新城疫病毒单感染及猪流感病毒与猪链球菌共感染差异蛋白组学分析
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摘要
本课题是应用基于双向电泳的蛋白质组学技术及MALDI TOF/TOF质谱检测技术，分析不同禽源的新城疫病毒（NA-1及F48E9株）体外感染原代鸡胚成纤维细胞（CEF）全蛋白变化情况。实验分为三组比较：比较新城疫病毒NA-1感染细胞前后全细胞蛋白；比较新城疫病毒F48E9感染细胞前后全细胞蛋白；比较不同NA-1及F48E9新城疫病毒感染细胞后全细胞蛋白。通过比较鉴定差异表达的蛋白，分析差异蛋白的功能。进而选取其中两种蛋白进行功能分析，采用构建真核表达质粒转染细胞的方法，研究蛋白过表达对细胞增殖的影响。首先用NA-1株病毒体外感染原代鸡胚成纤维细胞12h、24h、36h观察细胞病变及间接免疫荧光试验确定病毒感染细胞最佳时期，通过以上两种方法，确定病毒感染全细胞蛋白提取时间为病毒感染细胞后24h，在这个时期，大部分（90%）细胞已经被病毒感染，但并没有死亡，是病毒感染研究的最佳时间。在确定时间点后，扩大培养细胞，然后将病毒NA-1及F48E9感染鸡胚成纤维细胞24h，感染结束后加入全细胞蛋白提取液提取感染及未感染的鸡胚成纤维全细胞蛋白，离心去除细胞碎片后，上清液即为粗提蛋白样品。在双向电泳分离蛋白质前，先用BCA法测定蛋白浓度，并用SDS-PAGE检测蛋白是否降解，然后用双向电泳分离蛋白、银染染色、图像扫描与分析比较，最后选取2倍以上的差异表达蛋白点进行胶内酶解及质谱分析。最后应用荧光定量qPCR技术验证双向电泳的结果。质谱共鉴定40个蛋白点，代表27个差异表达蛋白，这些蛋白包括：驱动蛋白样蛋白KIF18、小泛素相关修饰前体、类似APC、膜联蛋白A6、角蛋白、α-S1酪蛋白、磷脂结合蛋白1、肌动蛋白、波形蛋白、钙调素（RGN）、血红素结合蛋白1、钙网蛋白、磷酸丙糖异构酶（TPI）、核苷二磷酸激酶等。应用GO及David对这些蛋白进行功能预测分析，分析后，选取其中两个感染后上调表达的蛋白磷酸丙糖异构酶（TPI）及钙调素（RGN）进行构建pEGFP-N1-TPI和pEGFP-N1-RGN的真核表达载体，本实验选择瞬时转染方法检测蛋白过表达对细胞增殖情况的影响，结果显示当细胞内这两种蛋白过表达的时候抑制细胞增殖。
在另外一个课题的研究中，对猪流感病毒与2型猪链球菌混合感染（共感染）、猪流感病毒单独感染、2型猪链球菌单独感染及未感染的新生猪气管上皮细胞（New born pig treacheal epithelial cells, Nptr细胞）应用蛋白质组学及转录组学方法进行研究。近年来一些研究人员通过预感染流感病毒而后感染革兰氏阳性菌及革兰氏阴性菌，研究细菌对细胞的黏附情况，结果显示流感病毒的预先感染可以有助于革兰氏阳性菌对细胞的黏附增加，而革兰氏阳性菌对细胞的黏附没有变化。同时本课题组已经证明了，预先将猪流感病毒感染猪气管上皮细胞12小时，而后加入2型猪链球菌感染2h，混合感染组2型猪链球菌细菌黏附数要远远高于2型链球菌单独感染的细菌黏附数(100倍以上)。同时又证明了，2型猪链球菌的荚膜多糖（CPS）可以与猪流感病毒的血凝素（HA）结合，这说明2型猪链球菌可以以两种形式感染猪气管上皮细胞：一种是与猪流感病毒的HA结合，随着猪流感病毒同时感染细胞；另一种是与猪流感病毒感染细胞后在细胞表面表达的HA结合感染细胞。所以，本课题是基于以上的研究，希望用蛋白质组和转录组学方法全面研究猪流感病毒-2型猪链球菌混合感染对宿主细胞的影响，进而深入了解猪流感病毒-2型猪链球菌协同感染机制。
实验方法为：首先用1MOI猪流感病毒预感染猪气管上皮细胞12h，而后加入10MOI的2型猪链球菌，继续感染12h，感染结束后，提取细胞RNA进行转录组研究；提取全细胞蛋白进行蛋白质组研究，将混合感染的细胞与正常的猪气管上皮（Nptr）细胞、2型猪链球菌单独感染的细胞及猪流感病毒单独感染的细胞进行比较。通过转录组的比较，结果显示2型猪链球菌单独感染组、猪流感病毒单独感染组、猪流感病毒与2型猪链球菌混合感染组与未感染组比较分别有393、2797、3254个差异表达探针，对应104、594、681个差异表达基因，功能主要包括代谢、信号调节因子、干扰素调节基因、干扰素刺激基因、糖蛋白、受体、外界刺激反应、免疫系统过程、细胞因子炎症因子及其受体、脂蛋白、凋亡及细胞周期调节、细胞骨架、转录因子及其调节、细胞表面受体相关信号转导、细胞黏附等。