戊型肝炎病毒在家禽、家畜中的流行及其ORF3蛋白与人肝细胞蛋白相互作用的研究
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摘要
戊型肝炎病毒(Hepatitis E Virus, HEV)是戊型肝炎的病原体,是一种重要的传染因子。逐渐积累起来的研究结果显示戊型肝炎是一种人兽共患病,自然界存在HEV的动物宿主。我国是戊型肝炎的流行区,既有爆发流行也有散发病例,近年来散发病例报告数持续增加,可能与动物源性HEV的传播有关。了解HEV在我国动物中的流行情况,对于预防和控制戊型肝炎的流行、减少发病具有重要意义。在本研究中,我们从不同省份采集我国主要饲养动物的血清,对HEV在各种动物中的感染率、感染水平进行了调查分析,并对HEV基因型、基因亚型的分布进行了分析研究。为了进一步探索HEV感染、致病以及不同基因型别HEV宿主差异的分子机制,我们应用酵母双杂交系统对人肝cDNA文库进行筛选,筛选了与HEV ORF3蛋白有相互作用的蛋白分子,并对不同基因型HEV ORF3蛋白与肝细胞蛋白的相互作用进行比较；通过对这些蛋白分子的生物学信息分析,对ORF3蛋白的功能及其对宿主细胞生物过程可能产生的影响进行了分析、推测。
1.HEV在我国家畜、家禽中流行情况的调查
从我国的27个省(市)共采集了猪、牛、羊、家兔、鸡和鸭血清6329份,应用EIA方法测定血清中HEV抗体和抗原。结果显示,猪、牛、羊和家兔的平均HEV抗体阳性率分别为82.2%、28.2%、10.4%和15.4%,猪HEV抗体阳性率明显高于牛、羊和家兔。鸡和鸭的抗体阳性率分别为3.58%和7.1%,二者都明显低于猪、牛羊和家兔。来源于不同省份的动物HEV抗体的阳性率有明显差异,猪、牛、羊和家兔HEV抗体阳性率范围分别为10.9%-100%、0～92.9%、0～48%和0-53.4%。大约1.9%的猪、0.8%的牛、1.6%的羊以及3.8%的兔血清样本为HEV抗原阳性。鸡和鸭的抗原阳性率分别为1.79%和1.43%。
应用Nested RT-PCR在15份猪血清和22份不同品种的家兔的血清中检测到了HEV RNA,而牛、羊、鸡和鸭血清中未检测到HEV RNA。通过对ORF2区域304bp长的核苷酸序列进行比对和进化树分析,15株猪HEV均属于基因4型。在进化树上,这15株4型HEV被分在不同的四组,分别为4a、4d及两个新的亚型。综合分析表明,我国猪群中流行的HEV主要为基因4型HEV,包括4a,4b,4d,4f,4g以及本研究新发现的两个亚型。从家兔中分离到的22株HEV均属于兔HEV,在进化树上,兔HEV又进一步分成了3组,很可能代表三个基因亚型。
本研究表明HEV在我国家畜、家禽中普遍流行,猪HEV感染率最高,我国流行的猪HEV主要为基因4型,包括4a,4b,4d,4f,4g以及两个新亚型。证实了兔HEV在我国不同地区不同品种的家兔中均有流行,支持兔HEV属于一个新基因型的观点。牛、羊、鸡和鸭血清样本中都检测到了HEV抗原,但未能检测出HEVRNA,仍需进一步研究。
2. HEV ORF3蛋白与肝细胞蛋白相互作用的研究
本研究以基因1型和4型HEV ORF3蛋白为诱饵,通过酵母配对杂交实验对人肝cDNA文库进行筛选,筛选结果应用酵母杂交共转化实验进行验证。经过三次实验,筛选出了32种与ORF3蛋白有相互作用的肝细胞蛋白。其中4种蛋白(4/32,12.5%)已经有报告能够与ORF3蛋白结合。进一步应用哺乳动物细胞内化学发光免疫共沉淀实验对酵母杂交实验的筛选结果的可靠性进行评估,显示筛选结果的可信度比较高。
生物信息学分析发现这32种相互作用蛋白在细胞核、细胞质、细胞膜、细胞外基质、以及线粒体、内涵体膜中均有分布,大多数蛋白定位于细胞的多个部位。这些蛋白分别参与细胞代谢、细胞免疫、细胞黏附等多个生物学过程。因此推测ORF3蛋白可能通过与这些蛋白相互作用,发挥多重作用。通过对蛋白功能富集聚类分析,发现分别有显著多数量的相互作用蛋白参与血液凝固、氧化应激和铁代谢过程。结合戊型肝炎临床表现和肝组织的病理特征进行分析,推测ORF3可能通过与宿主细胞蛋白的相互作用,影响凝血、脂质代谢以及铁代谢,而引发相应的病理过程。
通过酵母杂交共转化实验分别检测基因1型HEV、4型HEV、兔HEV以及禽HEV ORF3蛋白与以基因4型和1型HEV ORF3为诱饵筛选到的这32种人肝细胞蛋白是否有相互作用。结果显示,基因1型、4型和兔HEV的ORF3蛋白都能够与这些蛋白结合,然而禽HEV的ORF3蛋白只与其中的13种蛋白有相互作用。因此,禽HEV对人肝细胞的影响作用可能不同于哺乳动物HEV,这种蛋白相互作用的差别是否与禽HEV与哺乳动物HEV宿主范围等的差别有关联,还需要进一步研究。
这些发现为我们进一步研究ORF3蛋白的致病作用,以及研究HEV感染、复制和宿主限制性的分子机制提供了线索和方向。
