新型重组猪α-干扰素的结构与生物功能研究
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摘要
干扰素是一类Ⅱ型细胞因子,具有调节机体免疫、抗病毒、抗肿瘤等多种生物功能。根据其表面受体、染色体定位、酸稳定性等的不同,可将干扰素分为Ⅰ、Ⅱ、Ⅲ三种类型。其中α-干扰素属于Ⅰ型干扰素,具有强大的抗病毒功能。为了进一步提高干扰素的生物活性以及扩大干扰素在临床上的使用,我们进行了复合猪α-干扰素的设计、表达、结构和功能的研究工作。本研究的目的在于设计重组复合猪α-干扰素,研制出安全、高效、新型的抗病毒制剂和免疫增强剂用于增强猪体的抵抗力和提高现有疫苗的保护率。我们同时还尝试解析猪a-干扰素的结构,并通过分子模拟的方法模建干扰素与其受体的空间结构,以便确定干扰素与受体的结合位点,为以后研究干扰素的功能并设计具有更高生物活性的干扰素打下基础。
1. CoPoIFN-α的设计、基因扩增与克隆
从NCBI网站上搜索得到17个亚型的猪α-干扰素氨基酸序列,用Bioedit序列分析软件进行比对后选取等位基因上出现频率最高的氨基酸进行组合,设计出本研究中的新型猪α-干扰素蛋白序列,命名为CoPoIFN-α。根据酵母密码子偏嗜性设计得到CoPoIFN-α基因序列。根据基因序列设计14条引物,用SOE-PCR方法扩增后,通过EcoRI和Xbal内切酶酶切后连接入毕赤酵母表达载体pPICZα,得到带有干扰素基因的阳性克隆,并经酶切鉴定及核酸序列测定确定其正确性。
2. CoPoIFN-α的表达与纯化
将重组质粒pPICZα-CoPoIFN-α整合进毕赤酵母X-33菌株,在毕赤酵母中用甲醇在28℃条件下诱导表达CoPoIFN-α和本实验室保存的重组野生型猪IFN-α:PoIFN-α。诱导72h后,12000r/min4℃离心15min收集酵母表达上清液。首先用30%饱和度的硫酸铵沉淀去除酵母表达上清液中的部分杂蛋白,然后再用45%饱和度的硫酸铵沉淀得到含有干扰素的粗组分,再依次经过疏水层析,阴离子交换层析和凝胶过滤层析纯化得到纯的干扰素蛋白PoIFN-α和CoPoIFN-α。用鼠抗重组猪IFN-α1单抗作为一抗,经Western blot方法鉴定,结果显示所得蛋白即为PoIFN-α和CoPoIFN-α。用圆二色谱方法对纯化的PoIFN-α和CoPoIFN-α进行二级结构分析,分析结果表明PoIFN-α和CoPoIFN-α在溶液中都主要是以α-螺旋形式存在的。
3. CoPoIFN-α的体外生物活性测定
我们从4个方面检测CoPoIFN-α的体外生物学功能,同时比较了CoPoIFN-α和PoIFN-a活性之间的差别。首先研究两种干扰素在MDBK、PK-15和MARC-145三个细胞系上抑制水疱性口炎病毒(VSV)感染的能力。我们发现CoPoIFN-a抑制VSV产生细胞病变的能力比PoIFN-a分别高46.4、63.6和53.5倍。其次用1ng CoPoIFN-a或者1ng PoIFN-a预处理PK-15细胞24h,然后感染PRV；同时用1ng CoPoIFN-a或者1ng PoIFN-a预处理MARC-145细胞24h,然后感染PRRSV;用TCID50测定方法测定细胞培养液中的病毒滴度,荧光定量PCR方法测定细胞中的病毒基因组拷贝数。结果表明,PoIFN-a预处理组中PRV和PRRSV的滴度分别比CoPoIFN-a预处理组高25倍和10倍；PoIFN-a预处理组中PRV和PRRSV的基因组拷贝数分别比CoPoIFN-a预处理组分别高4.8倍和5倍。另外我们用MTT方法检测并比较了两种干扰素抑制PK-15细胞增殖的能力。用两倍倍比稀释的CoPoIFN-a(0-8μg/mL)或者PoIFN-a(0-8μg/mL)处理PK-15细胞72h后,用MTT方法检测PK-15细胞的增殖情况。结果显示,在0.125μg/mL-0.5干扰素浓度范围内,CoPoIFN-a的抗增殖活性显著高于PoIFN-a;在1μg/mL-8μg/mL干扰素浓度范围内,CoPoIFN-a的抗增殖活力亦高于PoIFN-a,并呈现极显著差异。最后我们用荧光定量PCR方法比较了PoIFN-a和CoPoIFN-a在PK-15细胞上对干扰素刺激基因Mx1、OAS1和PKR基因表达的影响。用1ng CoPoIFN-a或者PoIFN-a处理PK-15细胞24h后,通过Taqman荧光定量PCR方法检测细胞中干扰素诱导基因Mx1、OAS1和PKR的mRNA水平。结果显示,CoPoIFN-a或者PoIFN-a预处理的PK-15细胞中Mx1和OAS1的mRNA水平都明显提高。其中,CoPoIFN-a预处理组的OAS1的]mRNA水平比PoIFN-a预处理组高3.2倍,而CoPoIFN-a预处理组Mx1的mRNA水平比PoIFN-a预处理组高4.6倍。本实验中没有检测到PKR mRNA的表达。