通路包括：细胞因子-细胞因子受体关系、Toll样受体信号途径、PPAR信号途径、补体和凝血级联、MAPK信号途径、炎症信号途径、Jak-STAT信号途径、RIG-l样受体信号途径、细胞黏附因子、内吞作用、TGF-beta信号途径、ECM-受体相互作用、NOD样受体信号途径、紧密连接等。为了验证转录组（Microarray）实验结果的可靠性，本实验选取了9个基因设计引物，用荧光定量PCR方法检测。其中选取的VCAM1、PLAU、IFNB1、IL1a、TNF、IL6、IL8、COX2基因在混合感染结果中相对于病毒或细菌单独感染显著变化。荧光定量PCR上述基因变化结果与转录组检测结果趋势一致。对比分析猪流感病毒单独感染、2型猪链球菌单独感染、及二者混合感染的基因变化情况，结果表明混合感染后一些基因协同作用增强，是协同感染通路增强的原因。通过蛋白组的比较鉴定了包括抗病毒蛋白及细胞因子等在内的27种差异表达蛋白，包括：干扰素诱导蛋白3（IFIT3）、双链断裂修复的蛋白质MRE11A异构体2、ATP依赖的RNA解旋酶DDX39A、甲硫氨酸氨基肽酶1、酰基辅酶A硫酯酶6、延伸因子1-α、丙酮酸脱氢酶E1成分β亚基、蛋白酶激活剂复合物亚基2、蛋白酶激活剂复合物亚基1、胰蛋白酶前体、热休克蛋白β-1、FGFR1基因、热休克蛋白β-1、视黄醇结合蛋白（RBP）、泛素ISG15结合酶E2L6、超氧化物歧化酶1、干扰素诱导蛋白17、巨噬细胞移动抑制因子及干扰素诱导蛋白1(IFIT1)等，这些蛋白可能与猪流感病毒及2型猪链球菌混合感染机制有关。
Newcastle disease is a serotype Ⅰ avian paramyxovirus (ie Newcastle diseasevirus) causes chicken and turkey acute highly contagious disease, Newcastle diseaseis harmful to the poultry industry is still the most important infectious diseases. On aglobal scale, highly pathogenic Newcastle disease virus constantly threatening thepoultry industry, for Newcastle disease infected host mechanism is very important.Swine influenza virus infections show its fatality rate is not high, but the incidence isvery high. Once the sudden onset of a single individual can and quickly spread to theentire group. Clinical studies have shown that the swine flu virus infection, usuallyaccompanied by a secondary infection of the respiratory tract pathogens thatsecondary bacterial infections. Streptococcus suis type2, is a Gram-positive bacteria,but also secondary infection frequently isolated bacteria that can cause human or pigmeningitis, arthritis, septicemia and pneumonia. And when a large number of pigsinfected with type2Streptococcus epithelial cells, which can damage cells showedstrong ability and invasion of epithelial cell adhesion ability. So for swine and swineinfluenza virus type2streptococcus infection research is very necessary.