Hepatitis E virus (HEV), the causative agent of hepatitis E, is an important public health concern in many countries. Accumulating evidences indicate that hepatitis E is a zoonotic disease, which means that the HEV virus exists in natural animal reservoirs. HEV infection is known to be endemic in China. Increasing reports of sporadic hepatitis E cases are likely related to animal origins. Fully understanding the molecular prevalence of HEV in animals is significant important for the control and prevention of hepatitis E. In this study, we collected animal serum samples from different provinces across the country. The prevalence and the genomic diversity of HEV in these animals were investigated and evaluated. To further investigate the molecular mechanism of host range restriction of different HEV genotypes and the pathogenesis of HEV, yeast two-hybrid system was used to screen a human liver cDNA library for identifying proteins interacting with HEV-ORF3. The molecular functions of ORF3 were analyzed and predicted through bioinformatics analysis of the interacting host proteins.
1. The prevalence of and genomic diversity of HEV in domestic animals
A total of 6,329 domestic animal sera were collected from 27 provinces and detected for HEV-specific antibodies and antigens by enzyme immunoassays. The average antibody positive rates were 82.2%,28.2%,10.4% and 15.4% in pigs, cattle, goats and rabbits respectively. The positive rate of pigs was statistically higher than those of other animal species.3.58% and 7.1% chicken and ducks were also found to be anti-HEV positive although the positive rates of both of these two animals were significantly lower than those of mammalian animals. The prevalence of anti-HEV antibody in animals varied from province to province, ranging from 10.9% to 100% in pigs,0 to 48% in goats and 0 to 92.9% in cattle. The positive rates for HEV antigen were 1.9% in pigs,1.6% in goats,0.8% in cattle and 3.8% in rabbits tested in the study. HEV antigen positive rates of chicken and ducks were 1.79% and 1.43% respectively.
HEV RNA was detected in 15 swine and 22 rabbit samples of various breeds. Phylogenetic analysis of the 304-bp sequences within the viral ORF2 classified all of the 15 swine HEV isolates into HEV Genotype 4, which were further divided into four different subtypes,4a,4b, and two new subtypes. Thus far,4a,4b,4d,4f,4g and the two new subgenotypes were found to be circulating in pigs across the country. All the 22 isolates from rabbit sera were belonged to rabbit HEV-associated genotypes. The rabbit HEV strains were genetically heterogeneous entities, commonly divided into divergent genetic groups.