4. CoPoIFN-a作为猪瘟多肽疫苗佐剂的研究
为了评估CoPoIFN-a作为猪瘟病毒多肽疫苗的佐剂效果,我们将pET-32a融合表达的CSFV囊膜蛋白E2上693-716位的氨基酸纯化浓缩后与206佐剂乳化成猪瘟多肽疫苗pb,联合104U、105U和106U的CoPoIFN-a共同免疫30日龄家猪,首免后两周加强免疫一次。首免前一周和首免后每周采集外周血用ELISA方法检测血清中的CSFV抗体,首免后14d进行病毒中和抗体测定,同时采集抗凝血并分离外周血淋巴细胞,用多肽抗原刺激分离的淋巴细胞后进行淋巴细胞增殖实验,并测定淋巴细胞分泌的IL-4和IFN-y的水平。结果显示,pb多肽疫苗可以诱导家猪产生体液免疫反应,CoPoIFN-a可以提高pb多肽疫苗诱导产生的体液免疫水平,并呈剂量依赖性；105U的CoPoIFN-a能显著增加pb诱导家猪产生的CSFV特异性抗体水平,但104U的CoPoIFN-a和106U的CoPoIFN-a只能稍微增加pb诱导家猪产生的CSFV特异性抗体水平；另外,105U的CoPoIFN-a能显著增加pb诱导家猪产生的CSFV特异性中和抗体水平；在pb和CoPoIFN-α联合免疫组,随着CoPoIFN-a量的增加,淋巴细胞增殖水平和IFN-γ的分泌水平也越来越高。此结果表明,CoPoIFN-α可以提高猪瘟多肽疫苗诱导家猪产生的免疫反应水平。
5. CoPoIFN-a的晶体生长和计算机模拟分析干扰素及其受体的三级结构
为了准确从空间结构的角度对CoPoIFN-a的高活力进行诠释以便对其进行进一步的改造,我们尝试通过蛋白质结晶学的方法解析CoPoIFN-a的空间结构。我们将纯化的CoPoIFN-a分别浓缩至10mg/mL和20mg/mL两个浓度,并用商品化晶体生长试剂盒Crystal Scree、Crystal Screen2、Index和MembFac对干扰素晶体生长条件进行筛选。初步筛选出两个蛋白晶体生长条件。通过对在这些条件下生长得到的晶体进行初步X-光射线衍射分析发现这些晶体的分辨率并不理想。目前正在对这些结晶条件进一步优化,以便能够得到衍射能力良好的晶体。
在对CoPoIFN-a晶体生长条件摸索的同时,我们利用discovery studio结构模拟软件分别模拟出CoPoIFN-a与猪Ⅰ型干扰素受体和PoIFN-a与猪Ⅰ型干扰素受体三元复合物的空间结构,并对干扰素与受体的相互作用进行了分析。在复合物模型中,我们没有观察到两个干扰素中有差异的残基与受体的直接相互作用。其中,PoIFN-a上的38位丝氨酸、151位丝氨酸和43位苯丙氨酸分别突变成了CoPoIFN-a中的苯丙氨酸、丙氨酸和亮氨酸,这些突变了的氨基酸残基侧链朝内指向干扰素结构的核心,它们改变了局部的疏水性。156位的苏氨酸突变成了精氨酸,蛋白质表面静电势分析结果显示此突变在干扰素和其受体结合的表面引入了更多的正的静电势。引入的正的静电势可能会促使干扰素和其受体更快更紧密的结合；另一方面,也可能是该残基变化影响了附近与干扰素受体相互作用的残基的构象,从而增强了干扰素与其受体的相互作用而导致活性的增加。
Interferon is a type Ⅱ cytokine which possesses many biological functions including immunomodulation, antiviral activities and antiproliferative activity. According to difference in receptor, chromosomal localization and acid stability, interferon can be classified into three types I, II and III. IFN-a belongs to type I interferon, which has powerful antiviral activity. In order to study the biological activity of interferon and expand their clinical application, we designed and expressed a consensus porcine IFN-a (CoPoIFN-a), and studied its structure and functions. The purpose of the experiments is to design a recombinant consensus porcine IFN-a and