The research project is divided into two parts: single NDV infected chickenembryo fibroblasts proteomics research and swine influenza virus co-infection withStreptococcus suis proteomics and transcriptomics studies.
Two-dimensional electrophoresis and mass spectrometry techniques, analysis ofdifferent avian Newcastle disease virus (NA-1and F48E9strain) in vitro infection ofprimary chicken embryo fibroblasts (CEF) and Protein situation. Newcastle diseasevirus were compared NA-1infected cells entire protein, Newcastle diseasevirus-infected cells F48E9total proteins and uninfected cells whole cell proteins. Bycomparing the identification of differentially expressed proteins, analyze differencesin protein function. Mass40protein spots were identified, representing27differentially expressed proteins, which include: kinesin-like protein KIF18, smallubiquitin-related modifier precursor, similar to APC, annexin A6, keratin, α-S1casein, phospholipid binding protein1, actin, vimentin, calmodulin (RGN), heme-bindingprotein1, calreticulin, triosephosphate isomerase (TPI), nucleoside diphosphatekinase. Application GO and David for these protein function prediction analysis,analysis, select one of the two proteins upregulated after infection triosephosphateisomerase (TPI) and calmodulin (RGN) to build pEGFP-N1-TPI and pEGFP-N1-RGN eukaryotic expression vectors, transient transfection in this experiment todetect overexpression of cell proliferation, the results shows that when cellsoverexpressing these two proteins, when inhibited cell proliferation.
The topic of swine influenza virus and porcine type2streptococcus(co-infection), swine influenza virus infection alone, streptococcus swine type2infection alone and uninfected pig tracheal epithelial cells (Nptr cells) Application ofproteomics and transcription genomics research methods. In recent years someresearchers then through the pre-infection with influenza virus infection of Grampositive bacteria and Gram-negative bacteria, studies on cell adhesion of bacteria, theresults shown previously infected with influenza virus may help Gram-positivebacteria increased cell adhesion, and Gram-positive bacteria cell adhesion has notchanged. Meanwhile, the research group has demonstrated, advance to the swine fluvirus of swine tracheal epithelial cells for12hours, then added two streptococcusswine2h, mixed group of pigs infected with type2streptococcus bacterial adhesion ismuch higher than the number of type2streptococcal infection alone2h number ofbacterial adhesion. At the same time proved streptococcus swine type2capsularpolysaccharide (CPS) can be used with swine influenza virus hemagglutinin (HA)binding, indicating streptococcus swine type2can be in two forms of swine trachealepithelial cells: a species is swine influenza virus HA binding, as swine influenzavirus-infected cells while; other is the swine influenza virus infected cells expressedon the cell surface of infected cells with HA. Therefore, this topic is based on theabove study, hoping to use proteomics and transcriptomics approach a comprehensivestudy of the swine flu virus-swine streptococcus type2effects on host cells, and thusunderstand the swine flu virus-swine streptococcus type2coordination mechanismsof infection.