These results indicated that HEV is widely prevalent in domestic animals in China. The highest rate of HEV infection was found in pigs among the tested animals. Genotype 4 HEV as the most common swine HEV is highly diverse, including 4a,4b,4d,4f,4g and two new subgenotypes, which are prevalent in pigs in China. We first demonstrated that rabbit HEV with considerable genetic diversity are prevalent in various breeds of fanned rabbits in China. The view that rabbit HEV belongs to a new genotype was supported by the results of this study. Goats, cattle, chicken and ducks also may be infected with HEV and further studies are needed.
2. Analysis of HEV ORF3 protein and host protein interactions
Screenings for host proteins that interact with ORF3 protein derived from genotype 1 HEV W2 strain and genotype 4 W3 strian were performed by using yeast mating hybrid assays. Interactomes were further characterized by co-transforming the ORF3 bait plasmid with each of positive prey plasmids into competent yeast cells. Thirty two genes encoding proteins that interact with the HEV-ORF3 protein were identified. Four of them were reported previously to be the interacting partners of ORF3 protein. The rest of 28 proteins were new HEV-ORF3 binding partners identified in this study. The screening result was further evaluated by a chemiluminescent co-immunoprecipitation assay.
We proceeded to map these interactions onto an overall visualized interaction network that comprised a repertoire of connections potentially required for ORF3 protein linked up with the components of the host cellular networks. We then analyzed the biological information of these proteins and tried to understand the context of their connections with ORF3 protein in HEV pathogens. According to "GO DATABASE", the subcellular locations of the 32 proteins include extracellular space, extracellular parts, extracellular region, membrane fraction, mitochondrion, cytoplasmic part, etc. Most of the proteins have multiple locations. These proteins involved in the biological processes of apoptosis, cell adhesion, cell communication, immune system process, ect,. Thus, ORF3 protein may function in multiple ways via interacting with these proteins. The analysis of the interaction network revealed an enrichment of canonical pathways (p<0.05) encompassing blood coagulation, oxidative stress, cellular iron ion homeostasis. Considering the clinical manifestations of hepatitis E and the biological analysis results may suggested that ORF3 likely affect these biological pathways by direct interacting with hub proteins and then trigger the corresponding pathological processes.
Tested by yeast two hybrid co-transformation, the binding capacities of ORF3 proteins from 1,3 and rabbit HEV with the 32 host proteins has no significant difference. In comparison, only 13 of the 32 human liver proteins preyed by genotype 1 ORF3 protein were found to interact with the ORF3 protein of avian HEV. Whether the host ranges variation among avian HEV and mammalian HEVs is related to the difference of ORF3 interacting capacity with host proteins is needed further investigation.