explore its safety and effectivity to produce a novel interferon-a to increase pig immunity and the protective capacity of current vaccines. We also screened the crystal growth conditions of CoPoIFN-a and modeled the ternary structure of the IFN-as with its receptors in order to determine the interactions between interferon and the receptors, which will help us to study the activity of interferons and design the novel interferions with higher biological activities.
1. The design, gene synthesis and cloning of CoPoIFN-a
We searched protein sequences of17native porcine IFN-a subtypes from NCBI, and aligned the sequences using Bioedit and assigned the most frequently observed amino acid in each corresponding position. The designed interferon-α was named as CoPoIFN-a. Based on codon usage of yeast, the nucleotide sequence of CoPoIFN-a was designed, and14primers were designed and synthesized to amplify CoPoIFN-a gene using gene splicing by overlap extension PCR (SOE-PCR) method. The full length CoPoIFN-α gene was then cloned into pPICZa expression vector using an upstream EcoRl site and a downstream XbaIsite. The positive Pichia pastoris transformant carrying CoPoIFN-a gene were confirmed by PCR and DNA sequencing.
2. The expression and purification of CoPoIFN-α
The Pichia pastoris X-33strain carrying CoPoIFN-a or control PoIFN-a gene was induced with methanol under28℃for72h. The supernatant was separated from the cells by centrifuging at12000r/min under4℃. The supernatant was first precipitated with30%(NH4)2SO4to remove some contaminant proteins, and the fraction containing IFN was obtained by precipitate with45%(NH4)2SO4. Further purification steps were carried out by using hydrophobic, ion exchange and gel filtration chromatography. The purified proteins were confirmed by using mouse anti-porcine IFN-al monoclonal antibody. The secondary structure of purified CoPoIFN-α and PoIFN-a were analyzed by circular dichroism spectroscopy method, the data showed they exists mainly as α-helixes in solution.
