猪肺免疫防御相关基因—肺表面活性蛋白A的研究
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摘要
猪呼吸系统疾病(PRD)已成为影响全球养猪业的头号疾病,肺免疫防御相关基因的研究和挖掘对于从遗传本质上提高猪对呼吸系统疾病的抗性具有重要意义。本文利用比较基因组学方法,以肺免疫防御相关基因-猪肺表面活性蛋白A(SP-A)作为猪呼吸系统免疫防御功能的候选基因,开展了猪肺表面活性蛋白A序列及其多态性、mRNA表达和蛋白质含量变化的系列研究,取得了以下结果:
①采用RT-PCR和RACE技术获得了长度为1 910 bp的猪SP-A完整cDNA序列,此序列包含了编码248个氨基酸的长为747 bp的完整开放阅读框。生物信息学分析发现,猪SP-A的N端有20个残基的信号肽,从N端到C端依次为4个结构域:短的N-端区、胶原样区域、茎区和碳水化合物识别区域。然后又用比较基因组学方法和引物步移法获得了长度为4 229 bp的猪SP-A DNA全序列,它由4个外显子和3个内含子组成。
②以同一时期饲养在相同条件下的引进品种大白猪361头、培育品种松辽黑猪132头为试验群1,采用PCR-SSCP技术检测到33个单核苷酸多态性(SNPs)位点,其中有5个SNPs位于外显子上,3个为同义突变,2个为错义突变;这2个错义突变位于猪SP-A的碳水化合物识别区域,分别造成了丙氨酸变异为苏氨酸、苯丙氨酸变异为酪氨酸。这些SNPs位点呈完全连锁不平衡状态,组成了Ⅰ、Ⅱ和Ⅲ三种单体型。经χ2检验表明,在大白猪试验群中,SP-A的基因频率和基因型频率都达到了Hardy-Weinberg平衡状态(P>0.05);但是在松辽黑猪试验群中,SP-A的基因频率和基因型频率都未达到Hardy-Weinberg平衡状态(P<0.01)。目前,两个品种猪的SP-A基因都处于中度多态。
在品种内,不同性别SP-A单体型频率分布差异不显著(P>0.05)。在大白猪中,SP-AⅡ单体型猪的PRD发病率最高,达33.67%,并且不同SP-A基因单体型大白猪PRD发病率差异极显著(P<0.01);在松辽黑猪中,也是SP-AⅡ单体型猪的PRD发病率最高,为10.53%,不同SP-A基因单体型松辽黑猪的PRD发病率差异显著(P<0.05);表明在大白猪和松辽黑猪中,单体型与PRD发病率之间存在一定的关联度。其中SP-A基因Ⅰ单体型为抗PRD单体型,推测以SP-AⅠ单体型猪具有较强的肺免疫防御功能。
③通过以0.05 ml/kg体重,少量分次,耳静脉注射油酸成功建立了猪油酸-急性肺损伤模型,为进一步开展有关猪肺损伤以及肺免疫防御相关研究奠定了基础。
④以包含SP-A基因Ⅰ、Ⅱ和Ⅲ单体型共54头仔猪建立试验群2,在仔猪断奶稳定后50±1日龄建立油酸-急性肺损伤模型。以肺含水量的变化作为反映肺损伤程度的指标,分别采用荧光定量PCR和western blot技术对肺组织中SP-A mRNA表达量和支气管-肺泡灌洗液(BALF)中SP-A蛋白含量进行检测与分析,发现:在1 h时相点伴随肺含水量的增加,SP-A mRNA表达量和SP-A蛋白含量均下降;在3 h时相点伴随肺含水量增加至最高(3个时相点中相比较),SP-A mRNA表达量和SP-A蛋白含量也降至三个时相点的最低水平;与1 h时相点相比较,在6 h时相点伴随肺含水量的下降,SP-A mRNA表达量和SP-A蛋白含量分别极显著上升(P<0.01)和显著上升(P<0.05)。另外,与Ⅱ和Ⅲ单体型相比较,各时相点SP-AⅠ单体型猪的肺含水量较对照组的升高幅度要小;BALF中SP-A蛋白含量较高,更接近于对照组水平;1 h和3 h时相点SP-AⅠ单体型猪肺组织中的SP-A mRNA表达量也较高,也更接近于对照组水平,并且在6 h时相点SP-AⅠ单体型猪的SP-A mRNA表达量显著高于Ⅱ和Ⅲ单体型。上述结果表明,肺组织中SP-A mRNA表达量、BALF中SP-A蛋白含量与肺含水量即肺损伤程度的变化趋势恰好相反;在同时受到病原致损伤的情况下,SP-AⅠ单体型猪的SP-A水平会在较短时间内恢复而有利于尽快缓解病原对肺的损伤,因此,推测SP-AⅠ单体型猪具有较高的应对病原损伤肺的能力。
以上结果表明,猪SP-A同人、小鼠等的SP-A一样,也具有肺免疫防御功能;不同SP-A单体型与PRD发病率之间存在一定关联性,其中又以SP-AⅠ单体型的猪具有较强的肺免疫防御能力,能够使外来因素对肺脏的损伤程度降至最低,损伤时间降至最短,因而也降低了猪只由于长时间处于致病原损伤状态下而引起继发感染的可能,具有较低的PRD发病率。
本研究结果首次较全面地揭示了猪SP-A的肺免疫防御功能,同时也为判断发生PRD时猪只肺损伤的程度,为PRD的临床诊断以及防治PRD新型药物的研发和选择肺免疫防御功能强的种猪个体奠定了一定的理论依据。
Porcine Respiratory Disease (PRD) is regarded as the first disease which affects the global porcine production. It’s important to study and excavate on pulmonary immune defence related genes, which will improve the porcine ability of anti-PRD in heredity. Pulmonary immune defence related gene- porcine Surfactant Protein A (SP-A) was taken as the candidate gene which had immune defence function in porcine respiratory system in this research. These main results were as follows:
①Full length cDNA of porcine SP-A was isolated by combination with RT-PCR and RACE, and the complete cDNA sequence was 1 910 bp including a 747 bp open reading frame (ORF) encoding a 248-amino-acid protein. It was found the porcine SP-A had a signal peptide in the N-terminal segment which was composition of 20 amino acids residues, and had four structural domains: a short N-terminal segment, a collagen-like region (CLR), a neck region, and a C-terminal carbohydrate recognition domain (CRD) by bioinformatics. Then the full-length DNA sequences of porcine SP-A was obtained by comparative genomics and primer walking. The results showed SP-A gene spanned about 4 229 bp which composed of 4 exons and 3 introns.
②The experiment group 1 was composition of 361 Large White pigs (LW) and 132 Songliao Black pigs (SB) which were reared in the same conditions and period. Thirty-three single nucleotide polymorphisms (SNPs) were found by PCR-SSCP. There were five SNPs in exon, three of them were same-sense mutation, and two of them were missense mutation resulted in alanine changed to threonine, and phenylalanine changed to tyrosine. The results showed that the SNPs which we found in LW and SB were whole linkage disequilibrium, and there wasⅠhaplotype,Ⅱhaplotype andⅢhaplotype. A chi-square analysis suggested that the allele frequencies and genotype frequencies of SP-A were in Hardy-Weinberg equilibrium (P>0.05) in LW, but were in disequilibrium (P<0.01) in SB. And the SP-A gene had intermediate polymorphism in LW and SB.
The frequencies of the SP-A haplotypes in different sex were not statistiatics difference (P>0.05) in LW and SB. The pigs of SP-AⅡhaplotype had the highest incidence of PRD which was 33.67%, and there was exceeding significant difference between incidence of PRD and different haplotypes (P<0.01) in LW. The pigs of SP-AⅡhaplotype had the highest incidence of PRD which was 10.53%, and there was significant difference between the incidence of PRD and different haplotypes (P<0.05) in SB. It indicated there was a certain association extent between haplotype and the incidence of PRD. And the SP-AⅠhaplotype was anti-PRD haplotype. It’s predicted the pigs of SP-AⅠhaplotype had higher pulmonary immune defence function.
