VP1蛋白影响鸡传染性法氏囊病毒致病性的分子机制
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摘要
鸡传染性法氏囊病（Infectious Bursal Disease，IBD）是由鸡传染性法囊病病毒（Infectious bursaldisease virus, IBDV）引起的一种急性、高度接触性传染病。IBD是危害世界养禽业最严重的疾病之一。除经典毒株外，具有致病性的血清I型毒株目前还包括弱毒株、抗原变异毒株和超强毒株（very virulent Infectious bursal disease virus, vvIBDV）。IBDV各型毒株致病性不尽相同，特别是1987年vvIBDV的出现给IBD的防控带来了新的挑战。vvIBDV的高致死率给养禽业造成了严重的损失。探索各型毒株致病性差异的分子基础及分子机制一直是IBDV研究的热点之一。IBDV基因功能及致病机制的早期研究主要聚焦在基因组A节段及其编码的VP2蛋白。近来的流行病学数据显示，基因组B节段及其编码的VP1蛋白与vvIBDV的爆发关系密切。本研究将进一步证实B节段及其编码的VP1蛋白与IBDV致病性增强的关系，定位其具体分子基础，并从病毒自身和宿主因子两个角度探讨其分子机制。
克隆获得HuB-1、HeB10XS02、SD10LY013株IBDV流行毒株的全基因组序列。遗传进化分析表明，IBDV VP1蛋白分为明显的3个亚群，即第I亚群（非超强毒）、第II亚群（中国新型vvIBDV）、第III亚群（经典vvIBDV）。HuB-1及SD10LY01VP1属于第III亚群，HeB10XS02的VP1则属于第II亚群。VP1氨基酸序列比对结果表明，I、II、III亚群之间共存在17个保守氨基酸差异位点。根据IBDV毒株的全基因组序列分析和致病性研究，筛选到VP1来源于不同亚群的代表病毒，即Gt（其VP1属于第I亚群）、HLJ0504（其VP1属于第II亚群）、HuB-1（其VP1属于第III亚群）。
分别将弱毒Gt、vvIBDV HuB-1的A节段与上述筛选的3个不同亚群代表病毒的B节段进行组合，共拯救6个重组病毒。研究结果表明，VP1蛋白影响IBDV的复制及致病性，第II、III亚群的VP1促进病毒在体内、外的复制，使IBDV的致病性增强，而第I亚群的VP1则降低病毒在体内、外的复制的能力，使IBDV的致病性减弱。
根据VP1的三维结构，将VP1划分为3个功能结构域，即N-端结构域、中心活性区（M段）和C-端结构域。以HuB-1毒株VP1的N端、M段、C端替换Gt株的相应区域，拯救获得3个细胞适应重组病毒；同时，以Gt株VP1的N端替换HuB-1株的相应区域，拯救获得1个细胞非适应重组病毒。致病性研究结果表明，VP1N端由强变弱，病毒体外复制能力降低，体内复制能力提高，病毒致病性明显降低。VP1N端（1-167aa）氨基酸序列比对结果表明，VP1N端145-147位氨基酸形成3个独特的三联体基序。不同亚群的B节段具有不同的三联体基序，I亚群为NEG、II亚群为TEG、III亚群为TDN。在此基础上，以弱毒Gt为骨架，将NEG分别替换为TEG或TDN，拯救了2个点突变病毒（rGtTEG，rGtTDN）；相应的，以vvIBDV HuB-1为骨架，将TDN分别替换为NDN、TEG或NEG，拯救了3个点突变病毒（rHuBNDN，rHuBTEG，rHuBNEG）。研究结果表明，由NEG替换为TEG或TDN，病毒体外复制能力降低，体内的复制能力增强，致病性增强；反之，则使其体外复制能力增强，体内复制能力降低，病毒致病性降低。聚合酶活性检测结果表明，VP1N端145-147位氨基酸影响VP1聚合酶活性，由NEG替换为TEG或TDN，聚合酶活性明显降低；反之，其聚合酶活性明显提高。VP1聚合酶活性的改变进而引起病毒复制能力的改变，是145-147位氨基酸影响病毒致病性的分子机制之一。
为了进一步探索影响VP1聚合酶活性的分子机制，本研究从病毒和宿主两个方面入手探寻影响其活性的因素。研究表明，IBDVVP3蛋白是VP1发挥聚合酶活性的必要因素，但VP3蛋白对病毒聚合酶活性的影响与VP1145-147位氨基酸影响聚合酶活性无正相关性。另一方面，通过酵母共转化实验、CO-IP、激光共聚焦实验证明宿主eIF4AII因子与VP1之间存在相互作用；该蛋白通过与VP1相互作用抑制其聚合酶的活性，进而限制IBDV的复制；进一步聚合酶活性检测表明，宿主eIF4AII因子能够抑制VP1野生型及突变型的聚合酶活性，但eIF4AII抑制聚合酶活性与VP1145-147位氨基酸影响聚合酶活性无正相关性。
综上，本研究证实：VP1蛋白是影响IBDV致病力的重要因素；VP1N端145-147位氨基酸是影响IBDV致病性的重要分子基础，其分子机制是通过改变VP1的聚合酶活性进而影响到病毒复制；病毒蛋白（VP3）和宿主因子（eIF4AII）均参与调控VP1的聚合酶活性的发挥，eIF4AII通过与IBDVVP1之间的相互作用而抑制VP1聚合酶活性，进而限制IBDV的复制，是宿主抵抗病毒感染的天然防御因子之一。