3. The in vitro biological studies on CoPoIFN-α
We assayed biological activities of CoPoIFN-a, and compared the differences between CoPoIFN-a and PoIFN-a. First of all, we compared their inhibitory abilities on the VSV infection in MDBK, PK-15and MARC-145cells. We observed that the antiviral activity of CoPoIFN-α was46.4,63.6,53.5-fold higher than that of PoIFN-a in MDBK, PK-15and MARC-145cells, respectively. We next compared the ability of CoPoIFN-a or PoIFN-a in inhibiting PRV and PRRSV replication in the cells that have been pretreated with CoPoIFN-a or PoIFN-a. We found that the viral titers of PRV in PK-15cells pretreated with PoIFN-a were higher than that pretreated with CoPoIFN-a by25-fold, and real-time PCR result showed that the amount of PRV mRNA in PK-15cells pretreated with PoIFN-a was4.8-fold higher than that pretreated with CoPoIFN-a. The results on PRRSV indicated that the viral titers of PRRSV in MARC-145cells pretreated with PoIFN-a were higher than that pretreated with CoPoIFN-a by10-fold, and real-time PCR result showed that the amount of PRRSV mRNA in MARC-145cells pretreated with PoIFN-a was5-fold higher than that pretreated with CoPoIFN-a. The antiproliferative activity of IFN-as against PK-15cells was investigated in vitro using the MTT assay after treating the cells with serial dilution of8-0μg/mL CoPoIFN-a or PoIFN-a, the results showed the antiproliferative activity of CoPoIFN-a was higher than that of PoIFN-a within a concentration range of0.25-0.5μg/mL, and significantly higher within a concentration range of1-8μg/mL. Finally, we assayed the stimulation ability of the CoPoIFN-a or PoIFN-a on Mxl, OAS1and PKR gene induction. The Q-PCR results showed the mRNA levels of Mx1and OAS1 gene in the PK-15cells were significantly enhanced. In the CoPoIFN-a treatment group, the mRNA level of OAS1was enhanced by about3.2-fold compared with PoIFN-α treatment group, while the level of Mxl was increased by about4.6-fold. We did not detect PKR mRNA expression in PK-15cells.
4. The studies of adjuvant effect of CoPoIFN-a in CSFV peptide vaccine
To assess the adjuvant effect of CoPoIFN-a in CSFV peptide vaccine, we ligated a gene corresponding to the peptide (aa693-716) from CSVF envelope protein E2downstream of trxA gene in the pET-32a vector. We purified the fusion peptide from E. coli. from inclusion body. The fusion peptide was emulsified with206adjuvant to generate CSFV peptide vaccine pb. The30-day old pigs were immunized with pb combined with104unit,105unit or106unit CoPoIFN-a and boosterd two weeks later. The peripheral blood was colleted each week before and after the first immunization. The CSFV antibody in the blood was detected using ELISA. Two weeks after the first immunization, we carried out antibody neutralizing test. We also seperated peripheral blood lymphocyte and stimulated the cells with fusion peptide antigen to test their proliferative and IL-4, IFN-y secretion ablities. The results showed pb peptide vaccine can induce the humoral immune reaction in pigs, and CoPoIFN-α can increase the reaction level in dose-dependent manner. CoPoIFN-a at105units could increase antibody level significantly based on ELISA results, while104and106units of CoPoIFN-a only slightly increased the antibody level. CoPoIFN-a at105units could increase the neutralizing antibody specific to CSFV. These results showed that CoPoIFN-a can increase immunological reaction level induced by pb.
5. The crystallization of CoPoIFN-a and computational modeling of CoPoIFN-a/IFNAR2
To explore the mechanism for the high biological activity of CoPoIFN-a from structure, we purified CoPoIFN-a from yeast, and concentrated the protein to10mg/mL or20mg/mL. We screened the crystal growth conditions of CoPoIFN-a using commerical crystal screening kits, including Crystal Screen、Crystal Screen2、Index and MembFac.Two protein crystal growth conditions were found. Unfortunately, the diffraction ability of these crystals was poor. We are now trying to refine the conditions to get the crystal with good diffraction quality.