③It was successful to establish the model of acute lung injure (ALI) in pigs via intravenous injection of 0.05 ml/kg avoirdupois oleic acid (OA) by a few each time and more times. It contributes to the further study on ALI and innate immune of the lung.
④The experiment group 2 was composition of 54 pigs which containedⅠ,ⅡandⅢhaplotypes. They were established the model of OA-ALI in 50±1 day-old, and the level of lung water content was taken as marker of the degree of lung injury. The SP-A mRNA expression quantity in lung tissue and the SP-A content in BALF were determined with FQ-PCR and western blot method, respectively. The results showed: with the lung water content increasing, the SP-A mRNA expression quantity and the SP-A content decreased at 1h time point. Comparing to the 1h, 3h and 6h, the lung water content increased to the highest, and the SP-A mRNA expression quantity and the SP-A content decreased to the lowest at 3h time point. Comparing to the 1h time point, the lung water content decreased, the SP-A mRNA expression quantity exceeding significant increased (P<0.01), and the SP-A content significant increased (P<0.05) at 6h time point. Moreover, comparing to theⅡandⅢhaplotype, the lung water content of SP-AⅠhaplotype heightened smallest, the SP-A content of SP-AⅠhaplotype was higher, and was closed to the control group; at 1h and 3h time point, SP-A mRNA expression quantity of SP-AⅠhaplotype was also higher, and was also closed to the control group, and at 6h time point, mRNA expression quantity of SP-AⅠhaplotype was higher thanⅡandⅢhaplotype significantly. These results indicated: the SP-A mRNA expression quantity in lung tissue and the SP-A content in BALF had the reverse trend with the level of lung water content, and the same with the degree of lung injury. In the condition of the same etiological agent damage, pigs of SP-AⅠhaplotype could recover SP-A of pigs with SP-AⅠhaplotype in shorter time, which was profit to relieving etiological agent damage to the lung as soon as possible。So, it’s predicted pigs with SP-AⅠhaplotype had higher ability to coping etiological agent damage.
The above findings indicated, the same to human and mouse, porcine SP-A also had function of pulmonary immune defence. There were association between haplotypes and the incidence of PRD. The pigs of SP-AⅠhaplotype had higer ability of pulmonary immune defence, which could make the degree and time of injury by etiological agent the lowest, and made the possibility of secondary infection decrease, so the incidence of PRD was lower in pigs of SP-AⅠhaplotype.