Infectious bursal disease (IBD) caused by infectious bursal disease virus (IBDV) is an acute and highlycontagious disease. IBD is one of the most economically significant diseases of chickens worldwide. Besidesthe classical virulent strains, the pathogenic serotype1viruses also include attenuated strains, antigenicvariant strains and very virulent IBDV (vvIBDV) strains. The emergence of vvIBDV causing severe andacute IBD with more than sixty percent mortality since1987brings new challenges for effective preventionand control of IBD. The exploration of the molecular determinants of vvIBDV virulence is an area of activeresearch. Some reports showed that segment A was not the sole factor that determines the virulence of IBDV.The segment A was not the major contributing factor in the emergence and expansion of vvIBDV. But thevvVP1played an important role in the initiation of vvIBDV expansion. This study further confirmed the VP1protein contributed to IBDV pathogenicity.
The complete genome sequences of HuB-1, HeB10XS02and SD10LY01were cloned and the furtheranalysis of the nucleotide and amino acid sequences showed that VP1of IBDVs were divided into threedistinct subgroups, subgroup I (non-vvIBDV), subgroup II (China vvIBDV) and subgroup III (typicalvvIBDV). The VP1proteins of HuB-1and SD10LY01belong to subgroup III and HeB10XS02belongs tosubgroup II. The alignment of VP1deduced amino acid sequences showed that a total of17conservativeamino acid changes were found among I, II and III subgroups. Gt, HLJ0504and HuB-1with different VP1sfrom different subsets were screened by analysis of the genome sequences.
Three recombinant cell-adapted viruses and three recombinant non-cell-adapted viruses were rescuedbased on the sequences of the attenuated IBDV Gt and vvIBDV HuB-1. The results showed that VP1ofIBDV contributed to its replication and virulence. The VP1proteins from subgroups II and III enhanced thevirulence of IBDV due to their positive effects on viral replication in vitro and in vivo. However, VP1fromsubgroup I reduced the virulence of IBDV due to its negative effects on viral replication in vitro and in vivo.
