猪瘟病毒影响RANTES产生分子机制的研究
摘要
猪瘟(Classical Swine Fever, CSF)又称猪霍乱(Hog Cholera,HC),是由猪瘟病毒(CSFV)引起的猪的一种急性热性致死性疾病,给世界养猪业造成了巨大的经济损失。近几年猪瘟的免疫失败、猪瘟与其它疫病的混合感染及继发感染不断出现,使疫病的防控形式日趋严峻。深入研究CSFV感染细胞后的免疫反应及其分子机制进一步阐明猪瘟病毒的免疫机理,对猪瘟新型疫苗研制和防控措施制定具有十分重要的意义。
调节活化正常T细胞表达与分泌的因子(Regulated upon Activation, Normal T cell Expressed and Secreted, RANTES)是趋化因子CC家族的重要因子之一,也是一种多效性的趋化因子。它不仅对多种细胞有趋化作用,还可以激活淋巴细胞,参与炎症反应的发生,调节细胞的生长和分化。目前的研究已经证实：RANTES在包括细菌、病毒在内的多种微生物的感染与致病中扮演十分重要的角色,但迄今为止猪瘟病毒感染与RANTES表达之间的关系尚不清楚。鉴于此,本研究开展了猪瘟病毒感染后RANTES的表达动力学研究,并探讨了猪瘟病毒调控RANTES表达的信号通路。主要研究内容如下：
1、CSFV感染PK-15细胞后RANTES mRNA表达的动力学
采用荧光定量Real-time PCR分析了CSFV感染PK-15细胞后不同时间RANTES的表达,发现CSFV感染PK-15细胞后早期RANTES mRNA的表达水平没有明显的变化,但感染后72h显著低于未感染细胞,而且CSFV感染能显著抑制poly(I:C)诱导的RANTES表达。为了进一步验证荧光定量PCR的结果,随后构建了猪RANTES基因启动子荧光素酶报告系统,发现CSFV能抑制RANTES启动子的激活。
2、CSFV Npro参与抑制RANTES表达
为了确定猪瘟病毒编码的蛋白在抑制RANTES中的作用,分别构建了猪瘟病毒12种编码蛋白的真核表达表达质粒,采用RANTES启动子荧光素酶报告系统分析不同编码对RANTES启动子活性的影响,发现转染Npro的表达质粒能显著抑制RANTES启动子的活性。进一步对RANTES启动子中不同转录因子结合位点进行突变分析,发现ISRE结合位点在CSFV Npro抑制RANTES中起重要作用。为了确定Npro抑制RANTES的必需区域,构建了Npro的一系列突变体,发现Npro的N端21个氨基酸对抑制RANTES的表达是非必需的,而突变与Npro切割活性有关的第69位及第112、136位氨基酸后可以完全或部分消除Npro对RANTES表达的抑制,提示Npro的切割活性在抑制RANTES中扮演重要角色。
3、CSFV Npro抑制RANTES表达的信号通路研究
为了进一步揭示CSFV Npro是否抑制RANTES产生的上游信号通路,分别利用RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7等激活RANTES信号通路的信号分子和转录因子进行分析,发现Npro可以抑制RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7超表达诱导的RANTES,表明Npro通过抑制RIG-I/MDA5信号通路,从而抑制RANTES的表达。
CSF (also called Hog Cholera), caused by Classical Swine Fever virus,is a serious acute and fatal disease for pigs causing significant economic losses worldwidely for the pig industry. In recent years, due to the failure of imuunization for CSF, and the emergence of combined infection and secondary infection of CSF, the prevention and control of this disease is increasingly urgent. To study intensively the immune response and its molecular mechanism upon the infection with CSFV and further demonstrate the immune mechanism of CSF virus is of great significance for the development of novel vaccines to CSF as well as for more effective strategies for controlling and preventing the disease.