Through transcriptome comparison showed streptococcus swine type2infectionalone group, swine influenza virus infection alone group, swine influenza virus andporcine type2streptococcus group compared with the uninfected group were 393,2797,3254differentially expression probes corresponding to104,594,681differentially expressed genes, functions including metabolism, signal conditioningfactor, interferon-regulated genes, interferon stimulated genes, glycoproteins,receptors, external stimuli, the process of the immune system, cytokines inflammatorycytokines and their receptors, lipoproteins, apoptosis and cell cycle regulation,cytoskeleton, and regulation of transcription factors, cell surface receptor signaltransduction, cell adhesion, etc. Path includes: cytokine-cytokine receptorrelationships, Toll-like receptor signaling pathway, PPAR signaling pathway,complement and coagulation cascade, MAPK signaling pathway, inflammatorysignaling pathway, Jak-STAT signaling pathway, RIG-I-like receptor signalingpathway, cell adhesion factor, endocytosis, TGF-beta signaling pathway,ECM-receptor interaction, NOD-like receptor signaling pathway, tight connections.To verify the transcriptome (Microarray) the reliability of experimental results, thisstudy selected nine gene primers were designed using fluorescence quantitative PCRmethod. Which selected VCAM1, PLAU, IFNB1, IL1a, TNF, IL6, IL8, COX2generesults in a mixed infection with respect to viral or bacterial infection alone changesignificantly. Quantitative PCR results of the above-mentioned changes in thetranscriptome gene test results trend. Comparative analysis of swine influenza virusinfection alone, swine streptococcus infection alone type2, and two mixed infectionsgenetic changes, the results showed that some of the genes mixed infection enhancedsynergy is enhanced synergistic infection pathway causes. Identified by comparison ofproteins, including the group of antiviral cytokines, including protein and27differentially expressed proteins, mainly involved in transcriptional regulation, mRNAprocessing, translation control, lipid metabolism, protein synthesis, DNA damageresponse, stress reaction of cytokine-mediated signal transduction pathway,anti-apoptotic, anti-viral defense, inflammatory response. These differences in proteinand swine influenza virus-swine streptococcus mixed type2infection and play animportant role.
在另外一个课题的研究中，对猪流感病毒与2型猪链球菌混合感染（共感染）、猪流感病毒单独感染、2型猪链球菌单独感染及未感染的新生猪气管上皮细胞（New born pig treacheal epithelial cells, Nptr细胞）应用蛋白质组学及转录组学方法进行研究。近年来一些研究人员通过预感染流感病毒而后感染革兰氏阳性菌及革兰氏阴性菌，研究细菌对细胞的黏附情况，结果显示流感病毒的预先感染可以有助于革兰氏阳性菌对细胞的黏附增加，而革兰氏阳性菌对细胞的黏附没有变化。同时本课题组已经证明了，预先将猪流感病毒感染猪气管上皮细胞12小时，而后加入2型猪链球菌感染2h，混合感染组2型猪链球菌细菌黏附数要远远高于2型链球菌单独感染的细菌黏附数(100倍以上)。同时又证明了，2型猪链球菌的荚膜多糖（CPS）可以与猪流感病毒的血凝素（HA）结合，这说明2型猪链球菌可以以两种形式感染猪气管上皮细胞：一种是与猪流感病毒的HA结合，随着猪流感病毒同时感染细胞；另一种是与猪流感病毒感染细胞后在细胞表面表达的HA结合感染细胞。所以，本课题是基于以上的研究，希望用蛋白质组和转录组学方法全面研究猪流感病毒-2型猪链球菌混合感染对宿主细胞的影响，进而深入了解猪流感病毒-2型猪链球菌协同感染机制。
