losses to the swine industry in our country. PRRSV can cause a strong interstitial pneumonia in infected pigs, suggesting that the inflammatory response plays a very important role in PRRSV infection and pathogenicity, however, it is poorly understood. For this new PRRSV, we analyzed the signal transduction mechanism of inflammatory response in PRRSV-infected host cell to provide a theoretical basis in order to clarify the pathogenesis of PRRSV. The specific studies include:
1. The molecular mechanism of highly pathogenic PRRSV infection activate IL-ip and its biological significance
IL-1β is a pro inflammatory cytokines primarily produced by monocytes, macrophages and lymphocytes, the center medium of body regulating immune and inflammatory responses, can mediate a variety of inflammatory reactions, induces other inflammatory cytokines expression and secretion, plays a very important role in the pathogenesis of inflammatory diseases. Previous studies have found out that PRRSV can induce high levels of IL-1β, but the molecular mechanisms are not yet elucidated. In this study, we used PAMs, the target cells of PRRSV-infected pigs, found PRRSV activates IL-1β both at mRNA expression and protein secretion level. We also analyzed several pattern recognition receptor and its adapter molecule, found out that TLR4/MyD88signal cascade and its downstream signaling pathways including NF-κB, ERK1/2and p38MAPK are involved in the the PRRSV activation of IL-1β. The siRNA interference and specific inhibitor treatment indicated that NLRP3inflammasome involved in PRRSV-induced IL-1β secretion, but didn't affect the activation of the expression of IL-1β mRNA levels. We also found that the activator to induce NLRP3inflammasome formation-ROS and K+efflux is also involved in PRRSV-induced IL-1β secretion. We also found TLR4/MyD88/NF-KB signaling pathway involved in PRRSV-induced NLRP3inflammasome component expression. In addition, we also analyzed the biological significance of PRRSV-induced IL-1β. Treatment of purified IL-1β protein and its neutralizing antibody on PAMs had no significant effect on the proliferation of PRRSV, but IL-1β neutralizing antibodies can inhibit the the PRRSV activation of other proinflammatory (IL-6, IL-8), indicating the centrol role of IL-1β in PRRSV-induced inflammatory response.
2. The molecular mechanism of highly pathogenic PRRSV infection activate IL-6
IL-6is a pleiotropic cytokine regulating a variety of biological processes, including the nervous system, the hematopoietic system, stress response, inflammation and immune response. Usually, produced together with the pro-inflammatory cytokines TNF-a and IL-1, IL-6is usually induced in the case of the body in acute reaction, is primarily be used to maintain cell homeostasis, and is also involved in the regulation of inflammation, cytokines and tissue inflammation reaction. As a pro-inflammatory cytokines, IL-6plays a very important role in viral infection. PRRSV infection is also capable of activating the expression of IL-6, but its specific molecular mechanisms are still unclear. Our study found that, PRRSV can induce high levels of IL-6, either on the mRNA or protein levels. We also found that TLR4/MyD88signaling cascade and its downstream signaling pathway of NF-κB, ERK1/2and p38MAPK are involved in PRRSV-induced IL-6. The siRNA interference and specific inhibitor treatment indicated that NLRP3inflammasome involved in PRRSV-induced IL-6production. We also found that ROS and K+efflux is also involved in PRRSV-induced IL-6secretion. In addition, we also analyzed the impact of IL-6on PRRSV proliferation. Treatment of purified IL-6protein on PAMs had no significant effect on the proliferation of PRRSV.
3. The molecular mechanism of highly pathogenic PRRSV infection activate IL-8
IL-8, or referred to CXCL8, is a CXC family pro-inflammatory chemokine. IL-8production mainly regulated by NF-κB, meanwhile NF-IL-6transcription binding sites is also involved in the regulation of the activity of the IL-8promoter. A variety of stimuli such as inflammatory response signal (IL-1(3and TNF-a generation), chemical and environmental stress (chemotherapy and hypoxia) and steroids can produce IL-8. As a pro-inflammatory chemokine IL-8plays a very important role in the inflammatory response summary. PRRSV is able to induce high level of IL-8in different organization. We used the PAMs, the target cells of PRRSV-infected pigs, to analyze the molecular mechanism of PRRSV infection activats IL-8. Our study found that, PRRSV can induce high levels of IL-8, either the mRNA or protein levels. We also found that TLR4/MyD88 signaling cascade and its downstream signaling pathway of NF-κB, ERK1/2and p38MAPK are involved in PRRSV-induced IL-8. The siRNA interference and specific inhibitor treatment indicated that NLRP3inflammasome involved in PRRSV-induced IL-8production. We also found that ROS and K+efflux is also involved in PRRSV-induced IL-8secretion. In addition, we also analyzed the impact of IL-8on PRRSV proliferation. Treatment of purified IL-8protein on PAMs had no significant effect on the proliferation of PRRSV.
引文
1.蔡雪晖,柴文君,翁长江.猪繁殖与呼吸综合征及其在我国的现状与对策.中国预防兽医学报,2000,22:202-205
2.郭宝清,陈章水,刘文兴.从疑似PRRS流产胎儿分离PRRSV的研究.中国畜禽转染病,1996,2：1-4
3. 罗锐.PRRSV感染抑制Ⅰ型和Ⅲ型干扰素及激活NF-kB的分子机制研究.[博士论文].华中农业大学,2009
4. Ahlers J D, Belyakov I M and Berzofsky J A. Cytokine, chemokine, and costimulatory molecule modulation to enhance efficacy of HIV vaccines. Curr Mol Med,2003,3(3):285-301.
5. Akira S and Takeda K. Toll-like receptor signalling. Nat Rev Immunol,2004,4(7): 499-511.
6. Alexopoulou L, Holt A C, Medzhitov R and Flavell R A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature, 2001,413(6857):732-738.
7. Barlan A U, Griffin T M, McGuire K A and Wiethoff C M. Adenovirus membrane penetration activates the NLRP3 inflammasome. J Virol,2011,85(1):146-155.
8. Barranco I, Gomez-Laguna J, Rodriguez-Gomez I M, Salguero F J, Pallares F J and Carrasco L. Differential expression of proinflammatory cytokines in the lymphoid organs of porcine reproductive and respiratory syndrome virus-infected pigs. Transbound Emerg Dis,2012,59(2):145-153.
9. Bauernfeind F, Ablasser A, Bartok E, Kim S, Schmid-Burgk J, Cavlar T and Hornung V. Inflammasomes:current understanding and open questions. Cell Mol Life Sci, 2011,68(5):765-783.
10. Bauernfeind F G, Horvath G, Stutz A, Alnemri E S, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks B G, Fitzgerald K A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol,2009,183(2): 787-791.
11. Beura L K, Dinh P X, Osorio F A and Pattnaik A K. Cellular poly(c) binding proteins 1 and 2 interact with porcine reproductive and respiratory syndrome virus nonstructural protein lbeta and support viral replication. J Virol,2011,85(24): 12939-12949.
12. Beutler B. TLR4 as the mammalian endotoxin sensor. Curr Top Microbiol Immunol, 2002,270:109-120.
13. Borghetti P, Saleri R, Ferrari L, Morganti M, De Angelis E, Franceschi V, Bottarelli E and Martelli P. Cytokine expression, glucocorticoid and growth hormone changes after porcine reproductive and respiratory syndrome virus (PRRSV-1) infection in vaccinated and unvaccinated naturally exposed pigs. Comp Immunol Microbiol Infect Dis,2011,34(2):143-155.
14. Brat D J, Bellail A C and Van Meir E G. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol,2005,7(2):122-133.
15. Burdette D, Haskett A, Presser L, McRae S, Iqbal J and Waris G. Hepatitis C virus activates interleukin-lbeta via caspase-l-inflammasome complex. J Gen Virol,2012, 93(Pt 2):235-246.
16. Calzada-Nova G, Schnitzlein W M, Husmann R J and Zuckermann F A. North American porcine reproductive and respiratory syndrome viruses inhibit type I interferon production by plasmacytoid dendritic cells. J Virol,2011,85(6): 2703-2713.
17. Cassel S L, Eisenbarth S C, Iyer S S, Sadler J J, Colegio O R, Tephly L A, Carter A B, Rothman P B, Flavell R A and Sutterwala F S. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A,2008,105(26): 9035-9040.