Regulated upon Activation, Normal T cell Expressed and Secreted, RANTES is an important member of chemokine CC family, and is a chemokine with multiple activities. It not only has chemotaxis effect on different types of cells, but also activates lymphocytes, participate to the pathogenesis of inflammation and regulate the growth and differentiation of cells. Studies by now have revealed that RANTES plays a rather important role in the infection anf pathogenesis of many bacterial and viral pathogens. However, the relationship between CSF infection and RANTES expression is still not well understood. For this reason, we studied the dynamics of RANTES expression after CSF virus infection, and discussed the signal pathway of CSF regulation on RANTES expression. The main content are as follows
1. The dynamics of RANTES mRNA expression after the PK-15 cells is infected with CSFV
Using Real-time PCR to analyze the expression of RANTES t different time points after PK-15 cells was infected with CSFV. We found no significant change of RANTES mRNA expression level in the early stage after CSFV infection on PK-15 cells. But 72 hours after infection, it was significantly lower than cells without infection, and CSFV infection significantly inhibited RANTES expression induced by poly (I:C). To further verify the result of real-time PCR, the luciferase reporter system of porcine RANTES promoter was constructed, and it was found that CSFV inhibited the activation of RANTES promoter.
2. CSFV Npro is involved in the inhibition of RANTES expression
To determine which proteins of CSFV play a vital role in the inhibition of RANTES, we built the eukaryotic expression plasmids of twelve CSFV proteins and analysed the affect on different protein on the activity of RANTES promoter by RANTES promoter luciferase reporter system. We found the transfection of expression plasmid for Npro could significantly inhibit the activity of RANTES promoter. Subsequently, mutation analysis was conducted on different transcription factor binding sites in RANTES promoter. It was shown that ISRE binding site played an important role in the inhibition of RANTES by CSFV Npro. To determine the essential region for Npro to inhibit RANTES, a series of mutants of Npro was constructed. The result indicated 21 amino acids on N terminal of Npro were not essential for the inhibition of RANTES expression. But the mutation of the 69th,112nd, and 136th amino acid related to the cleavage activity of Npro could partially or completely disable the Npro's inhibition on RANTES expression. It can be inferred that the cleavage activity of Npro is crucial for the inhibition of RANTES expression.
3, Study on the Signal pathways of CSFV Npro on the inhibition of RANTES
To comprehend the upstream signal pathways of CSFV Npro on the inhibition of RANTES,The signal molecules and transcription factors activating RANTES signal pathway, including RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7 were used for analyzing,and we found that the Npro inhibited the RANTES which is induced by the overexpresiion of RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7.It demonstrated that Npro suppressed RANTES through the RIG-I/MDA5 signal pathway
调节活化正常T细胞表达与分泌的因子(Regulated upon Activation, Normal T cell Expressed and Secreted, RANTES)是趋化因子CC家族的重要因子之一,也是一种多效性的趋化因子。它不仅对多种细胞有趋化作用,还可以激活淋巴细胞,参与炎症反应的发生,调节细胞的生长和分化。目前的研究已经证实：RANTES在包括细菌、病毒在内的多种微生物的感染与致病中扮演十分重要的角色,但迄今为止猪瘟病毒感染与RANTES表达之间的关系尚不清楚。鉴于此,本研究开展了猪瘟病毒感染后RANTES的表达动力学研究,并探讨了猪瘟病毒调控RANTES表达的信号通路。主要研究内容如下：
1、CSFV感染PK-15细胞后RANTES mRNA表达的动力学
采用荧光定量Real-time PCR分析了CSFV感染PK-15细胞后不同时间RANTES的表达,发现CSFV感染PK-15细胞后早期RANTES mRNA的表达水平没有明显的变化,但感染后72h显著低于未感染细胞,而且CSFV感染能显著抑制poly(I:C)诱导的RANTES表达。为了进一步验证荧光定量PCR的结果,随后构建了猪RANTES基因启动子荧光素酶报告系统,发现CSFV能抑制RANTES启动子的激活。
2、CSFV Npro参与抑制RANTES表达
为了确定猪瘟病毒编码的蛋白在抑制RANTES中的作用,分别构建了猪瘟病毒12种编码蛋白的真核表达表达质粒,采用RANTES启动子荧光素酶报告系统分析不同编码对RANTES启动子活性的影响,发现转染Npro的表达质粒能显著抑制RANTES启动子的活性。进一步对RANTES启动子中不同转录因子结合位点进行突变分析,发现ISRE结合位点在CSFV Npro抑制RANTES中起重要作用。为了确定Npro抑制RANTES的必需区域,构建了Npro的一系列突变体,发现Npro的N端21个氨基酸对抑制RANTES的表达是非必需的,而突变与Npro切割活性有关的第69位及第112、136位氨基酸后可以完全或部分消除Npro对RANTES表达的抑制,提示Npro的切割活性在抑制RANTES中扮演重要角色。
3、CSFV Npro抑制RANTES表达的信号通路研究
