PCV2感染、氧化应激与硒的相互作用关系及其机理研究

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英文题名：Interaction among PCV2Infection, Oxidative Stress and Selenium and Their Mechanism 作者：陈兴祥 论文级别：博士 学科专业名称：临床兽医学 中文关键词：PCV2 ; 氧化应激 ; 硒 ; 硒蛋白 ; 断奶仔猪 ; 抗氧化能力 ; 免疫 英文关键词：porcine circovirus type2 ; oxidative stress ; selenium ; selenoproteins ; piglets ; antioxidant capacity ; immunity 学位年度：2012 导师：黄克和 学科代码：090603 学位授予单位：南京农业大学 论文提交日期：2012-04-01

摘要

猪圆环病毒2型(PCV2)是一种新近发现的猪传染性疾病的病原,它与多种猪病的发生密切相关,如猪皮炎肾病综合征、繁殖障碍、猪呼吸道综合征、肉芽肿性肠炎、坏死性淋巴腺炎、渗出性皮炎和仔猪先天性震颤等,其中影响最为严重的是断奶仔猪多系统衰竭综合征PMWS,该病已在全世界范围内广泛存在,给全球养猪业造成了巨大的经济损失,但目前其致病机制还不是很清楚。已有研究表明,该病的发生还与氧化应激有关。硒是动物和人所必需的微量元素之一,具有增强机体抗氧化能力、提高机体免疫力、抵抗病毒感染等多种重要的生物学功能。当前研究显示,硒主要以硒半胱胺酸的形式掺入硒蛋白中,通过后者发挥其生物学功能,但对于很多硒蛋白具体的生物学功能与作用还有待于进一步地去研究、认识。富硒酵母主要含硒蛋氨酸,与无机硒(如亚硒酸钠)相比,它具有毒性小、生物利用率高的特点。本论文主要对PCV2的感染和复制与宿主细胞氧化还原状态之间的相互作用关系及其机理、硒影响PCV2感染与复制的机理、硒对PCV2感染阳性猪场断奶仔猪生长、抗氧化能力、PCV2感染水平以及免疫机能的影响进行了研究和探讨,以期从宿主氧化应激的角度阐述PCV2的致病机制,为硒特别是有机硒在养猪生产上的广泛应用提供理论依据。
     试验一：PCV2的感染和复制与宿主细胞氧化还原状态之间的相互作用研究
     本试验对PCV2的感染和复制与宿主细胞氧化还原状态之间的相互作用关系进行了研究。试验结果显示,PCV2感染后48小时细胞内还原型谷胱甘肽(GSH)和超氧化物歧化酶(SOD)活性均显著降低,而主要脂质过氧化代谢产物MDA的浓度在PCV2感染后48小时显著升高。GSH生成前体N-乙酰半胱氨酸NAC处理细胞能显著增加细胞内还原型谷胱甘肽(GSH)的浓度,进而抑制PCV2的复制。相反,利用H202的氧化性降低细胞内的还原型谷胱甘肽(GSH)浓度能促进PCV2的复制。本试验研究结果表明,PCV2感染改变了宿主细胞的氧化还原状态,导致氧化应激的产生,同时,宿主细胞氧化还原状态的改变也可影响PCV2的复制。
     试验二：活性氧(ROS)通过NF-κB信号途径调节猪圆环病毒2型(PCV2)的复制
     研究表明,细胞内的氧化还原状态对不同病毒在宿主细胞内的复制有不同的影响。本试验主要研究了活性氧(ROS)对猪圆环病毒2型(PCV2)在PK15细胞中复制的影响。试验结果显示,PCV2感染后PK15细胞中ROS水平升高,并随着时间的推移而变化,在感染后72小时达到最高,而后逐渐下降。抗氧化物N-乙酰半胱氨酸NAC能够降低PK15细胞内的ROS水平进而抑制PCV2的复制；相反地,还原型谷胱甘肽(GSH)合成酶抑制剂BSO则可提高PK15细胞内的ROS水平并促进PCV2的复制。通过抑制剂BAY11-7082抑制NF-κB信号途径的激活后发现,BSO诱导的ROS升高不再促进PCV2的复制。本试验研究结果表明,PCV2感染本身会诱导宿主细胞产生ROS; ROS可通过NF-κB信号途径调节PCV2的复制。
     试验三：硒通过提高GPX1的表达阻断氧化应激对PCV2复制的促进作用
     本试验主要对PCV2复制、氧化应激以及硒之间的相互作用关系进行了研究。通过测定PCV2的DNA拷贝数和PCV2阳性感染的细胞数发现,过氧化氢诱导的氧化应激能够促进PCV2的复制；高剂量的硒蛋氨酸(6gM)能够抑制PCV2的复制；而生理剂量的硒蛋氨酸(2或4μM)则能够阻断氧化应激对PCV2复制的促进作用；PCV2感染PK15细胞后GPX1活性下降,但GPX1mRNA水平却在PCV2感染后显著升高,该结果预示在PCV2感染过程中GPX1可能对宿主细胞起到重要的保护作用。对GPX1进行RNA干扰后发现,硒蛋氨酸对氧化应激促进PCV2复制的阻断作用下降了,其表现与GPX1被干扰后硒蛋氨酸对GPX1表达的影响相一致,从而说明在硒阻断氧化应激促进PCV2复制的过程中,GPX1起着至关重要的作用。本试验研究结果提示,PCV2感染后所导致的不同猪场发病率和死亡率的差异可能与氧化应激有关,而硒则具有预防控制PCV2感染的潜力。
     试验四：硒对PCV2感染阳性猪场断奶仔猪生长性能、抗氧化性能及PCV2感染的影响
     从江苏某PCV2感染阳性猪场选择断奶仔猪60头,随机分成5组,每组3个重复,每个重复4头,对照组饲喂基础日粮,试验组分别饲喂基础日粮+亚硒酸钠或富硒酵母,其中每种硒的添加浓度均为0.3和0.6mg/kg。试验结果表明,饲粮中添加不同形式不同水平的硒均可显著改善饲料的报酬率,提高断奶仔猪的日增重,降低料肉比；加硒提高了断奶仔猪血清中的GPX和SOD活性,降低了血清中的MDA含量,提高其抗氧化性能；加硒增加了血液中GPx1、GPx4、TR1等硒蛋白的mRNA水平。此外,添加不同浓度的亚硒酸钠或富硒酵母均能够显著降低PCV2感染阳性猪场断奶仔猪血液中的PCV2DNA拷贝数。从改善机体抗氧化性能、提高硒蛋白mRNA水平以及抑制PCV2感染的效果来看,富硒酵母优于亚硒酸钠。
     试验五：硒对PCV2感染阳性猪场断奶仔猪免疫机能的影响
     从江苏某PCV2感染阳性猪场选择断奶仔猪60头,随机分成5组,每组3个重复,每个重复4头,对照组饲喂基础日粮,试验组分别饲喂基础日粮+亚硒酸钠或富硒酵母,其中每种硒的添加浓度均为0.3和O.6mg/kg.试验结果表明,饲料中添加不同浓度的亚硒酸钠或富硒酵母均能够显著提高断奶仔猪血清细胞因子IL-2和TNF-α的含量(P<0.05)；PCV2感染仔猪外周血液淋巴细胞转化试验结果表明,添加不同浓度的亚硒酸钠或富硒酵母可以提高其淋巴细胞的增殖水平；从提高断奶仔猪免疫机能的效果来看,富硒酵母优于亚硒酸钠。
Porcine circovirus diseases (PCVD) include porcine respiratory disease complex (PRDC), enteric disease, reproductive disease, and porcine dermatitis and nephropathy syndrome (PDNS). The most economically important PCVD is post-weaning multisystemic wasting syndrome (PMWS), characterized by wasting and growth retardation. PMWS primarily affects weanling piglets at the age of3to15weeks and has a high morbidity rate of up to60%. Several studies have linked PMWS expression to management measures, presence of concurrent viral infections, stimulation of the immune system, nutrition and oxidative stress, but the pathogenic mechanism of PCV2remains poorly understood. Selenium is an essential micronutrient for human and animals and its important biological functions have