18. Chen Z, Lawson S, Sun Z, Zhou X, Guan X, Christopher-Hennings J, Nelson E A and Fang Y. Identification of two auto-cleavage products of nonstructural protein 1 (nspl) in porcine reproductive and respiratory syndrome virus infected cells:nspl function as interferon antagonist. Virology,2010,398(1):87-97.
19. Christopher-Hennings J, Nelson E A, Nelson J K, Rossow K D, Shivers J L, Yaeger M J, Chase C C, Garduno R A, Collins J E and Benfield D A. Identification of porcine reproductive and respiratory syndrome virus in semen and tissues from vasectomized and nonvasectomized boars. Vet Pathol,1998,35(4):260-267.
20. Coban C, Ishii K J, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med,2005,201(1):19-25.
21. Correa-Costa M, Braga T T, Semedo P, Hayashida C Y, Bechara L R, Elias R M, Barreto C R, Silva-Cunha C, Hyane M I, Goncalves G M, et al. Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis. PLoS One,2011,6(12):e29004.
22. Craven R R, Gao X, Allen I C, Gris D, Bubeck Wardenburg J, McElvania-Tekippe E, Ting J P and Duncan J A. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One,2009,4(10): e7446.
23. Darwich L, Gimeno M, Sibila M, Diaz I, de la Torre E, Dotti S, Kuzemtseva L, Martin M, Pujols J and Mateu E. Genetic and immunobiological diversities of porcine reproductive and respiratory syndrome genotype I strains. Vet Microbiol, 2011,150(1-2):49-62.
24. Davis B K, Wen H and Ting J P. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol,2011,29:707-735.
25. Diebold S S, Kaisho T, Hemmi H, Akira S and Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science, 2004,303(5663):1529-1531.
26. Dinarello C A. Biologic basis for interleukin-1 in disease. Blood,1996,87(6): 2095-2147.
27. Drew T W. A review of evidence for immunosuppression due to porcine reproductive and respiratory syndrome virus. Vet Res,2000,31(1):27-39.
28. Eder C. Mechanisms of interleukin-lbeta release. Immunobiology,2009,214(7): 543-553.
29. Fang Y, Fang L, Wang Y, Lei Y, Luo R, Wang D, Chen H and Xiao S. Porcine reproductive and respiratory syndrome virus nonstructural protein 2 contributes to NF-kappaB activation. Virol J,2012,9:83.
30. Fang Y and Snijder E J. The PRRSV replicase:exploring the multifunctionality of an intriguing set of nonstructural proteins. Virus Res,2010,154(1-2):61-76.
31. Feng Y, Zhao T, Nguyen T, Inui K, Ma Y, Nguyen T H, Nguyen V C, Liu D, Bui Q A, To L T, et al. Porcine respiratory and reproductive syndrome virus variants, Vietnam and China,2007. Emerg Infect Dis,2008,14(11):1774-1776.
32. Gasse P, Riteau N, Charron S, Girre S, Fick L, Petrilli V, Tschopp J, Lagente V, Quesniaux V F, Ryffel B, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med, 2009,179(10):903-913.
33. Geldhof M F, Vanhee M, Van Breedam W, Van Doorsselaere J, Karniychuk U U and Nauwynck H J. Comparison of the efficacy of autogenous inactivated Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) vaccines with that of commercial vaccines against homologous and heterologous challenges. BMC Vet Res, 2012,8:182.
34. Georgel P, Jiang Z, Kunz S, Janssen E, Mols J, Hoebe K, Bahram S, Oldstone M B and Beutler B. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology,2007,362(2):304-313.
35. Ghosh S, May M J and Kopp E B. NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune responses. Annu Rev Immunol,1998,16:225-260.
36. Gomez-Laguna J, Salguero F J, Barranco I, Pallares F J, Rodriguez-Gomez I M, Bernabe A and Carrasco L. Cytokine expression by macrophages in the lung of pigs infected with the porcine reproductive and respiratory syndrome virus. J Comp Pathol,2010,142(1):51-60.
37. Gomez-Laguna J, Salguero F J, Pallares F J, Fernandez de Marco M, Barranco I, Ceron J J, Martinez-Subiela S, Van Reeth K and Carrasco L. Acute phase response in porcine reproductive and respiratory syndrome virus infection. Comp Immunol Microbiol Infect Dis,2010,33(6):e51-58.
38. Gram AM, Frenkel J and Ressing M E. Inflammasomes and viruses:cellular defence versus viral offence. J Gen Virol,2012,93(Pt 10):2063-2075.
39. Gross O, Thomas C J, Guarda G and Tschopp J. The inflammasome:an integrated view. Immunol Rev,2011,243(1):136-151.
40. Grote K, Schutt H and Schieffer B. Toll-like receptors in angiogenesis. Scientific WorldJournal,2011,11:981-991.
41. Haynes L M, Moore D D, Kurt-Jones E A, Finberg R W, Anderson L J and Tripp R A. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol,2001,75(22):10730-10737.
42. He Y, Franchi L and Nunez G. TLR agonists stimulate Nlrp3-dependent IL-lbeta production independently of the purinergie P2X7 receptor in dendritic cells and in vivo. J Immunol,2013,190(1):334-339.
43. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7,8 and 9 subfamily. Eur J Immunol,2003,33(11):2987-2997.
44. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H and Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science,2004,303(5663):1526-1529.
45. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K and Akira S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol,2002,3(2):196-200.
46. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, et al. A Toll-like receptor recognizes bacterial DNA. Nature, 2000,408(6813):740-745.
47. Hirano T. Interleukin 6 in autoimmune and inflammatory diseases:a personal memoir. Proc Jpn Acad Ser B Phys Biol Sci,2010,86(7):717-730.
48. Hirano T, Akira S, Taga T and Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today,1990,11(12):443-449.
49. Hoffmann E, Dittrich-Breiholz O, Holtmann H and Kracht M. Multiple control of interleukin-8 gene expression. JLeukoc Biol,2002,72(5):847-855.
50. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med,2005,11(3):263-270.
51. Hoshino S, Konishi M, Mori M, Shimura M, Nishitani C, Kuroki Y, Koyanagi Y, Kano S, Itabe H and Ishizaka Y. HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. J Leukoc Biol,2010,87(6): 1133-1143.
52. Hou J, Wang L, Quan R, Fu Y, Zhang H and Feng W H. Induction of interleukin-10 is dependent on p38 mitogen-activated protein kinase pathway in macrophages infected with porcine reproductive and respiratory syndrome virus. Virol J,2012,9:165.
53. Hu S, Sheng W S, Schachtele S J and Lokensgard J R. Reactive oxygen species drive herpes simplex virus (HSV)-l-induced proinflammatory cytokine production by murine microglia. J Neuroinflammation,2011,8:123.
54. Hu S P, Zhang Z, Liu Y G, Tian Z J, Wu D L, Cai X H and He X J. Pathogenicity and Distribution of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus in Pigs. Transbound Emerg Dis,2012.
55. Hu Y W, Rocheleau L, Larke B, Chui L, Lee B, Ma M, Liu S, Omlin T, Pelchat M and Brown E G. Immunoglobulin mimicry by Hepatitis C Virus envelope protein E2. Virology,2005,332(2):538-549.
56. Ichinohe T, Pang I K and Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol,2010,11(5):404-410.
57. Iwasaki A and Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol,2004,5(10):987-995.
58. Jacques A, Bleau C, Turbide C, Beauchemin N and Lamontagne L. Macrophage interleukin-6 and tumour necrosis factor-alpha are induced by coronavirus fixation to Toll-like receptor 2/heparan sulphate receptors but not carcinoembryonic cell adhesion antigen 1a. Immunology,2009,128(1 Suppl):e181-192.
59. Jensen S and Thomsen A R. Sensing of RNA viruses:a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol,2012,86(6): 2900-2910.
60. Jurk M, Heil F, Vollmer J, Schetter C, Krieg A M, Wagner H, Lipford G and Bauer S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol,2002,3(6):499.
61. Kanneganti T D, Body-Malapel M, Amer A, Park J H, Whitfield J, Franchi L, Taraporewala Z F, Miller D, Patton J T, Inohara N, et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem,2006,281(48):36560-36568.
62. Karin M and Greten F R. NF-kappaB:linking inflammation and immunity to cancer development and progression. Nat Rev Immunol,2005,5(10):749-759.
63. Kawai T and Akira S. TLR signaling. Cell Death Differ,2006,13(5):816-825.
64. Kelley J F, Kaufusi P H and Nerurkar V R. Dengue hemorrhagic fever-associated immunomediators induced via maturation of dengue virus nonstructural 4B protein in monocytes modulate endothelial cell adhesion molecules and human microvascular endothelial cells permeability. Virology,2012,422(2):326-337.