According to the three-dimensional structure of VP1, VP1is divided into N-terminal, the center of theactive activity and the C-terminal functional domains. Three recombinant cell-adapted viruses were rescuedby replacing N-terminal, central active domain and C-terminal of the B-segment of HuB-1(HuBB) with thecorresponding region of the B-segment of Gt (GtB). Meanwhile, a recombinant non-cell-adapted virus wasrescued by replacing N-terminal of GtB with the corresponding region of HuBB. The virulence of the viruswas enhanced by vvVP1N-domain due to its negative effects on viral replication in vitro but positive effectson viral replication in vivo. The results of VP1N-terminal (1-167aa) amino acid sequences alignment showedthat, the145-147amino acids formed three unique "triplet" motifs, and different subgroup had different motif.Subgroup I was "NEG", subgroup II was "TEG" and subgroup III was "TDN". On this basis, two site-mutantcell-adapted viruses (rGtTEG, rGtTDN) and three site-mutant non-cell-adapted viruses (rHuBNDN,rHuBTEG, and rHuBNEG) were rescued. The results showed that the replacement of "NEG" with "TEG" or"TDN" enhanced the virulence of Gt due to its increased ability to replicate in vivo and reduced ability toreplicate in vitro. On the other hand, the replacement of "TDN" with "TEG" or "NEG" reduced viralvirulence of HuB-1due to its reduced ability to replicate in vivo and enhanced ability to replicate in vitro. The results of the detection of polymerase activity indicated that the polymerase activity was significantlyreduced by replacing "NEG" with "TEG" or "TDN". Otherwise, the polymerase activity was significantlyincreased by replacing "TDN" with "NDN","TEG" or "NEG". One of molecular mechanism of145-147amino acids attributing to viral virulence was the polymerase activity changed that further hanged the viralreplication.
To further explore the molecular mechanism of VP1polymerase activity, the study was carried out fromvirus and host aspects. The results showed that VP3of IBDV was necessary for VP1polymerase activity.However, there was no positive relationship between the impact of VP3on the viral polymerase activity andthe different polymerase activity induced by VP1145-147amino acids mutation. On the other hand, the hostprotein eIF4AII was proved to interact with VP1by yeast co-transformation, CO-IP and confocal. Thepolymerase activity of VP1was inhibited by eIF4AII protein, inhibiting the viral replication of IBDV. Thehost protein eIF4AII inhibited the polymerase activity of wild-type VP1and its mutants by polymeraseactivity assay. However, there was no positive relationship between the inhibition of polymerase activityinduced by eIF4AII and the different polymerase activity induced by VP1145-147amino acids mutation.
