牛病毒性腹泻病毒囊膜蛋白E2与牛胚胎滋养层细胞相互作用的分子机制研究
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摘要
牛病毒性腹泻病(BVD)是由牛病毒性腹泻病毒(BVDV)引起的一类以腹泻、流产、呼吸道疾病和免疫机能障碍为主要症状的疾病,目前已在世界范围内广泛传播,给养牛业国家造成了巨大的经济损失。我国BVDV感染具有特征性临床症状的病例并不多见,多半是隐性感染,未能引起足够重视。BVDV感染胎盘组织,通过胎盘屏障将病毒传播给胎儿,造成母胎持续性感染是该病防治的难点和重点。妊娠母畜在怀孕早期通过子宫内感染非致细胞病变型(ncp) BVDV,此时胎儿免疫系统尚未成熟,不能产生免疫应答反应。此种牛一出生即为持续感染牛,外表健康,但终生带毒、排毒,成为畜群主要的传染源。胚胎滋养层细胞是母体和胎儿的联系纽带,同时也是BVDV垂直传播的靶细胞,目前有关BVDV感染胚胎滋养层细胞的分子机制尚不清楚。寻找与BVDV主要囊膜蛋白相互作用的细胞受体,确定受体在病毒感染细胞过程中的功能,是研究BVDV垂直传播机制的重要内容之一,也为家畜抗病育种提供新的理论依据。为此,本研究以BVDV和胚胎滋养层细胞为研究对象,主要展开以下研究工作：
1.新疆部分地区奶牛场BVDV的分子流行病学调查和基因型分布。根据BVDV保守区基因5'-UTR设计引物,采用RT-PCR方法,对新疆石河子、玛纳斯、喀什、等7个地区、14个奶牛场的274份牛粪样品进行核酸检测及测序。结果表明：BVDV阳性率为18.61%(51/274),北疆地区阳性率为21.34%(51/239),南疆地区未检测出病原。其中有23对母子对应样品,母牛阳性率为39.13%(9/23),犊牛阳性率为30.43%(7/23)。35头牛表现临床症状,阳性率为45.71%(16/35),其余为临床健康牛,阳性率为17.16%(35/204)。调查数据显示新疆地区奶牛BVDV存在隐性感染,且垂直感染较严重。通过序列比对,系统发生分析表明所分析序列与已公布的BVDVⅠ型序列核苷酸同源性最高,达97.5%,并且主要是BVDVⅠb亚型。对临床发病症状明显的初检阳性病料进一步分离培养和鉴定。采用免疫学实验、细胞培养和电镜观察、理化特性测定以及同源性比较等方法分离、鉴定了1株BVDV分离株,命名为BVDVshz132株。
2.牛胚胎滋养层细胞体外分离培养及BVDV shz132株感染实验：采用胶原酶消化方法,从牛子叶组织中分离双核滋养层巨细胞(Binucleate trophoblast giant cells,TGC)。实验分离的细胞经台盼蓝染色后记录细胞存活率大于90%,核染可见典型双核特征；经差异贴壁法纯化后纯度可达95%。抗细胞角蛋白抗体检测呈阳性,抗波形蛋白抗体检测呈阴性。细胞经过4次传代后,可以存活60天。通过制备细胞爬片,接种BVDVshzl32株,分别培养12-60h,采用BVDV5'-UTR基因实时荧光定量PCR检测病毒拷贝数在培养12h和60h的增殖情况。结果表明60h病毒拷贝数明显高于12h,病毒可在TGC细胞中复制、增殖。
3.建立牛胚胎滋养层细胞的cDNA文库,采用酵母双杂交技术筛选与BVDVshzl32株主要囊膜蛋白E2相互作用的TGC细胞结合蛋白。文库的库容为1.3×106,插入片段大小在0.2-4kb；取杂交后35个克隆进行测序,用BlastN进行序列同源性比对,筛选得到与BVDV感染TGC细胞相关的捕获蛋白有Bos taurus tryptophanyl-tRNA synthetase (色氨酰-转移核糖核酸合成酶)、similar to WARS protein(色氨酸-转移核糖核酸合成酶--TRRRS-基因标记符号)、actin and beta (肌动蛋白)、p21 protein (Cdc42/Rac)-activated kinase 4(p21-活性激酶,PAK4)、pyruvate kinase(丙酮酸激酶)和clathrin heavy-chain(网格蛋白重链)。通过在线软件分析捕获蛋白的二级结构,预测各个蛋白结构域的功能。结果发现网格蛋白重链接头蛋白(heavy-chain linker)介于网格蛋白与配体-受体复合物之间起到连接作用,通过网格蛋白包被囊泡的内吞作用使配体-受体复合物进入细胞。分析表明网格蛋白介导的内吞作用是BVDV感染细胞的一种途径。采用免疫共沉淀方法验证网格蛋白与诱饵蛋白之间的相互作用。
以上研究结果表明：通过对新疆地区的BVDV流行病学调查发现,本地区阳性感染率较高,垂直传播严重,基因型分布主要以BVDVIa和Ib型为主。对流行病学阳性样品进一步分离,鉴定了一株BVDV野毒株(shz132株),为非致细胞病变型；成功体外培养了牛胚胎滋养层巨细胞,对细胞进行了鉴定,并成功感染BVDV shz132株；构建了牛胚胎滋养层细胞的cDNA文库；通过酵母双杂交筛选得到6个与BVDV shz132株E2蛋白相互作用的牛胚胎滋养层细胞蛋白,其中网格蛋白是与BVDV感染滋养层细胞相关的蛋白。通过本研究,为揭示BVDV垂直传播,导致持续性感染的分子机制提供线索,也为该病新药物研发、防治及家畜抗病育种工作奠定基础。
Bovine viral diarrhea virus (BVDV) is an important cattle pathogen and widespread all over the world and cause diarrhea, abortion, respiratory passage disease or immun-function defilade. It generates significant economic losses. In our country, BVDV infections usually cause no or only mild clinical symptoms so as to leading less reconstruction. The emphasis and difficulty of preventing this diease is persistant infection(PI) which is caused by transplacental infection. Diaplacental infection of foetuses with a ncp BVDV strain during first trimester of gestation may result in the birth of immunotolerant PI calves which shed the virus through their lifetime. Therefore, they are the main viral reservoir and source for viral transmission. Binucleate trophoblast giant cells(TGC) is the vinculum between parent and fetus and also the target cell for BVDV vertical transmission. At present, there is less molecular mechanism about BVDV infecting TGC. It will be an useful work to find cellular receptors that interacted with BVDV envelope protein E2 and to definite the role of receptors during infection. This work also provide newly consept to breeding for disease resistance. So our investigation is focus on:
1. Epidemiology investigation and genotype distribution of BVDV in Xinjiang. Based on the sequence comparison of the highly conserved 5'-UTR among different genotypes and subgroups of BVDV strains, current primers were designed.274 dejecta samples which were collected from 14 cattle farms in Xinjiang were detected by RT-PCR assay and sequencing.18.61%(51/274) samples were positive for BVDV with RT-PCR.21.34%(51/239) were positive in north area but negative in south area. 23 matched-pairs specimens were detected. The cow-positive rate was 39.13%(9/23) and the calf was 30.43%(97/23).35 cattles showed clinical symptoms, the positive rate was 45.71%(16/35). The positive rate of the remaining normal cattle was 17.16% (35/204). Data shows BVDV vertical transmission was more seriously in this region. Alignment of the 5'-UTR sequences of the isolates showed 2 different sequences. In addition, Phylogenetic analysis revealed that all viruses were found in group BVDV-I b. No BVDV typeⅡvirus was discovered. These results suggest that the BVDV isolated reflect that the virus predominant genotype is BVDV-I b in Shihezi. And by the biological-type identification, the isolates were non-cytopathic type. Information obtained from this study would also be useful when carrying out epidemiological surveys of domestic BVDV and vaccine application in Chinese cattle population. A BVDV strain originated from Shihezi area in Xinjiang autonomous district, namely BVDV shzl32, was isolated and identified by immunological method, electron microscope observation, physico-chemical property analysis, PCR detection and homology comparison.
2. To establish a convenient method of purification and culture bovine trophoblast cells and BVDV shz132 infected cells. Healthy placental tissues were obtained and digested, then the cells were cultured, purified. The results shown livability was above 90% and typical two nucleus were stained blue. The isolated TGC were positive for cytokeratin and negative for vimentin throughout the duration of the experiment. The purified cells contained 95% TGC and unpurified contained only 45%-50%. The cells could passage four generations and survived for sixty days. Inoculated TGC with BVDV shzl32 for 12h to 60h and detected virions copies by Real-time RT-PCR according to BVDV 5'-UTR. The results shown that virions copies obtained from the latter was obviously higher than the former. That is to say BVDV can generate in TGC.
3. The cDNA library of TGC infected with BVDV shzl32 strain was constructed. The target protein were screened and verified. Here we found six cellular proteins interacted with BVDV shz132 E2 protein by yeast two-hybrid:Bos taurus tryptophanyl-tRNA synthetase、similar to WARS protein、actin and beta、p21 protein pyruvate kinase and clathrin. As a results, clathrin heavy-chain linker act as a adapter protein between clathrin and ligand-receptor compound and then entry cells by endocytosis in clathrin-coated vesicles. It is clearly that clathrin-mediated endocytosis is a route for BVDV infecting cells. Then clathrin was verified by immunoprecipitation.