been attributed largely to its presence in selenoproteins as the21st amino acid, selenocysteine. The physiological roles of selenoproteins are closely related to selenium status. Low selenium status has been reported both to influence progression of some viral diseases while selenium supplementation has been found to affect the progression of some viral infections. However, further work is needed to provide insight into the role of selenium and specific selenoproteins in relation to viral diseases. In addition, precious studies have suggested that organic forms of Se (e.g., Se-enriched yeast, which mainly contains selenomethionine) are less toxic than inorganic forms of Se such as sodium selenite, and the bioavailability of organic Se is relatively high. The present study was conducted to investigate the interaction among PCV2infection, oxidative stress and selenium and their mechanism.
     Experiment1:Interaction of porcine circovirus type2replication with intracellular redox status in vitro
     Redox status influences replication of some viruses but its effect on porcine circovirus type2(PCV2), the primary causative agent of the emerging swine disease postweaning multisystemic wasting syndrome is not known. In this study we examined the interaction of PCV2replication with intracellular redox status in PK15cells. Both intracellular glutathione (GSH) and total superoxide dismutase activity (SOD) decreased significantly48h post-infection and subsequently returned to normal levels after72h, while malondialdehyde (MDA) concentration increased significantly at72h post-infection. Furthermore, PCV2replication in PK15cells was significantly impaired after the elevation of intracellular GSH through treatment with the antioxidant N-acetyl-1-cysteine (NAC), a precursor in glutathione synthesis. In contrast, PCV2replication in PK15cells was enhanced after reduction of GSH levels through H2O2-mediated oxidation. We conclude that PCV2infection induces oxidative stress and that intracellular redox status influences PCV2replication in PK15cells. This is the first demonstration of the interaction of PCV2replication with intracellular redox status.
     Experiment2:Reactive oxygen species regulate the replication of porcine circovirus type2via NF-κB pathway
     Intracellular redox state has been suggested to have various effects on the replication of different viruses within host cells. The aim of the present study was to investigate the influence of reactive oxygen species (ROS) on replication of porcine circovirus type2(PCV2), in PK15cells. Following PCV2infection there was a time-dependent increase in ROS. Antioxidant N-acetyl-1-cysteine treatment of cells resulted lower ROS levels and lower PCV2replication. In contrast, treatment by buthionine sulfoximine (BSO), a GSH synthesis inhibitor, resulted in elevation of ROS levels and increased PCV2replication. Furthermore, inhibiting the activity of NF-κB, a redox-responsive transcription factor, suppressed BSO-mediated increase of PCV2replication, indicating that increased PCV2replication likely occurs via ROS activation of NF-κB. Taken together, our results indicate that the generation of ROS during PCV2infection is involved in its replication and this progression is associated with the alteration in NF-κB activity induced by ROS.
     Experiment3:Selenium blocks PCV2replication promotion induced by oxidative stress via improving GPxl expression