In summary, VP1is an important factor of IBDV virulence. The amino acids145-147located at VP1Nterminus is the molecular basis of the enhance virulence of vvIBDV and the molecular mechanism is themutation of145-147amino acids changed the viral polymerase activity and further changed the viralreplication. The viral proteins (VP3) and host factors (eIF4AII) are involved in the regulation of VP1polymerase activity. The eIF4AII interacts with VP1, which inhibits its viral polymerase activity and reducedthe replication of IBDV. The eIF4AII was shown to be a natural host defense factor against viral infection.
克隆获得HuB-1、HeB10XS02、SD10LY013株IBDV流行毒株的全基因组序列。遗传进化分析表明，IBDV VP1蛋白分为明显的3个亚群，即第I亚群（非超强毒）、第II亚群（中国新型vvIBDV）、第III亚群（经典vvIBDV）。HuB-1及SD10LY01VP1属于第III亚群，HeB10XS02的VP1则属于第II亚群。VP1氨基酸序列比对结果表明，I、II、III亚群之间共存在17个保守氨基酸差异位点。根据IBDV毒株的全基因组序列分析和致病性研究，筛选到VP1来源于不同亚群的代表病毒，即Gt（其VP1属于第I亚群）、HLJ0504（其VP1属于第II亚群）、HuB-1（其VP1属于第III亚群）。
分别将弱毒Gt、vvIBDV HuB-1的A节段与上述筛选的3个不同亚群代表病毒的B节段进行组合，共拯救6个重组病毒。研究结果表明，VP1蛋白影响IBDV的复制及致病性，第II、III亚群的VP1促进病毒在体内、外的复制，使IBDV的致病性增强，而第I亚群的VP1则降低病毒在体内、外的复制的能力，使IBDV的致病性减弱。
根据VP1的三维结构，将VP1划分为3个功能结构域，即N-端结构域、中心活性区（M段）和C-端结构域。以HuB-1毒株VP1的N端、M段、C端替换Gt株的相应区域，拯救获得3个细胞适应重组病毒；同时，以Gt株VP1的N端替换HuB-1株的相应区域，拯救获得1个细胞非适应重组病毒。致病性研究结果表明，VP1N端由强变弱，病毒体外复制能力降低，体内复制能力提高，病毒致病性明显降低。VP1N端（1-167aa）氨基酸序列比对结果表明，VP1N端145-147位氨基酸形成3个独特的三联体基序。不同亚群的B节段具有不同的三联体基序，I亚群为NEG、II亚群为TEG、III亚群为TDN。在此基础上，以弱毒Gt为骨架，将NEG分别替换为TEG或TDN，拯救了2个点突变病毒（rGtTEG，rGtTDN）；相应的，以vvIBDV HuB-1为骨架，将TDN分别替换为NDN、TEG或NEG，拯救了3个点突变病毒（rHuBNDN，rHuBTEG，rHuBNEG）。研究结果表明，由NEG替换为TEG或TDN，病毒体外复制能力降低，体内的复制能力增强，致病性增强；反之，则使其体外复制能力增强，体内复制能力降低，病毒致病性降低。聚合酶活性检测结果表明，VP1N端145-147位氨基酸影响VP1聚合酶活性，由NEG替换为TEG或TDN，聚合酶活性明显降低；反之，其聚合酶活性明显提高。VP1聚合酶活性的改变进而引起病毒复制能力的改变，是145-147位氨基酸影响病毒致病性的分子机制之一。
为了进一步探索影响VP1聚合酶活性的分子机制，本研究从病毒和宿主两个方面入手探寻影响其活性的因素。研究表明，IBDVVP3蛋白是VP1发挥聚合酶活性的必要因素，但VP3蛋白对病毒聚合酶活性的影响与VP1145-147位氨基酸影响聚合酶活性无正相关性。另一方面，通过酵母共转化实验、CO-IP、激光共聚焦实验证明宿主eIF4AII因子与VP1之间存在相互作用；该蛋白通过与VP1相互作用抑制其聚合酶的活性，进而限制IBDV的复制；进一步聚合酶活性检测表明，宿主eIF4AII因子能够抑制VP1野生型及突变型的聚合酶活性，但eIF4AII抑制聚合酶活性与VP1145-147位氨基酸影响聚合酶活性无正相关性。
综上，本研究证实：VP1蛋白是影响IBDV致病力的重要因素；VP1N端145-147位氨基酸是影响IBDV致病性的重要分子基础，其分子机制是通过改变VP1的聚合酶活性进而影响到病毒复制；病毒蛋白（VP3）和宿主因子（eIF4AII）均参与调控VP1的聚合酶活性的发挥，eIF4AII通过与IBDVVP1之间的相互作用而抑制VP1聚合酶活性，进而限制IBDV的复制，是宿主抵抗病毒感染的天然防御因子之一。
Infectious bursal disease (IBD) caused by infectious bursal disease virus (IBDV) is an acute and highlycontagious disease. IBD is one of the most economically significant diseases of chickens worldwide. Besidesthe classical virulent strains, the pathogenic serotype1viruses also include attenuated strains, antigenicvariant strains and very virulent IBDV (vvIBDV) strains. The emergence of vvIBDV causing severe andacute IBD with more than sixty percent mortality since1987brings new challenges for effective preventionand control of IBD. The exploration of the molecular determinants of vvIBDV virulence is an area of activeresearch. Some reports showed that segment A was not the sole factor that determines the virulence of IBDV.The segment A was not the major contributing factor in the emergence and expansion of vvIBDV. But thevvVP1played an important role in the initiation of vvIBDV expansion. This study further confirmed the VP1protein contributed to IBDV pathogenicity.