The above results show that positive ratio of BVDV infection is highly exist in Xinjiang with seriously vertical transmission. All BVDV isolates in this study have been divided into two genotypes, BVDV1 and BVDV2. One of these was isolated and identified as ncp BVDV which named BVDV shz132. TGC was successfully cultured and identified. The cDNA library of TGC infected with BVDV shz132 strain was successfully constructed. We found six proteins that interacted with BVDV envelope protein E2 and verificated clathrin by immunoprecipitation. These findings were useful to demonstrate molecular mechanism of persistent infection. It is also significent to screen specific candidate drugs and give a upstream work for breeding of antivirus livestock.
1.新疆部分地区奶牛场BVDV的分子流行病学调查和基因型分布。根据BVDV保守区基因5'-UTR设计引物,采用RT-PCR方法,对新疆石河子、玛纳斯、喀什、等7个地区、14个奶牛场的274份牛粪样品进行核酸检测及测序。结果表明：BVDV阳性率为18.61%(51/274),北疆地区阳性率为21.34%(51/239),南疆地区未检测出病原。其中有23对母子对应样品,母牛阳性率为39.13%(9/23),犊牛阳性率为30.43%(7/23)。35头牛表现临床症状,阳性率为45.71%(16/35),其余为临床健康牛,阳性率为17.16%(35/204)。调查数据显示新疆地区奶牛BVDV存在隐性感染,且垂直感染较严重。通过序列比对,系统发生分析表明所分析序列与已公布的BVDVⅠ型序列核苷酸同源性最高,达97.5%,并且主要是BVDVⅠb亚型。对临床发病症状明显的初检阳性病料进一步分离培养和鉴定。采用免疫学实验、细胞培养和电镜观察、理化特性测定以及同源性比较等方法分离、鉴定了1株BVDV分离株,命名为BVDVshz132株。
2.牛胚胎滋养层细胞体外分离培养及BVDV shz132株感染实验：采用胶原酶消化方法,从牛子叶组织中分离双核滋养层巨细胞(Binucleate trophoblast giant cells,TGC)。实验分离的细胞经台盼蓝染色后记录细胞存活率大于90%,核染可见典型双核特征；经差异贴壁法纯化后纯度可达95%。抗细胞角蛋白抗体检测呈阳性,抗波形蛋白抗体检测呈阴性。细胞经过4次传代后,可以存活60天。通过制备细胞爬片,接种BVDVshzl32株,分别培养12-60h,采用BVDV5'-UTR基因实时荧光定量PCR检测病毒拷贝数在培养12h和60h的增殖情况。结果表明60h病毒拷贝数明显高于12h,病毒可在TGC细胞中复制、增殖。
3.建立牛胚胎滋养层细胞的cDNA文库,采用酵母双杂交技术筛选与BVDVshzl32株主要囊膜蛋白E2相互作用的TGC细胞结合蛋白。文库的库容为1.3×106,插入片段大小在0.2-4kb；取杂交后35个克隆进行测序,用BlastN进行序列同源性比对,筛选得到与BVDV感染TGC细胞相关的捕获蛋白有Bos taurus tryptophanyl-tRNA synthetase (色氨酰-转移核糖核酸合成酶)、similar to WARS protein(色氨酸-转移核糖核酸合成酶--TRRRS-基因标记符号)、actin and beta (肌动蛋白)、p21 protein (Cdc42/Rac)-activated kinase 4(p21-活性激酶,PAK4)、pyruvate kinase(丙酮酸激酶)和clathrin heavy-chain(网格蛋白重链)。通过在线软件分析捕获蛋白的二级结构,预测各个蛋白结构域的功能。结果发现网格蛋白重链接头蛋白(heavy-chain linker)介于网格蛋白与配体-受体复合物之间起到连接作用,通过网格蛋白包被囊泡的内吞作用使配体-受体复合物进入细胞。分析表明网格蛋白介导的内吞作用是BVDV感染细胞的一种途径。采用免疫共沉淀方法验证网格蛋白与诱饵蛋白之间的相互作用。
以上研究结果表明：通过对新疆地区的BVDV流行病学调查发现,本地区阳性感染率较高,垂直传播严重,基因型分布主要以BVDVIa和Ib型为主。对流行病学阳性样品进一步分离,鉴定了一株BVDV野毒株(shz132株),为非致细胞病变型；成功体外培养了牛胚胎滋养层巨细胞,对细胞进行了鉴定,并成功感染BVDV shz132株；构建了牛胚胎滋养层细胞的cDNA文库；通过酵母双杂交筛选得到6个与BVDV shz132株E2蛋白相互作用的牛胚胎滋养层细胞蛋白,其中网格蛋白是与BVDV感染滋养层细胞相关的蛋白。通过本研究,为揭示BVDV垂直传播,导致持续性感染的分子机制提供线索,也为该病新药物研发、防治及家畜抗病育种工作奠定基础。
Bovine viral diarrhea virus (BVDV) is an important cattle pathogen and widespread all over the world and cause diarrhea, abortion, respiratory passage disease or immun-function defilade. It generates significant economic losses. In our country, BVDV infections usually cause no or only mild clinical symptoms so as to leading less reconstruction. The emphasis and difficulty of preventing this diease is persistant infection(PI) which is caused by transplacental infection. Diaplacental infection of foetuses with a ncp BVDV strain during first trimester of gestation may result in the birth of immunotolerant PI calves which shed the virus through their lifetime. Therefore, they are the main viral reservoir and source for viral transmission. Binucleate trophoblast giant cells(TGC) is the vinculum between parent and fetus and also the target cell for BVDV vertical transmission. At present, there is less molecular mechanism about BVDV infecting TGC. It will be an useful work to find cellular receptors that interacted with BVDV envelope protein E2 and to definite the role of receptors during infection. This work also provide newly consept to breeding for disease resistance. So our investigation is focus on:
1. Epidemiology investigation and genotype distribution of BVDV in Xinjiang. Based on the sequence comparison of the highly conserved 5'-UTR among different genotypes and subgroups of BVDV strains, current primers were designed.274 dejecta samples which were collected from 14 cattle farms in Xinjiang were detected by RT-PCR assay and sequencing.18.61%(51/274) samples were positive for BVDV with RT-PCR.21.34%(51/239) were positive in north area but negative in south area. 23 matched-pairs specimens were detected. The cow-positive rate was 39.13%(9/23) and the calf was 30.43%(97/23).35 cattles showed clinical symptoms, the positive rate was 45.71%(16/35). The positive rate of the remaining normal cattle was 17.16% (35/204). Data shows BVDV vertical transmission was more seriously in this region. Alignment of the 5'-UTR sequences of the isolates showed 2 different sequences. In addition, Phylogenetic analysis revealed that all viruses were found in group BVDV-I b. No BVDV typeⅡvirus was discovered. These results suggest that the BVDV isolated reflect that the virus predominant genotype is BVDV-I b in Shihezi. And by the biological-type identification, the isolates were non-cytopathic type. Information obtained from this study would also be useful when carrying out epidemiological surveys of domestic BVDV and vaccine application in Chinese cattle population. A BVDV strain originated from Shihezi area in Xinjiang autonomous district, namely BVDV shzl32, was isolated and identified by immunological method, electron microscope observation, physico-chemical property analysis, PCR detection and homology comparison.
2. To establish a convenient method of purification and culture bovine trophoblast cells and BVDV shz132 infected cells. Healthy placental tissues were obtained and digested, then the cells were cultured, purified. The results shown livability was above 90% and typical two nucleus were stained blue. The isolated TGC were positive for cytokeratin and negative for vimentin throughout the duration of the experiment. The purified cells contained 95% TGC and unpurified contained only 45%-50%. The cells could passage four generations and survived for sixty days. Inoculated TGC with BVDV shzl32 for 12h to 60h and detected virions copies by Real-time RT-PCR according to BVDV 5'-UTR. The results shown that virions copies obtained from the latter was obviously higher than the former. That is to say BVDV can generate in TGC.
3. The cDNA library of TGC infected with BVDV shzl32 strain was constructed. The target protein were screened and verified. Here we found six cellular proteins interacted with BVDV shz132 E2 protein by yeast two-hybrid:Bos taurus tryptophanyl-tRNA synthetase、similar to WARS protein、actin and beta、p21 protein pyruvate kinase and clathrin. As a results, clathrin heavy-chain linker act as a adapter protein between clathrin and ligand-receptor compound and then entry cells by endocytosis in clathrin-coated vesicles. It is clearly that clathrin-mediated endocytosis is a route for BVDV infecting cells. Then clathrin was verified by immunoprecipitation.
The above results show that positive ratio of BVDV infection is highly exist in Xinjiang with seriously vertical transmission. All BVDV isolates in this study have been divided into two genotypes, BVDV1 and BVDV2. One of these was isolated and identified as ncp BVDV which named BVDV shz132. TGC was successfully cultured and identified. The cDNA library of TGC infected with BVDV shz132 strain was successfully constructed. We found six proteins that interacted with BVDV envelope protein E2 and verificated clathrin by immunoprecipitation. These findings were useful to demonstrate molecular mechanism of persistent infection. It is also significent to screen specific candidate drugs and give a upstream work for breeding of antivirus livestock.
引文
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