This is the first report to predict the physiological function of the ORF3 protein. The results provide us a critical clue to further study the HEV pathogenesis.
1.HEV在我国家畜、家禽中流行情况的调查
从我国的27个省(市)共采集了猪、牛、羊、家兔、鸡和鸭血清6329份,应用EIA方法测定血清中HEV抗体和抗原。结果显示,猪、牛、羊和家兔的平均HEV抗体阳性率分别为82.2%、28.2%、10.4%和15.4%,猪HEV抗体阳性率明显高于牛、羊和家兔。鸡和鸭的抗体阳性率分别为3.58%和7.1%,二者都明显低于猪、牛羊和家兔。来源于不同省份的动物HEV抗体的阳性率有明显差异,猪、牛、羊和家兔HEV抗体阳性率范围分别为10.9%-100%、0～92.9%、0～48%和0-53.4%。大约1.9%的猪、0.8%的牛、1.6%的羊以及3.8%的兔血清样本为HEV抗原阳性。鸡和鸭的抗原阳性率分别为1.79%和1.43%。
应用Nested RT-PCR在15份猪血清和22份不同品种的家兔的血清中检测到了HEV RNA,而牛、羊、鸡和鸭血清中未检测到HEV RNA。通过对ORF2区域304bp长的核苷酸序列进行比对和进化树分析,15株猪HEV均属于基因4型。在进化树上,这15株4型HEV被分在不同的四组,分别为4a、4d及两个新的亚型。综合分析表明,我国猪群中流行的HEV主要为基因4型HEV,包括4a,4b,4d,4f,4g以及本研究新发现的两个亚型。从家兔中分离到的22株HEV均属于兔HEV,在进化树上,兔HEV又进一步分成了3组,很可能代表三个基因亚型。
本研究表明HEV在我国家畜、家禽中普遍流行,猪HEV感染率最高,我国流行的猪HEV主要为基因4型,包括4a,4b,4d,4f,4g以及两个新亚型。证实了兔HEV在我国不同地区不同品种的家兔中均有流行,支持兔HEV属于一个新基因型的观点。牛、羊、鸡和鸭血清样本中都检测到了HEV抗原,但未能检测出HEVRNA,仍需进一步研究。
2. HEV ORF3蛋白与肝细胞蛋白相互作用的研究
本研究以基因1型和4型HEV ORF3蛋白为诱饵,通过酵母配对杂交实验对人肝cDNA文库进行筛选,筛选结果应用酵母杂交共转化实验进行验证。经过三次实验,筛选出了32种与ORF3蛋白有相互作用的肝细胞蛋白。其中4种蛋白(4/32,12.5%)已经有报告能够与ORF3蛋白结合。进一步应用哺乳动物细胞内化学发光免疫共沉淀实验对酵母杂交实验的筛选结果的可靠性进行评估,显示筛选结果的可信度比较高。
生物信息学分析发现这32种相互作用蛋白在细胞核、细胞质、细胞膜、细胞外基质、以及线粒体、内涵体膜中均有分布,大多数蛋白定位于细胞的多个部位。这些蛋白分别参与细胞代谢、细胞免疫、细胞黏附等多个生物学过程。因此推测ORF3蛋白可能通过与这些蛋白相互作用,发挥多重作用。通过对蛋白功能富集聚类分析,发现分别有显著多数量的相互作用蛋白参与血液凝固、氧化应激和铁代谢过程。结合戊型肝炎临床表现和肝组织的病理特征进行分析,推测ORF3可能通过与宿主细胞蛋白的相互作用,影响凝血、脂质代谢以及铁代谢,而引发相应的病理过程。
通过酵母杂交共转化实验分别检测基因1型HEV、4型HEV、兔HEV以及禽HEV ORF3蛋白与以基因4型和1型HEV ORF3为诱饵筛选到的这32种人肝细胞蛋白是否有相互作用。结果显示,基因1型、4型和兔HEV的ORF3蛋白都能够与这些蛋白结合,然而禽HEV的ORF3蛋白只与其中的13种蛋白有相互作用。因此,禽HEV对人肝细胞的影响作用可能不同于哺乳动物HEV,这种蛋白相互作用的差别是否与禽HEV与哺乳动物HEV宿主范围等的差别有关联,还需要进一步研究。
这些发现为我们进一步研究ORF3蛋白的致病作用,以及研究HEV感染、复制和宿主限制性的分子机制提供了线索和方向。
Hepatitis E virus (HEV), the causative agent of hepatitis E, is an important public health concern in many countries. Accumulating evidences indicate that hepatitis E is a zoonotic disease, which means that the HEV virus exists in natural animal reservoirs. HEV infection is known to be endemic in China. Increasing reports of sporadic hepatitis E cases are likely related to animal origins. Fully understanding the molecular prevalence of HEV in animals is significant important for the control and prevention of hepatitis E. In this study, we collected animal serum samples from different provinces across the country. The prevalence and the genomic diversity of HEV in these animals were investigated and evaluated. To further investigate the molecular mechanism of host range restriction of different HEV genotypes and the pathogenesis of HEV, yeast two-hybrid system was used to screen a human liver cDNA library for identifying proteins interacting with HEV-ORF3. The molecular functions of ORF3 were analyzed and predicted through bioinformatics analysis of the interacting host proteins.
