Yu Dawei, Zhang Shoufeng, Du Weihua, Zhang Jinxia, Fan Zongxing, Hao Haisheng, Liu Yan, Zhao Xueming, Qin Tong, Zhu Huabin
Embryo Biotechnology and Reproduction Laboratory, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China; State Key Laboratories of Agrobiotechnology, College of Biological Science, China Agricultural University, Beijing, China.
Institute of Military Veterinary, Academy of Military Medical Science, Changchun, China.
PLoS One. 2014 Jul 8;9(7):e94444. doi: 10.1371/journal.pone.0094444. eCollection 2014.
Foot-and-mouth disease, one of the most significant diseases of dairy herds, has substantial effects on farm economics, and currently, disease control measures are limited. In this study, we constructed a vector with a human interferon-α (hIFN-α) (without secretory signal sequence) gene cassette containing the immediate early promoter of human cytomegalovirus. Stably transfected bovine fetal fibroblasts were obtained by G418 selection, and hIFN-α transgenic embryos were produced by somatic cell nuclear transfer (SCNT). Forty-six transgenic embryos were transplanted into surrogate cows, and five cows (10.9%) became pregnant. Two male cloned calves were born. Expression of hIFN-α was detected in transfected bovine fetal fibroblasts, transgenic SCNT embryos, and different tissues from a transgenic SCNT calf at two days old. In transfected bovine fetal fibroblasts, expression of intracellular IFN-α induced resistance to vesicular stomatitis virus infection, increased apoptosis, and induced the expression of double-stranded RNA-activated protein kinase gene (PKR) and the 2'-5'-oligoadenylate synthetase gene (2'-5' OAS), which are IFN-inducible genes with antiviral activity. Analysis by qRT-PCR showed that the mRNA expression levels of PKR, 2'-5' OAS, and P53 were significantly increased in wild-type bovine fetal fibroblasts stimulated with extracellular recombinant human IFN-α-2b, showing that intracellular IFN-α induces biological functions similar to extracellular IFN-α. In conclusion, expression of intracellular hIFN-α conferred antiviral properties in transfected bovine fetal fibroblasts and did not significantly affect the full development of SCNT embryos. Thus, IFN-α transgenic technology may provide a revolutionary way to achieve elite breeding of livestock.
口蹄疫是奶牛群中最严重的疾病之一,对农场经济有重大影响,目前疾病控制措施有限。在本研究中,我们构建了一个载体,其含有带有人类巨细胞病毒立即早期启动子的人干扰素-α(hIFN-α)(无分泌信号序列)基因盒。通过G418筛选获得稳定转染的牛胎儿成纤维细胞,并通过体细胞核移植(SCNT)产生hIFN-α转基因胚胎。将46个转基因胚胎移植到代孕母牛中,5头母牛(10.9%)怀孕。产下了两头雄性克隆小牛。在转染的牛胎儿成纤维细胞、转基因SCNT胚胎以及出生两天的转基因SCNT小牛的不同组织中检测到了hIFN-α的表达。在转染的牛胎儿成纤维细胞中,细胞内IFN-α的表达诱导了对水疱性口炎病毒感染的抗性,增加了细胞凋亡,并诱导了双链RNA激活蛋白激酶基因(PKR)和2'-5'-寡腺苷酸合成酶基因(2'-5' OAS)的表达,这两个基因是具有抗病毒活性的IFN诱导基因。qRT-PCR分析表明,用细胞外重组人IFN-α-2b刺激野生型牛胎儿成纤维细胞后,PKR、2'-5' OAS和P53的mRNA表达水平显著增加,表明细胞内IFN-α诱导的生物学功能与细胞外IFN-α相似。总之,细胞内hIFN-α的表达赋予了转染的牛胎儿成纤维细胞抗病毒特性,且对SCNT胚胎的完全发育没有显著影响。因此,IFN-α转基因技术可能为实现家畜优良品种培育提供一种革命性的方法。