65. Koyama S, Ishii K J, Coban C and Akira S. Innate immune response to viral infection. Cytokine,2008,43(3):336-341.
66. Kristiansen M, Graversen J H, Jacobsen C, Sonne O, Hoffman H J, Law S K and Moestrup S K. Identification of the haemoglobin scavenger receptor. Nature,2001, 409(6817):198-201.
67. Krug A, French A R, Barchet W, Fischer J A, Dzionek A, Pingel J T, Orihuela M M, Akira S, Yokoyama W M and Colonna M. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity,2004,21(1):107-119.
68. Lamkanfi M and Dixit V M. Modulation of inflammasome pathways by bacterial and viral pathogens. J Immunol,2011,187(2):597-602.
69. Lawson S R, Li Y, Patton J B, Langenhorst R J, Sun Z, Jiang Z, Christopher-Hennings J, Nelson E A, Knudsen D, Fang Y, et al. Interleukin-lbeta expression by a recombinant porcine reproductive and respiratory syndrome virus. Virus Res,2012,163(2):461-468.
70. Lee N, Wong C K, Hui D S, Lee S K, Wong R Y, Ngai K L, Chan M C, Chu Y J, Ho A W, Lui G C, et al. Role of human Toll-like receptors in naturally occurring influenza A infections. Influenza Other Respi Viruses,2013.
71. Lee S M and Kleiboeker S B. Porcine arterivirus activates the NF-kappaB pathway through IkappaB degradation. Virology,2005,342(1):47-59.
72. Lee S M and Kleiboeker S B. Porcine reproductive and respiratory syndrome virus induces apoptosis through a mitochondria-mediated pathway. Virology,2007,365(2): 419-434.
73. Lee Y J and Lee C. Cytokine production in immortalized porcine alveolar macrophages infected with porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol,2012,150(3-4):213-220.
74. Lee Y J and Lee C. Stress-activated protein kinases are involved in porcine reproductive and respiratory syndrome virus infection and modulate virus-induced cytokine production. Virology,2012,427(2):80-89.
75. Liu Y, Shi W, Zhou E, Wang S, Hu S, Cai X, Rong F, Wu J, Xu M and Li L. Dynamic changes in inflammatory cytokines in pigs infected with highly pathogenic porcine reproductive and respiratory syndrome virus. Clin Vaccine Immunol,2010,17(9): 1439-1445.
76. Lund J, Sato A, Akira S, Medzhitov R and Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med, 2003,198(3):513-520.
77. Lund J M, Alexopoulou L, Sato A, Karow M, Adams N C, Gale N W, Iwasaki A and Flavell R A. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA,2004,101(15):5598-5603.
78. Lunney J K, Benfield D A and Rowland R R. Porcine reproductive and respiratory syndrome virus:an update on an emerging and re-emerging viral disease of swine. Virus Res,2010,154(1-2):1-6.
79. Lunney J K, Fritz E R, Reecy J M, Kuhar D, Prucnal E, Molina R, Christopher-Hennings J, Zimmerman J and Rowland R R. Interleukin-8, interleukin-lbeta, and interferon-gamma levels are linked to PRRS virus clearance. Viral Immunol,2010,23(2):127-134.
80. Luo R, Fang L, Jiang Y, Jin H, Wang Y, Wang D, Chen H and Xiao S. Activation of NF-kappaB by nucleocapsid protein of the porcine reproductive and respiratory syndrome virus. Virus Genes,2011,42(1):76-81.
81. Luo R, Xiao S, Jiang Y, Jin H, Wang D, Liu M, Chen H and Fang L. Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon-beta production by interfering with the RIG-I signaling pathway. Mol Immunol,2008, 45(10):2839-2846.
82. Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K and Murakami S. Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J Biol Chem,1991,266(21):13759-13763.
83. Mamik M K, Banerjee S, Walseth T F, Hirte R, Tang L, Borgmann K. and Ghorpade A. HIV-1 and IL-lbeta regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-kappaB signaling mechanisms. J Neuroinflammation,2011, 8:145.
84. Mariathasan S, Weiss D S, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee W P, Weinrauch Y, Monack D M and Dixit V M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature,2006,440(7081):228-232.
85. Martinon F. Mayor A and Tschopp J. The inflammasomes:guardians of the body. Annu Rev Immunol,2009,27:229-265.
86. Medzhitov R, Preston-Hurlburt P and Janeway C A, Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature,1997, 388(6640):394-397.
87. Meissner F, Molawi K and Zychlinsky A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol,2008,9(8):866-872.
88. Miguel J C, Chen J, Van Alstine W G and Johnson R W. Expression of inflammatory cytokines and Toll-like receptors in the brain and respiratory tract of pigs infected with porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol,2010,135(3-4):314-319.
89. Monick M M, Yarovinsky T O, Powers L S, Butler N S, Carter A B, Gudmundsson G and Hunninghake G W. Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. JBiol Chem,2003,278(52):53035-53044.
90. Morgan S B, Graham S P, Salguero F J, Sanchez Cordon P J, Mokhtar H, Rebel J M, Weesendorp E, Bodman-Smith K B, Steinbach F and Frossard J P. Increased pathogenicity of European porcine reproductive and respiratory syndrome virus is associated with enhanced adaptive responses and viral clearance. Vet Microbiol,2013, 163(1-2):13-22.
91. Muruve D A, Petrilli V, Zaiss A K, White L R, Clark S A, Ross P J, Parks R J and Tschopp J. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature,2008,452(7183):103-107.
92. Netea M G, Nold-Petry C A, Nold M F, Joosten L A, Opitz B, van der Meer J H, van de Veerdonk F L, Ferwerda G, Heinhuis B, Devesa I, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-lbeta in monocytes and macrophages. Blood,2009,113(10):2324-2335.
93. Netea M G, Simon A, van de Veerdonk F, Kullberg B J, Van der Meer J W and Joosten L A. IL-lbeta processing in host defense:beyond the inflammasomes. PLoS Pathog,2010,6(2):e1000661.
94. O'Neill L A. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol,2002,270:47-61.
95. Okumura A, Pitha P M, Yoshimura A and Harty R N. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. J Virol,2010,84(1):27-33.
96. Opriessnig T, Gimenez-Lirola L G and Halbur P G. Polymicrobial respiratory disease in pigs. Anim Health Res Rev,2011,12(2):133-148.
97. Otsuka M, Jing Q, Georgel P, New L, Chen J, Mols J, Kang Y J, Jiang Z, Du X, Cook R, et al. Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression. Immunity,2007,27(1): 123-134.
98. Ozinsky A, Underhill D M, Fontenot J D, Hajjar A M, Smith K D, Wilson C B, Schroeder L and Aderem A. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA,2000,97(25):13766-13771.
99. Pang I K and Iwasaki A. Inflammasomes as mediators of immunity against influenza virus. Trends Immunol,2011,32(1):34-41.
100.Patel D, Nan Y, Shen M, Ritthipichai K, Zhu X and Zhang Y J. Porcine reproductive and respiratory syndrome virus inhibits type I interferon signaling by blocking STAT1/STAT2 nuclear translocation. J Virol,2010,84(21):11045-11055.
101.Petrilli V, Papin S, Dostert C, Mayor A, Martinon F and Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ,2007,14(9):1583-1589.
102.Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Hannesschlager N, Schlee M, Rothenfusser S, Barchet W, et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol,2010,11(1):63-69.
103.Poeck H and Ruland J. From virus to inflammation:mechanisms of RIG-I-induced IL-1 beta production. Eur J Cell Biol,2012,91(1):59-64.
104.Poltorak A, He X, Smirnova I, Liu M Y, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:mutations in Tlr4 gene. Science,1998,282(5396):2085-2088.
105.Pontillo A, Silva L T, Oshiro T M, Finazzo C, Crovella S and Duarte A J. HIV-1 induces NALP3-inflammasome expression and interleukin-1 beta secretion in dendritic cells from healthy individuals but not from HIV-positive patients. AIDS, 2012,26(1):11-18.
106.Pryor M J, Rawlinson S M, Butcher R E, Barton C L, Waterhouse T A, Vasudevan S G, Bardin P G, Wright P J, Jans D A and Davidson A D. Nuclear localization of dengue virus nonstructural protein 5 through its importin alpha/beta-recognized nuclear localization sequences is integral to viral infection. Traffic,2007,8(7): 795-807.