Meanwhile, we modeled the ternary structures of CoPoIFN-a or PoIFN-a with its receptors. Due to the high similarity between the terneary structures, we only analyzed the hydrogen bond and hydrophobic interations between CoPoIFN-a and the receptors. In our complex models, we did not observe the direct interactions of the different residues on CoPoIFN-a with the receptor. The original Ser-38, Ser-151and Phe-43in PoIFN-a were changed into Phe, Ala and Leu in CoPoIFN-a, respectively. The side chains of these residues are pointing inside towards the core of the structure, and they changed the local hydrophobicity distribution. Another mutation at position156to arginine seemed more significant, since such replacement introduced more positive potential at the interface in CoPoIFN-a according to surface electrostatic potential analysis. Since introduce of the positive potential on the interface can steer these two proteins to achieve fast or tight binding. On the other hand, it was also possible that mutated residues affected the conformation of the residues nearby that had interactions with the receptor, and consequently enhanced the biological activity of the engineered IFN-a.
1. CoPoIFN-α的设计、基因扩增与克隆
从NCBI网站上搜索得到17个亚型的猪α-干扰素氨基酸序列,用Bioedit序列分析软件进行比对后选取等位基因上出现频率最高的氨基酸进行组合,设计出本研究中的新型猪α-干扰素蛋白序列,命名为CoPoIFN-α。根据酵母密码子偏嗜性设计得到CoPoIFN-α基因序列。根据基因序列设计14条引物,用SOE-PCR方法扩增后,通过EcoRI和Xbal内切酶酶切后连接入毕赤酵母表达载体pPICZα,得到带有干扰素基因的阳性克隆,并经酶切鉴定及核酸序列测定确定其正确性。
2. CoPoIFN-α的表达与纯化
将重组质粒pPICZα-CoPoIFN-α整合进毕赤酵母X-33菌株,在毕赤酵母中用甲醇在28℃条件下诱导表达CoPoIFN-α和本实验室保存的重组野生型猪IFN-α:PoIFN-α。诱导72h后,12000r/min4℃离心15min收集酵母表达上清液。首先用30%饱和度的硫酸铵沉淀去除酵母表达上清液中的部分杂蛋白,然后再用45%饱和度的硫酸铵沉淀得到含有干扰素的粗组分,再依次经过疏水层析,阴离子交换层析和凝胶过滤层析纯化得到纯的干扰素蛋白PoIFN-α和CoPoIFN-α。用鼠抗重组猪IFN-α1单抗作为一抗,经Western blot方法鉴定,结果显示所得蛋白即为PoIFN-α和CoPoIFN-α。用圆二色谱方法对纯化的PoIFN-α和CoPoIFN-α进行二级结构分析,分析结果表明PoIFN-α和CoPoIFN-α在溶液中都主要是以α-螺旋形式存在的。
3. CoPoIFN-α的体外生物活性测定
我们从4个方面检测CoPoIFN-α的体外生物学功能,同时比较了CoPoIFN-α和PoIFN-a活性之间的差别。首先研究两种干扰素在MDBK、PK-15和MARC-145三个细胞系上抑制水疱性口炎病毒(VSV)感染的能力。我们发现CoPoIFN-a抑制VSV产生细胞病变的能力比PoIFN-a分别高46.4、63.6和53.5倍。其次用1ng CoPoIFN-a或者1ng PoIFN-a预处理PK-15细胞24h,然后感染PRV；同时用1ng CoPoIFN-a或者1ng PoIFN-a预处理MARC-145细胞24h,然后感染PRRSV;用TCID50测定方法测定细胞培养液中的病毒滴度,荧光定量PCR方法测定细胞中的病毒基因组拷贝数。结果表明,PoIFN-a预处理组中PRV和PRRSV的滴度分别比CoPoIFN-a预处理组高25倍和10倍；PoIFN-a预处理组中PRV和PRRSV的基因组拷贝数分别比CoPoIFN-a预处理组分别高4.8倍和5倍。另外我们用MTT方法检测并比较了两种干扰素抑制PK-15细胞增殖的能力。用两倍倍比稀释的CoPoIFN-a(0-8μg/mL)或者PoIFN-a(0-8μg/mL)处理PK-15细胞72h后,用MTT方法检测PK-15细胞的增殖情况。结果显示,在0.125μg/mL-0.5干扰素浓度范围内,CoPoIFN-a的抗增殖活性显著高于PoIFN-a;在1μg/mL-8μg/mL干扰素浓度范围内,CoPoIFN-a的抗增殖活力亦高于PoIFN-a,并呈现极显著差异。最后我们用荧光定量PCR方法比较了PoIFN-a和CoPoIFN-a在PK-15细胞上对干扰素刺激基因Mx1、OAS1和PKR基因表达的影响。用1ng CoPoIFN-a或者PoIFN-a处理PK-15细胞24h后,通过Taqman荧光定量PCR方法检测细胞中干扰素诱导基因Mx1、OAS1和PKR的mRNA水平。结果显示,CoPoIFN-a或者PoIFN-a预处理的PK-15细胞中Mx1和OAS1的mRNA水平都明显提高。其中,CoPoIFN-a预处理组的OAS1的]mRNA水平比PoIFN-a预处理组高3.2倍,而CoPoIFN-a预处理组Mx1的mRNA水平比PoIFN-a预处理组高4.6倍。本实验中没有检测到PKR mRNA的表达。
4. CoPoIFN-a作为猪瘟多肽疫苗佐剂的研究
