摘要
2006年,我国猪群中暴发一种以高热、腹式呼吸、咳嗽、食欲不振、便秘或腹泻、眼分泌物增多等为主要症状的传染病。最初对该病的病因没有明确定论,故将之定名为“猪无名高热”或“猪高热病”。为了研究“猪高热病”中主要病毒性病原在国内的流行情况,本研究对猪繁殖与呼吸综合征病毒和猪瘟病毒进行了分子流行病学调查;分析了PRRSV国内流行株与国内外其它毒株间的遗传演化关系。在对病原基因组本身认识加深的基础上,利用反向遗传学手段获得了一株PRRSV标记毒株株并对其进行了初步免疫实验研究；进一步对PRRSV活病毒载体疫苗的可行性进行了探索。本研究为我国猪群中主要病毒病原的分子流行病学特征提供科学依据,同时也为PRRSV的防控提供了新的思路,奠定了理论基础。本研究具体内容如下：
1、中国部分地区猪瘟病毒分子流行病学调查
为了研究中国猪瘟病毒(CSFV)的分子流行病学,本试验用巢式RT-PCR检测2008年1月到2011年3月送检的不同猪场病料,并对其中103个CSFV分离株的E2基因序列进行分析。进化分析结果表明这些毒株分属1群的1.1亚群和2群的2.1和2.2亚群,没有3群毒株存在。2.1亚群毒株为优势流行毒株,流行范围覆盖大陆绝大部分地区。这些结果丰富了国内CSFV基因变异情况的数据,将为新的诊断方法的建立、流行病学监测以及有效的防控措施制定提供理论基础。
2、中国部分地区猪繁殖与呼吸综合征病毒分子流行病学调查
对来自2006-2010年中国15个不同省、自治区、直辖市的疑似猪繁殖与呼吸合征(PRRS)发病猪场的送检病料进行猪繁殖与呼吸合征病毒(PRRSV)的检测,并对其部分ORF5基因进行测序,以确定当前PRRSV在中国的分子流行病学特征,并分析PRRSV在中国的遗传变异规律。使用RT-PCR的方法对采集的样品进行PRRSV检测,并对PRRSV检测呈阳性的69份病料进行ORF5基因的序列测定和分析。1196份病料中共检测到247份阳性样品,阳性率为20.7%。对ORF5序列进行分析表明,69株PRRSV毒株序列均属于2型,与GenBank中高致病性蓝耳病(HP-PRRSV)参考毒株的氨基酸同源性为94.0%-100%。所测序列与PRRSV参考株一并,共可分为5个亚型,亚型Ⅳ与HP-PRRSV遗传距离最近。同时,进化树分析结果表明,69个毒株在空间分布上存在散在性,来源于不同省市的PRRSV毒株的遗传关系存在交叉,病毒分型并没有呈现明显的地域性；PRRSV在中国的流行株为HP-PRRSV, PRRSV在目前中国的遗传演进相对稳定。
3、PRRSV中国流行株全基因组序列的测定与分析
为了进一步研究猪繁殖与呼吸综合征病毒在国内的遗传变异情况及分子生物学特征,本研究在上一章研究的基础上,对一株国内分离株JS0922株进行了全基因组的序列测定。根据ATCC VR-2332标准株和JX143高致病性蓝耳病代表株的序列设计引物,对1株2009年的PRRSV江苏分离毒株JS0922全基因进行了分段扩增并测序,将测序结果拼接后,得到病毒的全基因,然后进行序列的比对分析。分析数据显示,PRRSV JS0922株属于基因2毒株,它与2006年以前的分离株相比存在明显差异,与国内早期BJ-4株的核苷酸同源性仅为89%；而与高致病蓝耳病病毒(HP-PRRSV)的同源性较高,达98%以上。就基因组各开放阅读框而言,JS0922的ORF3、ORF4基因变异较大,ORF6则较为保守。分析发现,JS0922基因组具有HP-PRRSV的分子特征,但部分位点氨基酸的突变明显区别于HP-PRRSV。综上,JS0922毒株发生了部分变异,具备了一些新的特点,但总体上划归于HP-PRRSV演化中的一个分支,属于目前国内PRRSV的优势流行株。
4、猪繁殖与呼吸综合征病毒结构蛋白N蛋白N端非必需区的研究
为了确定猪繁殖与呼吸综合征病毒nucleocapsid (N)蛋白N末端非重叠区域的非必需区的范围,我们在单纯将PRRSV ORF6与ORF7重叠区拉开的背景质粒上进行了系列研究。本实验参照骨架质粒p7PNX的序列设计引物,选取其N蛋白N端从起始密码子之后的氨基酸进行系列缺失,构建一系列缺失突变体。通过转染BHK-21细胞进行病毒拯救,确定在ORF7无重叠区的情况下,N末端的2-7位氨基酸对于病毒的感染性是非必需的。对缺失体盲传后发现,缺失区域在体外遗传性能稳定。对缺失体进行多步生长曲线和空斑实验,发现缺失体生长动力学和空斑形态学特征与野生型相似。本研究首次确定了2型PRRSV的N蛋白non-overlapping背景下N末端的缺失区域,为进一步解析N蛋白结构与功能、创制新型基因工程标记疫苗奠定了基础。
5、猪繁殖与呼吸综合征结构蛋白N蛋白标记毒株的构建及初步免疫实验研究