107.Qiao S, Feng L, Bao D, Guo J, Wan B, Xiao Z, Yang S and Zhang G. Porcine reproductive and respiratory syndrome virus and bacterial endotoxin act in synergy to amplify the inflammatory response of infected macrophages. Vet Microbiol,2011, 149(1-2):213-220.
108.Qiao Y, Wang P, Qi J, Zhang L and Gao C. TLR-induced NF-kappaB activation regulates NLRP3 expression in murine macrophages. FEBS Lett,2012,586(7): 1022-1026.
109.Rachman A and Rinaldi I. Coagulopathy in dengue infection and the role of interleukin-6. Acta Med Indones,2006,38(2):105-108.
110.Rahman M M and McFadden G. Myxoma virus lacking the pyrin-like protein M013 is sensed in human myeloid cells by both NLRP3 and multiple Toll-like receptors, which independently activate the inflammasome and NF-kappaB innate response pathways. J Virol,2011,85(23):12505-12517.
111.Rajan J V, Rodriguez D, Miao E A and Aderem A. The NLRP3 inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection. J Virol,2011, 85(9):4167-4172.
112.Rallabhandi P, Phillips R L, Boukhvalova M S, Pletneva L M, Shirey K A, Gioannini T L, Weiss J P, Chow J C, Hawkins L D, Vogel S N, et al. Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. MBio,2012,3(4).
113.Randall R E and Goodbourn S. Interferons and viruses:an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol, 2008,89(Pt 1):1-47.
114.Rassa J C, Meyers J L, Zhang Y, Kudaravalli R and Ross S R. Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci U S A, 2002,99(4):2281-2286.
115.Rathinam V A and Fitzgerald K A. Inflammasomes and anti-viral immunity. J Clin Immunol,2010,30(5):632-637.
116.Rathinam V A, Jiang Z, Waggoner S N, Sharma S, Cole L E, Waggoner L, Vanaja S K, Monks B G, Ganesan S, Latz E, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol,2010,11(5): 395-402.
117.Rawlinson S M, Pryor M J, Wright P J and Jans D A. CRM1-mediated nuclear export of dengue virus RNA polymerase NS5 modulates interleukin-8 induction and virus production. JBiol Chem,2009,284(23):15589-15597.
118.Rossow K D. Porcine reproductive and respiratory syndrome. Vet Pathol,1998,35(1): 1-20.
119.Sahoo M, Ceballos-Olvera I, del Barrio L and Re F. Role of the inflammasome, IL-1beta, and IL-18 in bacterial infections. ScientificWorldJournal,2011,11: 2037-2050.
120.Sakakibara S and Tosato G. Viral interleukin-6:role in Kaposi's sarcoma-associated herpesvirus:associated malignancies. J Interferon Cytokine Res,2011,31(11): 791-801.
121.Schmitz N, Kurrer M, Bachmann M F and Kopf M. Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol,2005,79(10):6441-6448.
122.Schroder K and Tschopp J. The inflammasomes. Cell,2010,140(6):821-832.
123.Segovia J, Sabbah A, Mgbemena V, Tsai S Y, Chang T H, Berton M. T, Morris I R, Allen I C, Ting J P and Bose S. TLR2/MyD88/NF-kappaB pathway, reactive oxygen species, potassium efflux activates NLRP3/ASC inflammasome during respiratory syncytial virus infection. PLoS One,2012,7(1):e29695.
124.Sergerie Y, Rivest S and Boivin G. Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis. J Infect Dis,2007,196(6):853-860.
125.Shah A and Kumar A. HIV-1 gp120-mediated increases in IL-8 production in astrocytes are mediated through the NF-kappaB pathway and can be silenced by gp120-specific siRNA. JNeuromflammation,2010,7:96.
126.Shaulian E and Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol, 2002,4(5):E131-136.
127.Shi K C, Guo X, Ge X N, Liu Q and Yang H C. Cytokine mRNA expression profiles in peripheral blood mononuclear cells from piglets experimentally co-infected with porcine reproductive and respiratory syndrome virus and porcine circovirus type 2. Vet Microbiol,2010,140(1-2):155-160.
128.Snijder E J. The arterivirus replicase. The road from RNA to protein(s), and back again. Adv Exp Med Biol,1998,440:97-108.
129.Stadejek T, Oleksiewicz M B, Potapchuk D and Podgorska K. Porcine reproductive and respiratory syndrome virus strains of exceptional diversity in eastern Europe support the definition of new genetic subtypes. J Gen Virol,2006,87(Pt 7): 1835-1841.
130.Strowig T, Henao-Mejia J, Elinav E and Flavell R. Inflammasomes in health and disease. Nature,2012,481(7381):278-286.
131.Sun Q, Matta H, Lu G and Chaudhary P M. Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-kappaB activation. Oncogene,2006, 25(19):2717-2726.
132.Takeda K and Akira S. Toll-like receptors in innate immunity. Int Immunol,2005, 17(1):1-14.
133.Takeuchi O and Akira S. MyD88 as a bottle neck in Toll/IL-1 signaling. Curr Top Microbiol Immunol,2002,270:155-167.
134.Takeuchi O and Akira S. Pattern recognition receptors and inflammation. Cell,2010, 140(6):805-820.
135.Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K and Akira S. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity,1999,11(4):443-451.
136.Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K, Morr M, Muhlradt P F and Akira S. Cutting edge:preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2-and MyD88-dependent signaling pathway. J Immunol,2000, 164(2):554-557.
137.Takeuchi O, Kawai T, Muhlradt P F, Morr M, Radolf J D, Zychlinsky A, Takeda K and Akira S. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol,2001,13(7):933-940.
138.Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin R L and Akira S. Cutting edge:role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol,2002,169(1):10-14.
139.Thanawongnuwech R, Thacker B, Halbur P and Thacker E L. Increased production of proinflammatory cytokines following infection with porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae. Clin Diagn Lab Immunol,2004,11(5):901-908.
140.Tian K, Yu X, Zhao T, Feng Y, Cao Z, Wang C, Hu Y, Chen X, Hu D, Tian X, et al. Emergence of fatal PRRSV variants:unparalleled outbreaks of atypical PRRS in China and molecular dissection of the unique hallmark. PLoS One,2007,2(6):e526.
141.Toma C, Higa N, Koizumi Y, Nakasone N, Ogura Y, McCoy A J, Franchi L, Uematsu S, Sagara J, Taniguchi S, et al. Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-kappa B signaling. J Immunol,2010,184(9):5287-5297.
142.van de Veerdonk F L, Netea M G, Dinarello C A and Joosten L A. Inflammasome activation and IL-lbeta and IL-18 processing during infection. Trends Immunol,2011, 32(3):110-116.
143.Watkins L R, Hansen M K, Nguyen K T, Lee J E and Maier S F. Dynamic regulation of the proinflammatory cytokine, interleukin-lbeta:molecular biology for non-molecular biologists. Life Sci,1999,65(5):449-481.
144. Wilson K P, Black J A, Thomson J A, Kim E E, Griffith J P, Navia M A, Murcko M A, Chambers S P, Aldape R A, Raybuck S A, et al. Structure and mechanism of interleukin-1 beta converting enzyme. Nature,1994,370(6487):270-275.
145.Xiao S, Jia J, Mo D, Wang Q, Qin L, He Z, Zhao X, Huang Y, Li A, Yu J, et al. Understanding PRRSV infection in porcine lung based on genome-wide transcriptome response identified by deep sequencing. PLoS One,2010,5(6): el1377.
146.Xiao S, Mo D, Wang Q, Jia J, Qin L, Yu X, Niu Y, Zhao X, Liu X and Chen Y. Aberrant host immune response induced by highly virulent PRRSV identified by digital gene expression tag profiling. BMC Genomics,2010,11:544.
147.Xie J, Pan H, Yoo S and Gao S J. Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol,2005,79(24):15027-15037.
148.Yang C S, Shin D M and Jo E K. The Role of NLR-related Protein 3 Inflammasome in Host Defense and Inflammatory Diseases. Int Neurourol J,2012,1.6(1):2-12.
149.Yang Y, Wu J and Lu Y. Mechanism of HIV-1-TAT induction of interleukin-lbeta from human monocytes:Involvement of the phospholipase C/protein kinase C signaling cascade. J Med Virol,2010,82(5):735-746.
150.Yew K H, Carpenter C, Duncan R S and Harrison C J. Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PLoS One,2012,7(9): e44500.