     Porcine circovirus type2(PCV2) is recognized as a key infectious agent in post-weaning multisystemic wasting syndrome (PMWS), but not all pigs infected with PCV2will develop PMWS. The aim of this work was to explore the relationships between PCV2infection, oxidative stress and selenium in a PK-15cell culture model of PCV2infection. The results showed that oxidative stress induced by H2O2treatment increased PCV2replication as measured by PCV2DNA copies and the number of infected cells. Furthermore, PCV2replication was inhibited by selenomethionine (SeMet) at a high concentration (6μM) and the increase in PCV2replication by oxidative stress was blocked by SeMet at physiological concentrations (2or4μM). PCV2infection caused a decrease of glutathione peroxidase1(GPxl) activity but an increase of GPxl mRNA levels, suggesting that GPx1may represent an important defense mechanism during PCV2infection. SeMet did not significantly block the promotion of PCV2replication in GPxl-knockdown cells. This observation correlates with the observed influence of SeMet on GPxl mRNA and activity in GPxl-knockdown cells, indicating that GPxl plays a key role in blocking the promotion of PCV2replication. We conclude that differences in morbidity and severity of PMWS caused on different pig farms may be related to variations in oxidative stress and that selenium has a potential role in control of PCV2infection.
     Experiment4:Effects of selenium on growth performance, anti-oxidation, selenoprotein expression and PCV2infection of weaned piglets in a PCV2-infected pig farm.
     This trial was conducted to study the effect of selenium on growth performance, anti-oxidation, selenoprotein expression and PCV2infection of weaned piglets in a PCV2-infected pig farm.60Duroc X (Landrace X Largewhite) weaned piglets were allotted to five treatments with three replications per treatment and4weaned piglets per replication. The control group was given a basal diet and other four groups were given a basal diet supplemented with0.3or0.6mg/kg selenium (sodium selenite or selenium-riched yeast). The results showed that supplementation of sodium selenite or selenium-enriched yeast at various concentrations significantly improved the ADG and ADFI of weaned piglets, increased SOD and GSH-PX activity while significantly (P<0.05) reduced MDA content of serum. In addition, selenium supplmentaion increased the mRNA levels of GPx1, GPx4and TR1, and decreased the PCV2DNA copies in weaned piglets. Compared to sodium selenite, selenium-enriched yeast showed better effects on growth performance, anti-oxidation, selenoprotein expression and PCV2infection of weaned piglets.
     Experiment5:Effects of selenium on the immunity of weaned piglets in a PCV2-infected pig farm
     This trial was conducted to study the effect of selenium on the immunity of weaned piglets in a PCV2-infected pig farm.60Duroc X (Landrace X Largewhite) weaned piglets were allotted to five treatments with three replications per treatment and4weaned piglets per replication. The control group was given a basal diet and other four groups were given a basal diet supplemented with0.3or0.6mg/kg selenium (sodium selenite or selenium-riched yeast). The results showed that sodium selenite or selenium-enriched yeast supplemented at various concentrations improved the immunity of weaned piglets, with a significantly increase in IL-2and TNF-a levels (P<0.05). In addition, sodium selenite or selenium-riched yeast supplemented at various concentrations significantly promoted the proliferation of peripheral blood lymphocyte (P<0.05). Compared to sodium selenite, selenium-enriched yeast showed better effects on the immunity of PCV2-infected piglets.

引文

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