1. The prevalence of and genomic diversity of HEV in domestic animals
A total of 6,329 domestic animal sera were collected from 27 provinces and detected for HEV-specific antibodies and antigens by enzyme immunoassays. The average antibody positive rates were 82.2%,28.2%,10.4% and 15.4% in pigs, cattle, goats and rabbits respectively. The positive rate of pigs was statistically higher than those of other animal species.3.58% and 7.1% chicken and ducks were also found to be anti-HEV positive although the positive rates of both of these two animals were significantly lower than those of mammalian animals. The prevalence of anti-HEV antibody in animals varied from province to province, ranging from 10.9% to 100% in pigs,0 to 48% in goats and 0 to 92.9% in cattle. The positive rates for HEV antigen were 1.9% in pigs,1.6% in goats,0.8% in cattle and 3.8% in rabbits tested in the study. HEV antigen positive rates of chicken and ducks were 1.79% and 1.43% respectively.
HEV RNA was detected in 15 swine and 22 rabbit samples of various breeds. Phylogenetic analysis of the 304-bp sequences within the viral ORF2 classified all of the 15 swine HEV isolates into HEV Genotype 4, which were further divided into four different subtypes,4a,4b, and two new subtypes. Thus far,4a,4b,4d,4f,4g and the two new subgenotypes were found to be circulating in pigs across the country. All the 22 isolates from rabbit sera were belonged to rabbit HEV-associated genotypes. The rabbit HEV strains were genetically heterogeneous entities, commonly divided into divergent genetic groups.
These results indicated that HEV is widely prevalent in domestic animals in China. The highest rate of HEV infection was found in pigs among the tested animals. Genotype 4 HEV as the most common swine HEV is highly diverse, including 4a,4b,4d,4f,4g and two new subgenotypes, which are prevalent in pigs in China. We first demonstrated that rabbit HEV with considerable genetic diversity are prevalent in various breeds of fanned rabbits in China. The view that rabbit HEV belongs to a new genotype was supported by the results of this study. Goats, cattle, chicken and ducks also may be infected with HEV and further studies are needed.
2. Analysis of HEV ORF3 protein and host protein interactions
Screenings for host proteins that interact with ORF3 protein derived from genotype 1 HEV W2 strain and genotype 4 W3 strian were performed by using yeast mating hybrid assays. Interactomes were further characterized by co-transforming the ORF3 bait plasmid with each of positive prey plasmids into competent yeast cells. Thirty two genes encoding proteins that interact with the HEV-ORF3 protein were identified. Four of them were reported previously to be the interacting partners of ORF3 protein. The rest of 28 proteins were new HEV-ORF3 binding partners identified in this study. The screening result was further evaluated by a chemiluminescent co-immunoprecipitation assay.
We proceeded to map these interactions onto an overall visualized interaction network that comprised a repertoire of connections potentially required for ORF3 protein linked up with the components of the host cellular networks. We then analyzed the biological information of these proteins and tried to understand the context of their connections with ORF3 protein in HEV pathogens. According to "GO DATABASE", the subcellular locations of the 32 proteins include extracellular space, extracellular parts, extracellular region, membrane fraction, mitochondrion, cytoplasmic part, etc. Most of the proteins have multiple locations. These proteins involved in the biological processes of apoptosis, cell adhesion, cell communication, immune system process, ect,. Thus, ORF3 protein may function in multiple ways via interacting with these proteins. The analysis of the interaction network revealed an enrichment of canonical pathways (p<0.05) encompassing blood coagulation, oxidative stress, cellular iron ion homeostasis. Considering the clinical manifestations of hepatitis E and the biological analysis results may suggested that ORF3 likely affect these biological pathways by direct interacting with hub proteins and then trigger the corresponding pathological processes.
Tested by yeast two hybrid co-transformation, the binding capacities of ORF3 proteins from 1,3 and rabbit HEV with the 32 host proteins has no significant difference. In comparison, only 13 of the 32 human liver proteins preyed by genotype 1 ORF3 protein were found to interact with the ORF3 protein of avian HEV. Whether the host ranges variation among avian HEV and mammalian HEVs is related to the difference of ORF3 interacting capacity with host proteins is needed further investigation.
This is the first report to predict the physiological function of the ORF3 protein. The results provide us a critical clue to further study the HEV pathogenesis.
引文
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