151.Yin S, Huo Y, Dong Y, Fan L, Yang H, Wang L, Ning Y and Hu H. Activation of c-Jun NH(2)-terminal kinase is required for porcine reproductive and respiratory syndrome virus-induced apoptosis but not for virus replication. Virus Res,2012, 166(1-2):103-108.
152. Yoo D, Song C, Sun Y, Du Y, Kim O and Liu H C. Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus. Virus Res,2010,154(1-2):48-60.
153.Zhang D, Zhang G, Hayden M S, Greenblatt M B, Bussey C, Flavell R A and Ghosh S. A toll-like receptor that prevents infection by uropathogenic bacteria. Science, 2004,303(5663):1522-1526.
154.Zhou R, Tardivel A, Thorens B, Choi I and Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol,2010,11(2): 136-140.
155.Zhou Y, Zhu N, Wang X, Wang L, Gu L J and Yuan W J. The role of the toll-like receptor TLR4 in hepatitis B virus-associated glomerulonephritis. Arch Virol,2013, 158(2):425-433.
156.Ziebuhr J, Snijder E J and Gorbalenya A E. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol,2000,81(Pt 4):853-879.
2.郭宝清,陈章水,刘文兴.从疑似PRRS流产胎儿分离PRRSV的研究.中国畜禽转染病,1996,2：1-4
3. 罗锐.PRRSV感染抑制Ⅰ型和Ⅲ型干扰素及激活NF-kB的分子机制研究.[博士论文].华中农业大学,2009
4. Ahlers J D, Belyakov I M and Berzofsky J A. Cytokine, chemokine, and costimulatory molecule modulation to enhance efficacy of HIV vaccines. Curr Mol Med,2003,3(3):285-301.
5. Akira S and Takeda K. Toll-like receptor signalling. Nat Rev Immunol,2004,4(7): 499-511.
6. Alexopoulou L, Holt A C, Medzhitov R and Flavell R A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature, 2001,413(6857):732-738.
7. Barlan A U, Griffin T M, McGuire K A and Wiethoff C M. Adenovirus membrane penetration activates the NLRP3 inflammasome. J Virol,2011,85(1):146-155.
8. Barranco I, Gomez-Laguna J, Rodriguez-Gomez I M, Salguero F J, Pallares F J and Carrasco L. Differential expression of proinflammatory cytokines in the lymphoid organs of porcine reproductive and respiratory syndrome virus-infected pigs. Transbound Emerg Dis,2012,59(2):145-153.
9. Bauernfeind F, Ablasser A, Bartok E, Kim S, Schmid-Burgk J, Cavlar T and Hornung V. Inflammasomes:current understanding and open questions. Cell Mol Life Sci, 2011,68(5):765-783.
10. Bauernfeind F G, Horvath G, Stutz A, Alnemri E S, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks B G, Fitzgerald K A, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol,2009,183(2): 787-791.
11. Beura L K, Dinh P X, Osorio F A and Pattnaik A K. Cellular poly(c) binding proteins 1 and 2 interact with porcine reproductive and respiratory syndrome virus nonstructural protein lbeta and support viral replication. J Virol,2011,85(24): 12939-12949.
12. Beutler B. TLR4 as the mammalian endotoxin sensor. Curr Top Microbiol Immunol, 2002,270:109-120.
13. Borghetti P, Saleri R, Ferrari L, Morganti M, De Angelis E, Franceschi V, Bottarelli E and Martelli P. Cytokine expression, glucocorticoid and growth hormone changes after porcine reproductive and respiratory syndrome virus (PRRSV-1) infection in vaccinated and unvaccinated naturally exposed pigs. Comp Immunol Microbiol Infect Dis,2011,34(2):143-155.
14. Brat D J, Bellail A C and Van Meir E G. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol,2005,7(2):122-133.
15. Burdette D, Haskett A, Presser L, McRae S, Iqbal J and Waris G. Hepatitis C virus activates interleukin-lbeta via caspase-l-inflammasome complex. J Gen Virol,2012, 93(Pt 2):235-246.
16. Calzada-Nova G, Schnitzlein W M, Husmann R J and Zuckermann F A. North American porcine reproductive and respiratory syndrome viruses inhibit type I interferon production by plasmacytoid dendritic cells. J Virol,2011,85(6): 2703-2713.
17. Cassel S L, Eisenbarth S C, Iyer S S, Sadler J J, Colegio O R, Tephly L A, Carter A B, Rothman P B, Flavell R A and Sutterwala F S. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A,2008,105(26): 9035-9040.
18. Chen Z, Lawson S, Sun Z, Zhou X, Guan X, Christopher-Hennings J, Nelson E A and Fang Y. Identification of two auto-cleavage products of nonstructural protein 1 (nspl) in porcine reproductive and respiratory syndrome virus infected cells:nspl function as interferon antagonist. Virology,2010,398(1):87-97.
19. Christopher-Hennings J, Nelson E A, Nelson J K, Rossow K D, Shivers J L, Yaeger M J, Chase C C, Garduno R A, Collins J E and Benfield D A. Identification of porcine reproductive and respiratory syndrome virus in semen and tissues from vasectomized and nonvasectomized boars. Vet Pathol,1998,35(4):260-267.
20. Coban C, Ishii K J, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, et al. Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med,2005,201(1):19-25.
21. Correa-Costa M, Braga T T, Semedo P, Hayashida C Y, Bechara L R, Elias R M, Barreto C R, Silva-Cunha C, Hyane M I, Goncalves G M, et al. Pivotal role of Toll-like receptors 2 and 4, its adaptor molecule MyD88, and inflammasome complex in experimental tubule-interstitial nephritis. PLoS One,2011,6(12):e29004.
22. Craven R R, Gao X, Allen I C, Gris D, Bubeck Wardenburg J, McElvania-Tekippe E, Ting J P and Duncan J A. Staphylococcus aureus alpha-hemolysin activates the NLRP3-inflammasome in human and mouse monocytic cells. PLoS One,2009,4(10): e7446.
23. Darwich L, Gimeno M, Sibila M, Diaz I, de la Torre E, Dotti S, Kuzemtseva L, Martin M, Pujols J and Mateu E. Genetic and immunobiological diversities of porcine reproductive and respiratory syndrome genotype I strains. Vet Microbiol, 2011,150(1-2):49-62.
24. Davis B K, Wen H and Ting J P. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol,2011,29:707-735.
25. Diebold S S, Kaisho T, Hemmi H, Akira S and Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science, 2004,303(5663):1529-1531.
26. Dinarello C A. Biologic basis for interleukin-1 in disease. Blood,1996,87(6): 2095-2147.
27. Drew T W. A review of evidence for immunosuppression due to porcine reproductive and respiratory syndrome virus. Vet Res,2000,31(1):27-39.
28. Eder C. Mechanisms of interleukin-lbeta release. Immunobiology,2009,214(7): 543-553.
29. Fang Y, Fang L, Wang Y, Lei Y, Luo R, Wang D, Chen H and Xiao S. Porcine reproductive and respiratory syndrome virus nonstructural protein 2 contributes to NF-kappaB activation. Virol J,2012,9:83.
30. Fang Y and Snijder E J. The PRRSV replicase:exploring the multifunctionality of an intriguing set of nonstructural proteins. Virus Res,2010,154(1-2):61-76.
31. Feng Y, Zhao T, Nguyen T, Inui K, Ma Y, Nguyen T H, Nguyen V C, Liu D, Bui Q A, To L T, et al. Porcine respiratory and reproductive syndrome virus variants, Vietnam and China,2007. Emerg Infect Dis,2008,14(11):1774-1776.
32. Gasse P, Riteau N, Charron S, Girre S, Fick L, Petrilli V, Tschopp J, Lagente V, Quesniaux V F, Ryffel B, et al. Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis. Am J Respir Crit Care Med, 2009,179(10):903-913.
33. Geldhof M F, Vanhee M, Van Breedam W, Van Doorsselaere J, Karniychuk U U and Nauwynck H J. Comparison of the efficacy of autogenous inactivated Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) vaccines with that of commercial vaccines against homologous and heterologous challenges. BMC Vet Res, 2012,8:182.
34. Georgel P, Jiang Z, Kunz S, Janssen E, Mols J, Hoebe K, Bahram S, Oldstone M B and Beutler B. Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. Virology,2007,362(2):304-313.