为了评估CoPoIFN-a作为猪瘟病毒多肽疫苗的佐剂效果,我们将pET-32a融合表达的CSFV囊膜蛋白E2上693-716位的氨基酸纯化浓缩后与206佐剂乳化成猪瘟多肽疫苗pb,联合104U、105U和106U的CoPoIFN-a共同免疫30日龄家猪,首免后两周加强免疫一次。首免前一周和首免后每周采集外周血用ELISA方法检测血清中的CSFV抗体,首免后14d进行病毒中和抗体测定,同时采集抗凝血并分离外周血淋巴细胞,用多肽抗原刺激分离的淋巴细胞后进行淋巴细胞增殖实验,并测定淋巴细胞分泌的IL-4和IFN-y的水平。结果显示,pb多肽疫苗可以诱导家猪产生体液免疫反应,CoPoIFN-a可以提高pb多肽疫苗诱导产生的体液免疫水平,并呈剂量依赖性；105U的CoPoIFN-a能显著增加pb诱导家猪产生的CSFV特异性抗体水平,但104U的CoPoIFN-a和106U的CoPoIFN-a只能稍微增加pb诱导家猪产生的CSFV特异性抗体水平；另外,105U的CoPoIFN-a能显著增加pb诱导家猪产生的CSFV特异性中和抗体水平；在pb和CoPoIFN-α联合免疫组,随着CoPoIFN-a量的增加,淋巴细胞增殖水平和IFN-γ的分泌水平也越来越高。此结果表明,CoPoIFN-α可以提高猪瘟多肽疫苗诱导家猪产生的免疫反应水平。
5. CoPoIFN-a的晶体生长和计算机模拟分析干扰素及其受体的三级结构
为了准确从空间结构的角度对CoPoIFN-a的高活力进行诠释以便对其进行进一步的改造,我们尝试通过蛋白质结晶学的方法解析CoPoIFN-a的空间结构。我们将纯化的CoPoIFN-a分别浓缩至10mg/mL和20mg/mL两个浓度,并用商品化晶体生长试剂盒Crystal Scree、Crystal Screen2、Index和MembFac对干扰素晶体生长条件进行筛选。初步筛选出两个蛋白晶体生长条件。通过对在这些条件下生长得到的晶体进行初步X-光射线衍射分析发现这些晶体的分辨率并不理想。目前正在对这些结晶条件进一步优化,以便能够得到衍射能力良好的晶体。
在对CoPoIFN-a晶体生长条件摸索的同时,我们利用discovery studio结构模拟软件分别模拟出CoPoIFN-a与猪Ⅰ型干扰素受体和PoIFN-a与猪Ⅰ型干扰素受体三元复合物的空间结构,并对干扰素与受体的相互作用进行了分析。在复合物模型中,我们没有观察到两个干扰素中有差异的残基与受体的直接相互作用。其中,PoIFN-a上的38位丝氨酸、151位丝氨酸和43位苯丙氨酸分别突变成了CoPoIFN-a中的苯丙氨酸、丙氨酸和亮氨酸,这些突变了的氨基酸残基侧链朝内指向干扰素结构的核心,它们改变了局部的疏水性。156位的苏氨酸突变成了精氨酸,蛋白质表面静电势分析结果显示此突变在干扰素和其受体结合的表面引入了更多的正的静电势。引入的正的静电势可能会促使干扰素和其受体更快更紧密的结合；另一方面,也可能是该残基变化影响了附近与干扰素受体相互作用的残基的构象,从而增强了干扰素与其受体的相互作用而导致活性的增加。
Interferon is a type Ⅱ cytokine which possesses many biological functions including immunomodulation, antiviral activities and antiproliferative activity. According to difference in receptor, chromosomal localization and acid stability, interferon can be classified into three types I, II and III. IFN-a belongs to type I interferon, which has powerful antiviral activity. In order to study the biological activity of interferon and expand their clinical application, we designed and expressed a consensus porcine IFN-a (CoPoIFN-a), and studied its structure and functions. The purpose of the experiments is to design a recombinant consensus porcine IFN-a and explore its safety and effectivity to produce a novel interferon-a to increase pig immunity and the protective capacity of current vaccines. We also screened the crystal growth conditions of CoPoIFN-a and modeled the ternary structure of the IFN-as with its receptors in order to determine the interactions between interferon and the receptors, which will help us to study the activity of interferons and design the novel interferions with higher biological activities.
1. The design, gene synthesis and cloning of CoPoIFN-a
We searched protein sequences of17native porcine IFN-a subtypes from NCBI, and aligned the sequences using Bioedit and assigned the most frequently observed amino acid in each corresponding position. The designed interferon-α was named as CoPoIFN-a. Based on codon usage of yeast, the nucleotide sequence of CoPoIFN-a was designed, and14primers were designed and synthesized to amplify CoPoIFN-a gene using gene splicing by overlap extension PCR (SOE-PCR) method. The full length CoPoIFN-α gene was then cloned into pPICZa expression vector using an upstream EcoRl site and a downstream XbaIsite. The positive Pichia pastoris transformant carrying CoPoIFN-a gene were confirmed by PCR and DNA sequencing.