当前的PRRSV疫苗对疫苗免疫猪和自然感染猪上无法提供血清学鉴别。因此,我们需要利用新的方法制备一种新型的,更为有效的疫苗。利用反向遗传技术,我们构建了一个基因标记毒株—v7APMa,该候选株的核衣壳蛋白与野生毒株(vAPRRS,2型PRRSV)有所差异,v7APMa在体外的细胞培养中显示了良好的遗传稳定性,并且其基因标记的病毒特性在子代病毒中能够很好的得到复制。在体内感染实验中,标记病毒v7APMa和亲本病毒vAPRRS一样,能够诱导感染猪产生相当水平的抗N蛋白抗体,也能诱导相似滴度的中和抗体。同时,两组免疫组仔猪血清中的IL-4和IFN-γ的含量也明显升高。说明标记病毒和亲本病毒一样,能够刺激机体产生正常的免疫应答。v7APMa感染猪在在感染后14天能够产生抗基因标记特异性多肽的抗体。但是vAPRRS和对照组在整个过程未能产生针对基因标记特异性多肽的抗体。说明诊断ELISA方法能够区分vAPRRS病毒和标记病毒v7APMa。在实验28天PRRSV强毒株JX143攻毒后,对照组出现典型的PRRS临床症状,表现为体温升高、食欲下降,眼睑水肿,流鼻涕,咳嗽,皮肤发红等临床症状,且在攻毒后11天和14天分别有1头仔猪死亡。而v7APMa和vAPRRS免疫的猪体温也有体温升高,但持续时间短,临床症状较轻,无猪只死亡。说明vAPRRS和v7APMa均可以对异源毒株JX143攻毒提供一定的免疫保护。结果表明,通过这种新的方法制备出的基因标记毒株为PRRSV标记疫苗的创制提供了新的思路。
6、猪繁殖与呼吸综合征病毒活载体疫苗候选株的构建及其病毒学特性的研究
为了获得以PRRSV作为活病毒载体的疫苗候选株,并探究在PRRSV的ORF4与ORF5之间运载外源蛋白基因的可行性,本实验将(equine arteritis virus, EAV)的ORF4嵌合入PRRSV基因组中,经PCR、酶切和基因测序鉴定,筛选获得阳性重组质粒pAPRRS(EAV4)。转染对数生长期的BHK-21细胞,拯救获得了重组嵌合病毒vAPRRS(EAV4)。经MARC-145连续传代,证明其基因组在体外可以稳定遗传。Northern-blot、亚基因组测序和间接免疫荧光表明,PRRSV自身基因组可完成复制、转录、翻译各过程,但嵌合入的EAV的ORF4没有转录的发生。对嵌合体进行多步生长曲线和空斑实验,发现嵌合体生长动力学和空斑形态学特征与野生型相似。从而为进一步研究动脉炎病毒各个结构蛋白的功能、开发新型PRRSV活载体疫苗、标记疫苗奠定了基础。
There was an outbreak which was called "Mystery Fever Disease Syndrome" or "High Fever Disease" in pig herds in China in2006. In the beginning, it was happened in Jiangxi province. Then it spread to almost all the mainland covered more than20provinces. Tremendous loss was made via this desease to the pig industry in China. The symptom of this disease includes the anorexia, the high body temperature, constipation and diarrhoea, absorption in gestation sows and sometimes with nervous symptom, secretion with the nose especially with the eyes. The most sensitive stages were the gestation sows, the finishing and growing pigs. The desease has very highly incidence and the mortality. The purpose of this study was to investigate the epidemic situation of the PRRSV and CSFV in recent China, including uncover the "mystery" of the disease or syndrome eventually. We also sequencd and analysed the ful genome of one predominant PRRSV strain in China. On the base of these knwoledge, we generated a novel marker virus for the control of PRRS by using the reverse genetics. We also developed a PRRSV vector vaccine candidate and explored the possibilities of the foreign gene can stably exist in the PRRSV genome. These findings enhance our knowledge of the genetic diversity of pocine viral pathogens in China and contribute to the development effective strategies for swine disease control.