35. Ghosh S, May M J and Kopp E B. NF-kappa B and Rel proteins:evolutionarily conserved mediators of immune responses. Annu Rev Immunol,1998,16:225-260.
36. Gomez-Laguna J, Salguero F J, Barranco I, Pallares F J, Rodriguez-Gomez I M, Bernabe A and Carrasco L. Cytokine expression by macrophages in the lung of pigs infected with the porcine reproductive and respiratory syndrome virus. J Comp Pathol,2010,142(1):51-60.
37. Gomez-Laguna J, Salguero F J, Pallares F J, Fernandez de Marco M, Barranco I, Ceron J J, Martinez-Subiela S, Van Reeth K and Carrasco L. Acute phase response in porcine reproductive and respiratory syndrome virus infection. Comp Immunol Microbiol Infect Dis,2010,33(6):e51-58.
38. Gram AM, Frenkel J and Ressing M E. Inflammasomes and viruses:cellular defence versus viral offence. J Gen Virol,2012,93(Pt 10):2063-2075.
39. Gross O, Thomas C J, Guarda G and Tschopp J. The inflammasome:an integrated view. Immunol Rev,2011,243(1):136-151.
40. Grote K, Schutt H and Schieffer B. Toll-like receptors in angiogenesis. Scientific WorldJournal,2011,11:981-991.
41. Haynes L M, Moore D D, Kurt-Jones E A, Finberg R W, Anderson L J and Tripp R A. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol,2001,75(22):10730-10737.
42. He Y, Franchi L and Nunez G. TLR agonists stimulate Nlrp3-dependent IL-lbeta production independently of the purinergie P2X7 receptor in dendritic cells and in vivo. J Immunol,2013,190(1):334-339.
43. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S, et al. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7,8 and 9 subfamily. Eur J Immunol,2003,33(11):2987-2997.
44. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H and Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science,2004,303(5663):1526-1529.
45. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K and Akira S. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol,2002,3(2):196-200.
46. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, et al. A Toll-like receptor recognizes bacterial DNA. Nature, 2000,408(6813):740-745.
47. Hirano T. Interleukin 6 in autoimmune and inflammatory diseases:a personal memoir. Proc Jpn Acad Ser B Phys Biol Sci,2010,86(7):717-730.
48. Hirano T, Akira S, Taga T and Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today,1990,11(12):443-449.
49. Hoffmann E, Dittrich-Breiholz O, Holtmann H and Kracht M. Multiple control of interleukin-8 gene expression. JLeukoc Biol,2002,72(5):847-855.
50. Hornung V, Guenthner-Biller M, Bourquin C, Ablasser A, Schlee M, Uematsu S, Noronha A, Manoharan M, Akira S, de Fougerolles A, et al. Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat Med,2005,11(3):263-270.
51. Hoshino S, Konishi M, Mori M, Shimura M, Nishitani C, Kuroki Y, Koyanagi Y, Kano S, Itabe H and Ishizaka Y. HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency. J Leukoc Biol,2010,87(6): 1133-1143.
52. Hou J, Wang L, Quan R, Fu Y, Zhang H and Feng W H. Induction of interleukin-10 is dependent on p38 mitogen-activated protein kinase pathway in macrophages infected with porcine reproductive and respiratory syndrome virus. Virol J,2012,9:165.
53. Hu S, Sheng W S, Schachtele S J and Lokensgard J R. Reactive oxygen species drive herpes simplex virus (HSV)-l-induced proinflammatory cytokine production by murine microglia. J Neuroinflammation,2011,8:123.
54. Hu S P, Zhang Z, Liu Y G, Tian Z J, Wu D L, Cai X H and He X J. Pathogenicity and Distribution of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus in Pigs. Transbound Emerg Dis,2012.
55. Hu Y W, Rocheleau L, Larke B, Chui L, Lee B, Ma M, Liu S, Omlin T, Pelchat M and Brown E G. Immunoglobulin mimicry by Hepatitis C Virus envelope protein E2. Virology,2005,332(2):538-549.
56. Ichinohe T, Pang I K and Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat Immunol,2010,11(5):404-410.
57. Iwasaki A and Medzhitov R. Toll-like receptor control of the adaptive immune responses. Nat Immunol,2004,5(10):987-995.
58. Jacques A, Bleau C, Turbide C, Beauchemin N and Lamontagne L. Macrophage interleukin-6 and tumour necrosis factor-alpha are induced by coronavirus fixation to Toll-like receptor 2/heparan sulphate receptors but not carcinoembryonic cell adhesion antigen 1a. Immunology,2009,128(1 Suppl):e181-192.
59. Jensen S and Thomsen A R. Sensing of RNA viruses:a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol,2012,86(6): 2900-2910.
60. Jurk M, Heil F, Vollmer J, Schetter C, Krieg A M, Wagner H, Lipford G and Bauer S. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol,2002,3(6):499.
61. Kanneganti T D, Body-Malapel M, Amer A, Park J H, Whitfield J, Franchi L, Taraporewala Z F, Miller D, Patton J T, Inohara N, et al. Critical role for Cryopyrin/Nalp3 in activation of caspase-1 in response to viral infection and double-stranded RNA. J Biol Chem,2006,281(48):36560-36568.
62. Karin M and Greten F R. NF-kappaB:linking inflammation and immunity to cancer development and progression. Nat Rev Immunol,2005,5(10):749-759.
63. Kawai T and Akira S. TLR signaling. Cell Death Differ,2006,13(5):816-825.
64. Kelley J F, Kaufusi P H and Nerurkar V R. Dengue hemorrhagic fever-associated immunomediators induced via maturation of dengue virus nonstructural 4B protein in monocytes modulate endothelial cell adhesion molecules and human microvascular endothelial cells permeability. Virology,2012,422(2):326-337.
65. Koyama S, Ishii K J, Coban C and Akira S. Innate immune response to viral infection. Cytokine,2008,43(3):336-341.
66. Kristiansen M, Graversen J H, Jacobsen C, Sonne O, Hoffman H J, Law S K and Moestrup S K. Identification of the haemoglobin scavenger receptor. Nature,2001, 409(6817):198-201.
67. Krug A, French A R, Barchet W, Fischer J A, Dzionek A, Pingel J T, Orihuela M M, Akira S, Yokoyama W M and Colonna M. TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity,2004,21(1):107-119.
68. Lamkanfi M and Dixit V M. Modulation of inflammasome pathways by bacterial and viral pathogens. J Immunol,2011,187(2):597-602.
69. Lawson S R, Li Y, Patton J B, Langenhorst R J, Sun Z, Jiang Z, Christopher-Hennings J, Nelson E A, Knudsen D, Fang Y, et al. Interleukin-lbeta expression by a recombinant porcine reproductive and respiratory syndrome virus. Virus Res,2012,163(2):461-468.
70. Lee N, Wong C K, Hui D S, Lee S K, Wong R Y, Ngai K L, Chan M C, Chu Y J, Ho A W, Lui G C, et al. Role of human Toll-like receptors in naturally occurring influenza A infections. Influenza Other Respi Viruses,2013.
71. Lee S M and Kleiboeker S B. Porcine arterivirus activates the NF-kappaB pathway through IkappaB degradation. Virology,2005,342(1):47-59.
72. Lee S M and Kleiboeker S B. Porcine reproductive and respiratory syndrome virus induces apoptosis through a mitochondria-mediated pathway. Virology,2007,365(2): 419-434.
73. Lee Y J and Lee C. Cytokine production in immortalized porcine alveolar macrophages infected with porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol,2012,150(3-4):213-220.
74. Lee Y J and Lee C. Stress-activated protein kinases are involved in porcine reproductive and respiratory syndrome virus infection and modulate virus-induced cytokine production. Virology,2012,427(2):80-89.
75. Liu Y, Shi W, Zhou E, Wang S, Hu S, Cai X, Rong F, Wu J, Xu M and Li L. Dynamic changes in inflammatory cytokines in pigs infected with highly pathogenic porcine reproductive and respiratory syndrome virus. Clin Vaccine Immunol,2010,17(9): 1439-1445.
76. Lund J, Sato A, Akira S, Medzhitov R and Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med, 2003,198(3):513-520.
77. Lund J M, Alexopoulou L, Sato A, Karow M, Adams N C, Gale N W, Iwasaki A and Flavell R A. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci USA,2004,101(15):5598-5603.
78. Lunney J K, Benfield D A and Rowland R R. Porcine reproductive and respiratory syndrome virus:an update on an emerging and re-emerging viral disease of swine. Virus Res,2010,154(1-2):1-6.