2. The expression and purification of CoPoIFN-α
The Pichia pastoris X-33strain carrying CoPoIFN-a or control PoIFN-a gene was induced with methanol under28℃for72h. The supernatant was separated from the cells by centrifuging at12000r/min under4℃. The supernatant was first precipitated with30%(NH4)2SO4to remove some contaminant proteins, and the fraction containing IFN was obtained by precipitate with45%(NH4)2SO4. Further purification steps were carried out by using hydrophobic, ion exchange and gel filtration chromatography. The purified proteins were confirmed by using mouse anti-porcine IFN-al monoclonal antibody. The secondary structure of purified CoPoIFN-α and PoIFN-a were analyzed by circular dichroism spectroscopy method, the data showed they exists mainly as α-helixes in solution.
3. The in vitro biological studies on CoPoIFN-α
We assayed biological activities of CoPoIFN-a, and compared the differences between CoPoIFN-a and PoIFN-a. First of all, we compared their inhibitory abilities on the VSV infection in MDBK, PK-15and MARC-145cells. We observed that the antiviral activity of CoPoIFN-α was46.4,63.6,53.5-fold higher than that of PoIFN-a in MDBK, PK-15and MARC-145cells, respectively. We next compared the ability of CoPoIFN-a or PoIFN-a in inhibiting PRV and PRRSV replication in the cells that have been pretreated with CoPoIFN-a or PoIFN-a. We found that the viral titers of PRV in PK-15cells pretreated with PoIFN-a were higher than that pretreated with CoPoIFN-a by25-fold, and real-time PCR result showed that the amount of PRV mRNA in PK-15cells pretreated with PoIFN-a was4.8-fold higher than that pretreated with CoPoIFN-a. The results on PRRSV indicated that the viral titers of PRRSV in MARC-145cells pretreated with PoIFN-a were higher than that pretreated with CoPoIFN-a by10-fold, and real-time PCR result showed that the amount of PRRSV mRNA in MARC-145cells pretreated with PoIFN-a was5-fold higher than that pretreated with CoPoIFN-a. The antiproliferative activity of IFN-as against PK-15cells was investigated in vitro using the MTT assay after treating the cells with serial dilution of8-0μg/mL CoPoIFN-a or PoIFN-a, the results showed the antiproliferative activity of CoPoIFN-a was higher than that of PoIFN-a within a concentration range of0.25-0.5μg/mL, and significantly higher within a concentration range of1-8μg/mL. Finally, we assayed the stimulation ability of the CoPoIFN-a or PoIFN-a on Mxl, OAS1and PKR gene induction. The Q-PCR results showed the mRNA levels of Mx1and OAS1 gene in the PK-15cells were significantly enhanced. In the CoPoIFN-a treatment group, the mRNA level of OAS1was enhanced by about3.2-fold compared with PoIFN-α treatment group, while the level of Mxl was increased by about4.6-fold. We did not detect PKR mRNA expression in PK-15cells.