实验方法为：首先用1MOI猪流感病毒预感染猪气管上皮细胞12h，而后加入10MOI的2型猪链球菌，继续感染12h，感染结束后，提取细胞RNA进行转录组研究；提取全细胞蛋白进行蛋白质组研究，将混合感染的细胞与正常的猪气管上皮（Nptr）细胞、2型猪链球菌单独感染的细胞及猪流感病毒单独感染的细胞进行比较。通过转录组的比较，结果显示2型猪链球菌单独感染组、猪流感病毒单独感染组、猪流感病毒与2型猪链球菌混合感染组与未感染组比较分别有393、2797、3254个差异表达探针，对应104、594、681个差异表达基因，功能主要包括代谢、信号调节因子、干扰素调节基因、干扰素刺激基因、糖蛋白、受体、外界刺激反应、免疫系统过程、细胞因子炎症因子及其受体、脂蛋白、凋亡及细胞周期调节、细胞骨架、转录因子及其调节、细胞表面受体相关信号转导、细胞黏附等。通路包括：细胞因子-细胞因子受体关系、Toll样受体信号途径、PPAR信号途径、补体和凝血级联、MAPK信号途径、炎症信号途径、Jak-STAT信号途径、RIG-l样受体信号途径、细胞黏附因子、内吞作用、TGF-beta信号途径、ECM-受体相互作用、NOD样受体信号途径、紧密连接等。为了验证转录组（Microarray）实验结果的可靠性，本实验选取了9个基因设计引物，用荧光定量PCR方法检测。其中选取的VCAM1、PLAU、IFNB1、IL1a、TNF、IL6、IL8、COX2基因在混合感染结果中相对于病毒或细菌单独感染显著变化。荧光定量PCR上述基因变化结果与转录组检测结果趋势一致。对比分析猪流感病毒单独感染、2型猪链球菌单独感染、及二者混合感染的基因变化情况，结果表明混合感染后一些基因协同作用增强，是协同感染通路增强的原因。通过蛋白组的比较鉴定了包括抗病毒蛋白及细胞因子等在内的27种差异表达蛋白，包括：干扰素诱导蛋白3（IFIT3）、双链断裂修复的蛋白质MRE11A异构体2、ATP依赖的RNA解旋酶DDX39A、甲硫氨酸氨基肽酶1、酰基辅酶A硫酯酶6、延伸因子1-α、丙酮酸脱氢酶E1成分β亚基、蛋白酶激活剂复合物亚基2、蛋白酶激活剂复合物亚基1、胰蛋白酶前体、热休克蛋白β-1、FGFR1基因、热休克蛋白β-1、视黄醇结合蛋白（RBP）、泛素ISG15结合酶E2L6、超氧化物歧化酶1、干扰素诱导蛋白17、巨噬细胞移动抑制因子及干扰素诱导蛋白1(IFIT1)等，这些蛋白可能与猪流感病毒及2型猪链球菌混合感染机制有关。
Newcastle disease is a serotype Ⅰ avian paramyxovirus (ie Newcastle diseasevirus) causes chicken and turkey acute highly contagious disease, Newcastle diseaseis harmful to the poultry industry is still the most important infectious diseases. On aglobal scale, highly pathogenic Newcastle disease virus constantly threatening thepoultry industry, for Newcastle disease infected host mechanism is very important.Swine influenza virus infections show its fatality rate is not high, but the incidence isvery high. Once the sudden onset of a single individual can and quickly spread to theentire group. Clinical studies have shown that the swine flu virus infection, usuallyaccompanied by a secondary infection of the respiratory tract pathogens thatsecondary bacterial infections. Streptococcus suis type2, is a Gram-positive bacteria,but also secondary infection frequently isolated bacteria that can cause human or pigmeningitis, arthritis, septicemia and pneumonia. And when a large number of pigsinfected with type2Streptococcus epithelial cells, which can damage cells showedstrong ability and invasion of epithelial cell adhesion ability. So for swine and swineinfluenza virus type2streptococcus infection research is very necessary.
The research project is divided into two parts: single NDV infected chickenembryo fibroblasts proteomics research and swine influenza virus co-infection withStreptococcus suis proteomics and transcriptomics studies.
Two-dimensional electrophoresis and mass spectrometry techniques, analysis ofdifferent avian Newcastle disease virus (NA-1and F48E9strain) in vitro infection ofprimary chicken embryo fibroblasts (CEF) and Protein situation. Newcastle diseasevirus were compared NA-1infected cells entire protein, Newcastle diseasevirus-infected cells F48E9total proteins and uninfected cells whole cell proteins. Bycomparing the identification of differentially expressed proteins, analyze differencesin protein function. Mass40protein spots were identified, representing27differentially expressed proteins, which include: kinesin-like protein KIF18, smallubiquitin-related modifier precursor, similar to APC, annexin A6, keratin, α-S1casein, phospholipid binding protein1, actin, vimentin, calmodulin (RGN), heme-bindingprotein1, calreticulin, triosephosphate isomerase (TPI), nucleoside diphosphatekinase. Application GO and David for these protein function prediction analysis,analysis, select one of the two proteins upregulated after infection triosephosphateisomerase (TPI) and calmodulin (RGN) to build pEGFP-N1-TPI and pEGFP-N1-RGN eukaryotic expression vectors, transient transfection in this experiment todetect overexpression of cell proliferation, the results shows that when cellsoverexpressing these two proteins, when inhibited cell proliferation.