79. Lunney J K, Fritz E R, Reecy J M, Kuhar D, Prucnal E, Molina R, Christopher-Hennings J, Zimmerman J and Rowland R R. Interleukin-8, interleukin-lbeta, and interferon-gamma levels are linked to PRRS virus clearance. Viral Immunol,2010,23(2):127-134.
80. Luo R, Fang L, Jiang Y, Jin H, Wang Y, Wang D, Chen H and Xiao S. Activation of NF-kappaB by nucleocapsid protein of the porcine reproductive and respiratory syndrome virus. Virus Genes,2011,42(1):76-81.
81. Luo R, Xiao S, Jiang Y, Jin H, Wang D, Liu M, Chen H and Fang L. Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon-beta production by interfering with the RIG-I signaling pathway. Mol Immunol,2008, 45(10):2839-2846.
82. Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K and Murakami S. Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J Biol Chem,1991,266(21):13759-13763.
83. Mamik M K, Banerjee S, Walseth T F, Hirte R, Tang L, Borgmann K. and Ghorpade A. HIV-1 and IL-lbeta regulate astrocytic CD38 through mitogen-activated protein kinases and nuclear factor-kappaB signaling mechanisms. J Neuroinflammation,2011, 8:145.
84. Mariathasan S, Weiss D S, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee W P, Weinrauch Y, Monack D M and Dixit V M. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature,2006,440(7081):228-232.
85. Martinon F. Mayor A and Tschopp J. The inflammasomes:guardians of the body. Annu Rev Immunol,2009,27:229-265.
86. Medzhitov R, Preston-Hurlburt P and Janeway C A, Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature,1997, 388(6640):394-397.
87. Meissner F, Molawi K and Zychlinsky A. Superoxide dismutase 1 regulates caspase-1 and endotoxic shock. Nat Immunol,2008,9(8):866-872.
88. Miguel J C, Chen J, Van Alstine W G and Johnson R W. Expression of inflammatory cytokines and Toll-like receptors in the brain and respiratory tract of pigs infected with porcine reproductive and respiratory syndrome virus. Vet Immunol Immunopathol,2010,135(3-4):314-319.
89. Monick M M, Yarovinsky T O, Powers L S, Butler N S, Carter A B, Gudmundsson G and Hunninghake G W. Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. JBiol Chem,2003,278(52):53035-53044.
90. Morgan S B, Graham S P, Salguero F J, Sanchez Cordon P J, Mokhtar H, Rebel J M, Weesendorp E, Bodman-Smith K B, Steinbach F and Frossard J P. Increased pathogenicity of European porcine reproductive and respiratory syndrome virus is associated with enhanced adaptive responses and viral clearance. Vet Microbiol,2013, 163(1-2):13-22.
91. Muruve D A, Petrilli V, Zaiss A K, White L R, Clark S A, Ross P J, Parks R J and Tschopp J. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature,2008,452(7183):103-107.
92. Netea M G, Nold-Petry C A, Nold M F, Joosten L A, Opitz B, van der Meer J H, van de Veerdonk F L, Ferwerda G, Heinhuis B, Devesa I, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-lbeta in monocytes and macrophages. Blood,2009,113(10):2324-2335.
93. Netea M G, Simon A, van de Veerdonk F, Kullberg B J, Van der Meer J W and Joosten L A. IL-lbeta processing in host defense:beyond the inflammasomes. PLoS Pathog,2010,6(2):e1000661.
94. O'Neill L A. Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr Top Microbiol Immunol,2002,270:47-61.
95. Okumura A, Pitha P M, Yoshimura A and Harty R N. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. J Virol,2010,84(1):27-33.
96. Opriessnig T, Gimenez-Lirola L G and Halbur P G. Polymicrobial respiratory disease in pigs. Anim Health Res Rev,2011,12(2):133-148.
97. Otsuka M, Jing Q, Georgel P, New L, Chen J, Mols J, Kang Y J, Jiang Z, Du X, Cook R, et al. Hypersusceptibility to vesicular stomatitis virus infection in Dicer1-deficient mice is due to impaired miR24 and miR93 expression. Immunity,2007,27(1): 123-134.
98. Ozinsky A, Underhill D M, Fontenot J D, Hajjar A M, Smith K D, Wilson C B, Schroeder L and Aderem A. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA,2000,97(25):13766-13771.
99. Pang I K and Iwasaki A. Inflammasomes as mediators of immunity against influenza virus. Trends Immunol,2011,32(1):34-41.
100.Patel D, Nan Y, Shen M, Ritthipichai K, Zhu X and Zhang Y J. Porcine reproductive and respiratory syndrome virus inhibits type I interferon signaling by blocking STAT1/STAT2 nuclear translocation. J Virol,2010,84(21):11045-11055.
101.Petrilli V, Papin S, Dostert C, Mayor A, Martinon F and Tschopp J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ,2007,14(9):1583-1589.
102.Poeck H, Bscheider M, Gross O, Finger K, Roth S, Rebsamen M, Hannesschlager N, Schlee M, Rothenfusser S, Barchet W, et al. Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production. Nat Immunol,2010,11(1):63-69.
103.Poeck H and Ruland J. From virus to inflammation:mechanisms of RIG-I-induced IL-1 beta production. Eur J Cell Biol,2012,91(1):59-64.
104.Poltorak A, He X, Smirnova I, Liu M Y, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:mutations in Tlr4 gene. Science,1998,282(5396):2085-2088.
105.Pontillo A, Silva L T, Oshiro T M, Finazzo C, Crovella S and Duarte A J. HIV-1 induces NALP3-inflammasome expression and interleukin-1 beta secretion in dendritic cells from healthy individuals but not from HIV-positive patients. AIDS, 2012,26(1):11-18.
106.Pryor M J, Rawlinson S M, Butcher R E, Barton C L, Waterhouse T A, Vasudevan S G, Bardin P G, Wright P J, Jans D A and Davidson A D. Nuclear localization of dengue virus nonstructural protein 5 through its importin alpha/beta-recognized nuclear localization sequences is integral to viral infection. Traffic,2007,8(7): 795-807.
107.Qiao S, Feng L, Bao D, Guo J, Wan B, Xiao Z, Yang S and Zhang G. Porcine reproductive and respiratory syndrome virus and bacterial endotoxin act in synergy to amplify the inflammatory response of infected macrophages. Vet Microbiol,2011, 149(1-2):213-220.
108.Qiao Y, Wang P, Qi J, Zhang L and Gao C. TLR-induced NF-kappaB activation regulates NLRP3 expression in murine macrophages. FEBS Lett,2012,586(7): 1022-1026.
109.Rachman A and Rinaldi I. Coagulopathy in dengue infection and the role of interleukin-6. Acta Med Indones,2006,38(2):105-108.
110.Rahman M M and McFadden G. Myxoma virus lacking the pyrin-like protein M013 is sensed in human myeloid cells by both NLRP3 and multiple Toll-like receptors, which independently activate the inflammasome and NF-kappaB innate response pathways. J Virol,2011,85(23):12505-12517.
111.Rajan J V, Rodriguez D, Miao E A and Aderem A. The NLRP3 inflammasome detects encephalomyocarditis virus and vesicular stomatitis virus infection. J Virol,2011, 85(9):4167-4172.
112.Rallabhandi P, Phillips R L, Boukhvalova M S, Pletneva L M, Shirey K A, Gioannini T L, Weiss J P, Chow J C, Hawkins L D, Vogel S N, et al. Respiratory syncytial virus fusion protein-induced toll-like receptor 4 (TLR4) signaling is inhibited by the TLR4 antagonists Rhodobacter sphaeroides lipopolysaccharide and eritoran (E5564) and requires direct interaction with MD-2. MBio,2012,3(4).
113.Randall R E and Goodbourn S. Interferons and viruses:an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol, 2008,89(Pt 1):1-47.
114.Rassa J C, Meyers J L, Zhang Y, Kudaravalli R and Ross S R. Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci U S A, 2002,99(4):2281-2286.
115.Rathinam V A and Fitzgerald K A. Inflammasomes and anti-viral immunity. J Clin Immunol,2010,30(5):632-637.
116.Rathinam V A, Jiang Z, Waggoner S N, Sharma S, Cole L E, Waggoner L, Vanaja S K, Monks B G, Ganesan S, Latz E, et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol,2010,11(5): 395-402.