4. The studies of adjuvant effect of CoPoIFN-a in CSFV peptide vaccine
To assess the adjuvant effect of CoPoIFN-a in CSFV peptide vaccine, we ligated a gene corresponding to the peptide (aa693-716) from CSVF envelope protein E2downstream of trxA gene in the pET-32a vector. We purified the fusion peptide from E. coli. from inclusion body. The fusion peptide was emulsified with206adjuvant to generate CSFV peptide vaccine pb. The30-day old pigs were immunized with pb combined with104unit,105unit or106unit CoPoIFN-a and boosterd two weeks later. The peripheral blood was colleted each week before and after the first immunization. The CSFV antibody in the blood was detected using ELISA. Two weeks after the first immunization, we carried out antibody neutralizing test. We also seperated peripheral blood lymphocyte and stimulated the cells with fusion peptide antigen to test their proliferative and IL-4, IFN-y secretion ablities. The results showed pb peptide vaccine can induce the humoral immune reaction in pigs, and CoPoIFN-α can increase the reaction level in dose-dependent manner. CoPoIFN-a at105units could increase antibody level significantly based on ELISA results, while104and106units of CoPoIFN-a only slightly increased the antibody level. CoPoIFN-a at105units could increase the neutralizing antibody specific to CSFV. These results showed that CoPoIFN-a can increase immunological reaction level induced by pb.
5. The crystallization of CoPoIFN-a and computational modeling of CoPoIFN-a/IFNAR2
To explore the mechanism for the high biological activity of CoPoIFN-a from structure, we purified CoPoIFN-a from yeast, and concentrated the protein to10mg/mL or20mg/mL. We screened the crystal growth conditions of CoPoIFN-a using commerical crystal screening kits, including Crystal Screen、Crystal Screen2、Index and MembFac.Two protein crystal growth conditions were found. Unfortunately, the diffraction ability of these crystals was poor. We are now trying to refine the conditions to get the crystal with good diffraction quality.
Meanwhile, we modeled the ternary structures of CoPoIFN-a or PoIFN-a with its receptors. Due to the high similarity between the terneary structures, we only analyzed the hydrogen bond and hydrophobic interations between CoPoIFN-a and the receptors. In our complex models, we did not observe the direct interactions of the different residues on CoPoIFN-a with the receptor. The original Ser-38, Ser-151and Phe-43in PoIFN-a were changed into Phe, Ala and Leu in CoPoIFN-a, respectively. The side chains of these residues are pointing inside towards the core of the structure, and they changed the local hydrophobicity distribution. Another mutation at position156to arginine seemed more significant, since such replacement introduced more positive potential at the interface in CoPoIFN-a according to surface electrostatic potential analysis. Since introduce of the positive potential on the interface can steer these two proteins to achieve fast or tight binding. On the other hand, it was also possible that mutated residues affected the conformation of the residues nearby that had interactions with the receptor, and consequently enhanced the biological activity of the engineered IFN-a.
引文
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