1. Molecular epidemiology of CSFV field isolates in parts of China
To gain an insight into the molecular epidemiology of classical swine fever in China, we analyzed the E2gene of103Chinese CSFV isolates. Clinical samples were collected between January2008and March2011. CSFV was detected in103out of these samples by RT-nested PCR and were selected for sequencing. Further analysis based on E2sequences revealed that all Chinese isolates belonged to subgroupsl.l,2.1and2.2. CSFV isolate of genogroup3was not found. The most significant correlation between genetic and geographical distribution for the isolates in the study, especially for the subgroup2.1strains, was they take up the widest area, since these viruses existed throughout the mainland of China. These findings enhance our knowledge of the genetic diversity of Chinese CSFV isolates, and may contribute to the development of reliable diagnostic tests, the epidemiological surveillance, and the development of effective strategies for disease control.
2. Molecular epidemiology of PRRSV field isolates in parts of China
A total of1196clinical samples of dead or sick pigs obtained from15different provinces of China during2006-2010were detected for PRRSV. The ORF5genes of some field isolates were amplified and sequenced for further understanding of the molecular epidemiology and the genetic diversity of PRRSV in China. PRRS viruses were identified by RT-PCR from clinical samples. Sequences of ORF5of69PRRSV positive samples was amplified and analyzed with other17strains available on the GenBank of NCBI. A total of247samples were positive and the positive rate was20.7%. Sequence analysis showed that the69isolates in this study belong to the Type2PRRSV strains. They were related closely to the highly pathogenic PRRSV (HP-PRRSV) with94.0%-100%amino acid sequence identities. The phylogenetic analysis indicated that all these Type2PRRSV strains in China were further divided into five subgenotypes and subgenotype IV showed most highly identity with HP-PRRSV. Although cross-cutting phenomenon exists in the genetic relationship of PRRSV isolates obtained from different areas, there were no obvious relations between the distribution of PRRSV and the region. The PRRSV was widespread and HP-PRRSV was the predominate strain and the genetic evolution was relatively stable in China during2006-2010. These findings enhance our knowledge of the genetic diversity of Chinese PRRSV isolates, and may contribute to the development of reliable diagnostic tests, the epidemiological surveillance, and the development of effective strategies for disease control.
3. Genomic sequencing and phylogenetic analysis of predominant PRRSV in China
To gain an insight into the molecular characteristics and the genetic variety of porcine reproductive and respiratory syndrome virus (PRRSV) in China, we sequencd and analysed the ful genome of one Chinese isolate. Primers were designed according to ATCC VR-2332and HP-PRRSV JX143strain. The full genome of the PRRSV strain JS0922, which was isolated from Jiangsu province in2009, was amplified and then sequenced. The genomic sequence was obtained by splicing of correct sequencing and was further aligned with other reference strains. The results showed that JS0922fell into Type2PRRSV. Even though it showed significant differences from the strains isolated before the year2006, that the homology was only89%compared with BJ-4, it shared more than98%homology with HP-PRRSV. JS0922also had different characteristics variously that ORF3and ORF4varied greatly while ORF6revealed more conservative. Analysis showed that JS0922had general molecular characteristics with HP-PRRSV, but also existed a few amino acids mutations which differed from HP-PRRSV. In summary, JS0922strain presented a few new genomic features, but still fell into a same branch of HP-PRRSV and belonged to the current predominant PRRSV in China.