117.Rawlinson S M, Pryor M J, Wright P J and Jans D A. CRM1-mediated nuclear export of dengue virus RNA polymerase NS5 modulates interleukin-8 induction and virus production. JBiol Chem,2009,284(23):15589-15597.
118.Rossow K D. Porcine reproductive and respiratory syndrome. Vet Pathol,1998,35(1): 1-20.
119.Sahoo M, Ceballos-Olvera I, del Barrio L and Re F. Role of the inflammasome, IL-1beta, and IL-18 in bacterial infections. ScientificWorldJournal,2011,11: 2037-2050.
120.Sakakibara S and Tosato G. Viral interleukin-6:role in Kaposi's sarcoma-associated herpesvirus:associated malignancies. J Interferon Cytokine Res,2011,31(11): 791-801.
121.Schmitz N, Kurrer M, Bachmann M F and Kopf M. Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection. J Virol,2005,79(10):6441-6448.
122.Schroder K and Tschopp J. The inflammasomes. Cell,2010,140(6):821-832.
123.Segovia J, Sabbah A, Mgbemena V, Tsai S Y, Chang T H, Berton M. T, Morris I R, Allen I C, Ting J P and Bose S. TLR2/MyD88/NF-kappaB pathway, reactive oxygen species, potassium efflux activates NLRP3/ASC inflammasome during respiratory syncytial virus infection. PLoS One,2012,7(1):e29695.
124.Sergerie Y, Rivest S and Boivin G. Tumor necrosis factor-alpha and interleukin-1 beta play a critical role in the resistance against lethal herpes simplex virus encephalitis. J Infect Dis,2007,196(6):853-860.
125.Shah A and Kumar A. HIV-1 gp120-mediated increases in IL-8 production in astrocytes are mediated through the NF-kappaB pathway and can be silenced by gp120-specific siRNA. JNeuromflammation,2010,7:96.
126.Shaulian E and Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol, 2002,4(5):E131-136.
127.Shi K C, Guo X, Ge X N, Liu Q and Yang H C. Cytokine mRNA expression profiles in peripheral blood mononuclear cells from piglets experimentally co-infected with porcine reproductive and respiratory syndrome virus and porcine circovirus type 2. Vet Microbiol,2010,140(1-2):155-160.
128.Snijder E J. The arterivirus replicase. The road from RNA to protein(s), and back again. Adv Exp Med Biol,1998,440:97-108.
129.Stadejek T, Oleksiewicz M B, Potapchuk D and Podgorska K. Porcine reproductive and respiratory syndrome virus strains of exceptional diversity in eastern Europe support the definition of new genetic subtypes. J Gen Virol,2006,87(Pt 7): 1835-1841.
130.Strowig T, Henao-Mejia J, Elinav E and Flavell R. Inflammasomes in health and disease. Nature,2012,481(7381):278-286.
131.Sun Q, Matta H, Lu G and Chaudhary P M. Induction of IL-8 expression by human herpesvirus 8 encoded vFLIP K13 via NF-kappaB activation. Oncogene,2006, 25(19):2717-2726.
132.Takeda K and Akira S. Toll-like receptors in innate immunity. Int Immunol,2005, 17(1):1-14.
133.Takeuchi O and Akira S. MyD88 as a bottle neck in Toll/IL-1 signaling. Curr Top Microbiol Immunol,2002,270:155-167.
134.Takeuchi O and Akira S. Pattern recognition receptors and inflammation. Cell,2010, 140(6):805-820.
135.Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, Takeda K and Akira S. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity,1999,11(4):443-451.
136.Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K, Morr M, Muhlradt P F and Akira S. Cutting edge:preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2-and MyD88-dependent signaling pathway. J Immunol,2000, 164(2):554-557.
137.Takeuchi O, Kawai T, Muhlradt P F, Morr M, Radolf J D, Zychlinsky A, Takeda K and Akira S. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol,2001,13(7):933-940.
138.Takeuchi O, Sato S, Horiuchi T, Hoshino K, Takeda K, Dong Z, Modlin R L and Akira S. Cutting edge:role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol,2002,169(1):10-14.
139.Thanawongnuwech R, Thacker B, Halbur P and Thacker E L. Increased production of proinflammatory cytokines following infection with porcine reproductive and respiratory syndrome virus and Mycoplasma hyopneumoniae. Clin Diagn Lab Immunol,2004,11(5):901-908.
140.Tian K, Yu X, Zhao T, Feng Y, Cao Z, Wang C, Hu Y, Chen X, Hu D, Tian X, et al. Emergence of fatal PRRSV variants:unparalleled outbreaks of atypical PRRS in China and molecular dissection of the unique hallmark. PLoS One,2007,2(6):e526.
141.Toma C, Higa N, Koizumi Y, Nakasone N, Ogura Y, McCoy A J, Franchi L, Uematsu S, Sagara J, Taniguchi S, et al. Pathogenic Vibrio activate NLRP3 inflammasome via cytotoxins and TLR/nucleotide-binding oligomerization domain-mediated NF-kappa B signaling. J Immunol,2010,184(9):5287-5297.
142.van de Veerdonk F L, Netea M G, Dinarello C A and Joosten L A. Inflammasome activation and IL-lbeta and IL-18 processing during infection. Trends Immunol,2011, 32(3):110-116.
143.Watkins L R, Hansen M K, Nguyen K T, Lee J E and Maier S F. Dynamic regulation of the proinflammatory cytokine, interleukin-lbeta:molecular biology for non-molecular biologists. Life Sci,1999,65(5):449-481.
144. Wilson K P, Black J A, Thomson J A, Kim E E, Griffith J P, Navia M A, Murcko M A, Chambers S P, Aldape R A, Raybuck S A, et al. Structure and mechanism of interleukin-1 beta converting enzyme. Nature,1994,370(6487):270-275.
145.Xiao S, Jia J, Mo D, Wang Q, Qin L, He Z, Zhao X, Huang Y, Li A, Yu J, et al. Understanding PRRSV infection in porcine lung based on genome-wide transcriptome response identified by deep sequencing. PLoS One,2010,5(6): el1377.
146.Xiao S, Mo D, Wang Q, Jia J, Qin L, Yu X, Niu Y, Zhao X, Liu X and Chen Y. Aberrant host immune response induced by highly virulent PRRSV identified by digital gene expression tag profiling. BMC Genomics,2010,11:544.
147.Xie J, Pan H, Yoo S and Gao S J. Kaposi's sarcoma-associated herpesvirus induction of AP-1 and interleukin 6 during primary infection mediated by multiple mitogen-activated protein kinase pathways. J Virol,2005,79(24):15027-15037.
148.Yang C S, Shin D M and Jo E K. The Role of NLR-related Protein 3 Inflammasome in Host Defense and Inflammatory Diseases. Int Neurourol J,2012,1.6(1):2-12.
149.Yang Y, Wu J and Lu Y. Mechanism of HIV-1-TAT induction of interleukin-lbeta from human monocytes:Involvement of the phospholipase C/protein kinase C signaling cascade. J Med Virol,2010,82(5):735-746.
150.Yew K H, Carpenter C, Duncan R S and Harrison C J. Human cytomegalovirus induces TLR4 signaling components in monocytes altering TIRAP, TRAM and downstream interferon-beta and TNF-alpha expression. PLoS One,2012,7(9): e44500.
151.Yin S, Huo Y, Dong Y, Fan L, Yang H, Wang L, Ning Y and Hu H. Activation of c-Jun NH(2)-terminal kinase is required for porcine reproductive and respiratory syndrome virus-induced apoptosis but not for virus replication. Virus Res,2012, 166(1-2):103-108.
152. Yoo D, Song C, Sun Y, Du Y, Kim O and Liu H C. Modulation of host cell responses and evasion strategies for porcine reproductive and respiratory syndrome virus. Virus Res,2010,154(1-2):48-60.
153.Zhang D, Zhang G, Hayden M S, Greenblatt M B, Bussey C, Flavell R A and Ghosh S. A toll-like receptor that prevents infection by uropathogenic bacteria. Science, 2004,303(5663):1522-1526.
154.Zhou R, Tardivel A, Thorens B, Choi I and Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol,2010,11(2): 136-140.
155.Zhou Y, Zhu N, Wang X, Wang L, Gu L J and Yuan W J. The role of the toll-like receptor TLR4 in hepatitis B virus-associated glomerulonephritis. Arch Virol,2013, 158(2):425-433.
156.Ziebuhr J, Snijder E J and Gorbalenya A E. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J Gen Virol,2000,81(Pt 4):853-879.