为了进一步揭示CSFV Npro是否抑制RANTES产生的上游信号通路,分别利用RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7等激活RANTES信号通路的信号分子和转录因子进行分析,发现Npro可以抑制RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7超表达诱导的RANTES,表明Npro通过抑制RIG-I/MDA5信号通路,从而抑制RANTES的表达。
CSF (also called Hog Cholera), caused by Classical Swine Fever virus,is a serious acute and fatal disease for pigs causing significant economic losses worldwidely for the pig industry. In recent years, due to the failure of imuunization for CSF, and the emergence of combined infection and secondary infection of CSF, the prevention and control of this disease is increasingly urgent. To study intensively the immune response and its molecular mechanism upon the infection with CSFV and further demonstrate the immune mechanism of CSF virus is of great significance for the development of novel vaccines to CSF as well as for more effective strategies for controlling and preventing the disease.
Regulated upon Activation, Normal T cell Expressed and Secreted, RANTES is an important member of chemokine CC family, and is a chemokine with multiple activities. It not only has chemotaxis effect on different types of cells, but also activates lymphocytes, participate to the pathogenesis of inflammation and regulate the growth and differentiation of cells. Studies by now have revealed that RANTES plays a rather important role in the infection anf pathogenesis of many bacterial and viral pathogens. However, the relationship between CSF infection and RANTES expression is still not well understood. For this reason, we studied the dynamics of RANTES expression after CSF virus infection, and discussed the signal pathway of CSF regulation on RANTES expression. The main content are as follows
1. The dynamics of RANTES mRNA expression after the PK-15 cells is infected with CSFV
Using Real-time PCR to analyze the expression of RANTES t different time points after PK-15 cells was infected with CSFV. We found no significant change of RANTES mRNA expression level in the early stage after CSFV infection on PK-15 cells. But 72 hours after infection, it was significantly lower than cells without infection, and CSFV infection significantly inhibited RANTES expression induced by poly (I:C). To further verify the result of real-time PCR, the luciferase reporter system of porcine RANTES promoter was constructed, and it was found that CSFV inhibited the activation of RANTES promoter.
2. CSFV Npro is involved in the inhibition of RANTES expression
To determine which proteins of CSFV play a vital role in the inhibition of RANTES, we built the eukaryotic expression plasmids of twelve CSFV proteins and analysed the affect on different protein on the activity of RANTES promoter by RANTES promoter luciferase reporter system. We found the transfection of expression plasmid for Npro could significantly inhibit the activity of RANTES promoter. Subsequently, mutation analysis was conducted on different transcription factor binding sites in RANTES promoter. It was shown that ISRE binding site played an important role in the inhibition of RANTES by CSFV Npro. To determine the essential region for Npro to inhibit RANTES, a series of mutants of Npro was constructed. The result indicated 21 amino acids on N terminal of Npro were not essential for the inhibition of RANTES expression. But the mutation of the 69th,112nd, and 136th amino acid related to the cleavage activity of Npro could partially or completely disable the Npro's inhibition on RANTES expression. It can be inferred that the cleavage activity of Npro is crucial for the inhibition of RANTES expression.
3, Study on the Signal pathways of CSFV Npro on the inhibition of RANTES
To comprehend the upstream signal pathways of CSFV Npro on the inhibition of RANTES,The signal molecules and transcription factors activating RANTES signal pathway, including RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7 were used for analyzing,and we found that the Npro inhibited the RANTES which is induced by the overexpresiion of RIG-Ⅰ、MDA5、IPS-1、IRF3、IRF7.It demonstrated that Npro suppressed RANTES through the RIG-I/MDA5 signal pathway
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