4. Study on the N-terminal non-essential domain of PRRSV N protein non-overlapping region
To define the precise non-essential domain of porcine reproductive and respiratory syndrome virus (PRRSV) nucleocapsid (N) protein non-overlapping region, we studied a full-length infectious clone p7PNX, which overlapping region of ORF6and ORF7had been separated. Primers were designed according to the sequenc of the p7PNX. We focused on the N protein and constructed a series of N-terminal mutations, right behind the start codon of ORF7using reverse genetics. Transfection and virus rescue assay indicated that residues2-7at the N terminus were non-essential for virus viability. The series of mutants showed stable inheritance in cell culture. Growth kinetics and viral plaque assay in vitro showed that the virological characteristics of the mutant virus were samiliar with the wide type and the mutants replicated well as its parental strain. This was the first time of the investigation of N-terminal non-essential domain on N protein non-overlapping region of PRRSV. Besides, this study opens new pathways for the further elucidating the structure-function relationship of PRRSV N protein and may enable the development of novel gene marker vaccines.
5. Development of marker virus and the preliminary immunization study in the structural protein N region of porince reproductive and respiratory syndrome virus
Current PRRSV vaccines fail to provide serological differentiation between vaccinated and infected pigs and new strains of the virus have been isolated. Therefore, new, more efficacious vaccines developed using novel approaches are required. Using reverse genetics, a marker virus (v7APMa) was generated with a nucleocapsid protein that differs from the wild-type strains (vAPRRS, type2PRRSV). v7APMa shows stable inheritance in cell culture and the virological characteristics of the marker virus in vitro showed that v7APMa replicates well as its parental strain. In the pig model, the v7APMa marker virus induced a similar level of anti-N protein antibodies. The results also showed that all animals vaccinated with vAPRRS and v7APMa developed neutralizing antibody after14days post-infection, and both IL-4and IFN-y in serum samples were markedly induced compare with those in the control group. The v7APMa marker virus induced robust antibodies against the marker peptide, starting from14days post-infection, while the vAPRRS and the control groups didn't. Following challenge with HP-PRRSV JX143at28d, piglets in the control group showed classical PRRSV clinical signs, such as rise in temperature, decreased appetite, palpebral edema, runny nose and cough. Two piglets dead at11d and14d respectively. Meanwhile, piglets inoculated with vAPRRS and v7APMa, showing lighter clinical signs, lower viremia and no death. These indicates that v7APMa and vAPRRS could provide protection against virulent PRRSV JX143challenge in pigs. This approach, using a rationally designed marker virus, opens up a new avenue, for further development of PRRSV marker vaccines.
6. Construction and virological characteristics of PRRSV vector vaccine candidate
To develop a porcine reproductive and respiratory syndrome virus(PRRSV) vector vaccine candidate and to explore the possibilities of the foreign gene can stably exist and play function between ORF4and ORF5of PRRSV genome, we insert ORF4of EAV(equine arteritis virus) to gain a chimeric virus. By using PCR, enzyme digestion and sequencing analysis, the recombinant pAPRRS(EAV4) were selected and purified. After transfection of the recombinant plasmids into BHK-21cells, the recombinant viruses vAPRRS(EAV4) were obtained. The chimeric viruses showed stable inheritance in cell culture. The replication and translation of PRRSV genome was confirmed by RT-PCR and immunofluorescence assay. It was further demonstrated by Northern-blot and the sequencing of subgenome that the transcription of EAV ORF4was not detected. Growth kinetics and viral plaque assay in vitro showed that the virological characteristics of the chimeric viruses were samiliar with the wide type and the mutants replicated well as its parental strain. The chimeric virus vAPRRS(EAV4) should be useful for studying on function of the arterivius structural protein and developing novel PRRSV vector vaccine.
引文
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