The complete genome sequences of HuB-1, HeB10XS02and SD10LY01were cloned and the furtheranalysis of the nucleotide and amino acid sequences showed that VP1of IBDVs were divided into threedistinct subgroups, subgroup I (non-vvIBDV), subgroup II (China vvIBDV) and subgroup III (typicalvvIBDV). The VP1proteins of HuB-1and SD10LY01belong to subgroup III and HeB10XS02belongs tosubgroup II. The alignment of VP1deduced amino acid sequences showed that a total of17conservativeamino acid changes were found among I, II and III subgroups. Gt, HLJ0504and HuB-1with different VP1sfrom different subsets were screened by analysis of the genome sequences.
Three recombinant cell-adapted viruses and three recombinant non-cell-adapted viruses were rescuedbased on the sequences of the attenuated IBDV Gt and vvIBDV HuB-1. The results showed that VP1ofIBDV contributed to its replication and virulence. The VP1proteins from subgroups II and III enhanced thevirulence of IBDV due to their positive effects on viral replication in vitro and in vivo. However, VP1fromsubgroup I reduced the virulence of IBDV due to its negative effects on viral replication in vitro and in vivo.
According to the three-dimensional structure of VP1, VP1is divided into N-terminal, the center of theactive activity and the C-terminal functional domains. Three recombinant cell-adapted viruses were rescuedby replacing N-terminal, central active domain and C-terminal of the B-segment of HuB-1(HuBB) with thecorresponding region of the B-segment of Gt (GtB). Meanwhile, a recombinant non-cell-adapted virus wasrescued by replacing N-terminal of GtB with the corresponding region of HuBB. The virulence of the viruswas enhanced by vvVP1N-domain due to its negative effects on viral replication in vitro but positive effectson viral replication in vivo. The results of VP1N-terminal (1-167aa) amino acid sequences alignment showedthat, the145-147amino acids formed three unique "triplet" motifs, and different subgroup had different motif.Subgroup I was "NEG", subgroup II was "TEG" and subgroup III was "TDN". On this basis, two site-mutantcell-adapted viruses (rGtTEG, rGtTDN) and three site-mutant non-cell-adapted viruses (rHuBNDN,rHuBTEG, and rHuBNEG) were rescued. The results showed that the replacement of "NEG" with "TEG" or"TDN" enhanced the virulence of Gt due to its increased ability to replicate in vivo and reduced ability toreplicate in vitro. On the other hand, the replacement of "TDN" with "TEG" or "NEG" reduced viralvirulence of HuB-1due to its reduced ability to replicate in vivo and enhanced ability to replicate in vitro. The results of the detection of polymerase activity indicated that the polymerase activity was significantlyreduced by replacing "NEG" with "TEG" or "TDN". Otherwise, the polymerase activity was significantlyincreased by replacing "TDN" with "NDN","TEG" or "NEG". One of molecular mechanism of145-147amino acids attributing to viral virulence was the polymerase activity changed that further hanged the viralreplication.
To further explore the molecular mechanism of VP1polymerase activity, the study was carried out fromvirus and host aspects. The results showed that VP3of IBDV was necessary for VP1polymerase activity.However, there was no positive relationship between the impact of VP3on the viral polymerase activity andthe different polymerase activity induced by VP1145-147amino acids mutation. On the other hand, the hostprotein eIF4AII was proved to interact with VP1by yeast co-transformation, CO-IP and confocal. Thepolymerase activity of VP1was inhibited by eIF4AII protein, inhibiting the viral replication of IBDV. Thehost protein eIF4AII inhibited the polymerase activity of wild-type VP1and its mutants by polymeraseactivity assay. However, there was no positive relationship between the inhibition of polymerase activityinduced by eIF4AII and the different polymerase activity induced by VP1145-147amino acids mutation.
In summary, VP1is an important factor of IBDV virulence. The amino acids145-147located at VP1Nterminus is the molecular basis of the enhance virulence of vvIBDV and the molecular mechanism is themutation of145-147amino acids changed the viral polymerase activity and further changed the viralreplication. The viral proteins (VP3) and host factors (eIF4AII) are involved in the regulation of VP1polymerase activity. The eIF4AII interacts with VP1, which inhibits its viral polymerase activity and reducedthe replication of IBDV. The eIF4AII was shown to be a natural host defense factor against viral infection.
引文
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