The topic of swine influenza virus and porcine type2streptococcus(co-infection), swine influenza virus infection alone, streptococcus swine type2infection alone and uninfected pig tracheal epithelial cells (Nptr cells) Application ofproteomics and transcription genomics research methods. In recent years someresearchers then through the pre-infection with influenza virus infection of Grampositive bacteria and Gram-negative bacteria, studies on cell adhesion of bacteria, theresults shown previously infected with influenza virus may help Gram-positivebacteria increased cell adhesion, and Gram-positive bacteria cell adhesion has notchanged. Meanwhile, the research group has demonstrated, advance to the swine fluvirus of swine tracheal epithelial cells for12hours, then added two streptococcusswine2h, mixed group of pigs infected with type2streptococcus bacterial adhesion ismuch higher than the number of type2streptococcal infection alone2h number ofbacterial adhesion. At the same time proved streptococcus swine type2capsularpolysaccharide (CPS) can be used with swine influenza virus hemagglutinin (HA)binding, indicating streptococcus swine type2can be in two forms of swine trachealepithelial cells: a species is swine influenza virus HA binding, as swine influenzavirus-infected cells while; other is the swine influenza virus infected cells expressedon the cell surface of infected cells with HA. Therefore, this topic is based on theabove study, hoping to use proteomics and transcriptomics approach a comprehensivestudy of the swine flu virus-swine streptococcus type2effects on host cells, and thusunderstand the swine flu virus-swine streptococcus type2coordination mechanismsof infection.
Through transcriptome comparison showed streptococcus swine type2infectionalone group, swine influenza virus infection alone group, swine influenza virus andporcine type2streptococcus group compared with the uninfected group were 393,2797,3254differentially expression probes corresponding to104,594,681differentially expressed genes, functions including metabolism, signal conditioningfactor, interferon-regulated genes, interferon stimulated genes, glycoproteins,receptors, external stimuli, the process of the immune system, cytokines inflammatorycytokines and their receptors, lipoproteins, apoptosis and cell cycle regulation,cytoskeleton, and regulation of transcription factors, cell surface receptor signaltransduction, cell adhesion, etc. Path includes: cytokine-cytokine receptorrelationships, Toll-like receptor signaling pathway, PPAR signaling pathway,complement and coagulation cascade, MAPK signaling pathway, inflammatorysignaling pathway, Jak-STAT signaling pathway, RIG-I-like receptor signalingpathway, cell adhesion factor, endocytosis, TGF-beta signaling pathway,ECM-receptor interaction, NOD-like receptor signaling pathway, tight connections.To verify the transcriptome (Microarray) the reliability of experimental results, thisstudy selected nine gene primers were designed using fluorescence quantitative PCRmethod. Which selected VCAM1, PLAU, IFNB1, IL1a, TNF, IL6, IL8, COX2generesults in a mixed infection with respect to viral or bacterial infection alone changesignificantly. Quantitative PCR results of the above-mentioned changes in thetranscriptome gene test results trend. Comparative analysis of swine influenza virusinfection alone, swine streptococcus infection alone type2, and two mixed infectionsgenetic changes, the results showed that some of the genes mixed infection enhancedsynergy is enhanced synergistic infection pathway causes. Identified by comparison ofproteins, including the group of antiviral cytokines, including protein and27differentially expressed proteins, mainly involved in transcriptional regulation, mRNAprocessing, translation control, lipid metabolism, protein synthesis, DNA damageresponse, stress reaction of cytokine-mediated signal transduction pathway,anti-apoptotic, anti-viral defense, inflammatory response. These differences in proteinand swine influenza virus-swine streptococcus mixed type2infection and play animportant role.
引文
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