Results of this study revealed the function of pulmonary immune defence of porcine SP-A in all-around for first time. Furthermore, this work contributes to judgement the degree of lung injury during the PRD, and clinical diagnosis of PRD and exploitation of newtype medicine of prevention and cure PRD, and selection the pigs which had higher pulmonary immune defence.
①采用RT-PCR和RACE技术获得了长度为1 910 bp的猪SP-A完整cDNA序列,此序列包含了编码248个氨基酸的长为747 bp的完整开放阅读框。生物信息学分析发现,猪SP-A的N端有20个残基的信号肽,从N端到C端依次为4个结构域:短的N-端区、胶原样区域、茎区和碳水化合物识别区域。然后又用比较基因组学方法和引物步移法获得了长度为4 229 bp的猪SP-A DNA全序列,它由4个外显子和3个内含子组成。
②以同一时期饲养在相同条件下的引进品种大白猪361头、培育品种松辽黑猪132头为试验群1,采用PCR-SSCP技术检测到33个单核苷酸多态性(SNPs)位点,其中有5个SNPs位于外显子上,3个为同义突变,2个为错义突变;这2个错义突变位于猪SP-A的碳水化合物识别区域,分别造成了丙氨酸变异为苏氨酸、苯丙氨酸变异为酪氨酸。这些SNPs位点呈完全连锁不平衡状态,组成了Ⅰ、Ⅱ和Ⅲ三种单体型。经χ2检验表明,在大白猪试验群中,SP-A的基因频率和基因型频率都达到了Hardy-Weinberg平衡状态(P>0.05);但是在松辽黑猪试验群中,SP-A的基因频率和基因型频率都未达到Hardy-Weinberg平衡状态(P<0.01)。目前,两个品种猪的SP-A基因都处于中度多态。
在品种内,不同性别SP-A单体型频率分布差异不显著(P>0.05)。在大白猪中,SP-AⅡ单体型猪的PRD发病率最高,达33.67%,并且不同SP-A基因单体型大白猪PRD发病率差异极显著(P<0.01);在松辽黑猪中,也是SP-AⅡ单体型猪的PRD发病率最高,为10.53%,不同SP-A基因单体型松辽黑猪的PRD发病率差异显著(P<0.05);表明在大白猪和松辽黑猪中,单体型与PRD发病率之间存在一定的关联度。其中SP-A基因Ⅰ单体型为抗PRD单体型,推测以SP-AⅠ单体型猪具有较强的肺免疫防御功能。
③通过以0.05 ml/kg体重,少量分次,耳静脉注射油酸成功建立了猪油酸-急性肺损伤模型,为进一步开展有关猪肺损伤以及肺免疫防御相关研究奠定了基础。
④以包含SP-A基因Ⅰ、Ⅱ和Ⅲ单体型共54头仔猪建立试验群2,在仔猪断奶稳定后50±1日龄建立油酸-急性肺损伤模型。以肺含水量的变化作为反映肺损伤程度的指标,分别采用荧光定量PCR和western blot技术对肺组织中SP-A mRNA表达量和支气管-肺泡灌洗液(BALF)中SP-A蛋白含量进行检测与分析,发现:在1 h时相点伴随肺含水量的增加,SP-A mRNA表达量和SP-A蛋白含量均下降;在3 h时相点伴随肺含水量增加至最高(3个时相点中相比较),SP-A mRNA表达量和SP-A蛋白含量也降至三个时相点的最低水平;与1 h时相点相比较,在6 h时相点伴随肺含水量的下降,SP-A mRNA表达量和SP-A蛋白含量分别极显著上升(P<0.01)和显著上升(P<0.05)。另外,与Ⅱ和Ⅲ单体型相比较,各时相点SP-AⅠ单体型猪的肺含水量较对照组的升高幅度要小;BALF中SP-A蛋白含量较高,更接近于对照组水平;1 h和3 h时相点SP-AⅠ单体型猪肺组织中的SP-A mRNA表达量也较高,也更接近于对照组水平,并且在6 h时相点SP-AⅠ单体型猪的SP-A mRNA表达量显著高于Ⅱ和Ⅲ单体型。上述结果表明,肺组织中SP-A mRNA表达量、BALF中SP-A蛋白含量与肺含水量即肺损伤程度的变化趋势恰好相反;在同时受到病原致损伤的情况下,SP-AⅠ单体型猪的SP-A水平会在较短时间内恢复而有利于尽快缓解病原对肺的损伤,因此,推测SP-AⅠ单体型猪具有较高的应对病原损伤肺的能力。
以上结果表明,猪SP-A同人、小鼠等的SP-A一样,也具有肺免疫防御功能;不同SP-A单体型与PRD发病率之间存在一定关联性,其中又以SP-AⅠ单体型的猪具有较强的肺免疫防御能力,能够使外来因素对肺脏的损伤程度降至最低,损伤时间降至最短,因而也降低了猪只由于长时间处于致病原损伤状态下而引起继发感染的可能,具有较低的PRD发病率。
本研究结果首次较全面地揭示了猪SP-A的肺免疫防御功能,同时也为判断发生PRD时猪只肺损伤的程度,为PRD的临床诊断以及防治PRD新型药物的研发和选择肺免疫防御功能强的种猪个体奠定了一定的理论依据。
Porcine Respiratory Disease (PRD) is regarded as the first disease which affects the global porcine production. It’s important to study and excavate on pulmonary immune defence related genes, which will improve the porcine ability of anti-PRD in heredity. Pulmonary immune defence related gene- porcine Surfactant Protein A (SP-A) was taken as the candidate gene which had immune defence function in porcine respiratory system in this research. These main results were as follows:
①Full length cDNA of porcine SP-A was isolated by combination with RT-PCR and RACE, and the complete cDNA sequence was 1 910 bp including a 747 bp open reading frame (ORF) encoding a 248-amino-acid protein. It was found the porcine SP-A had a signal peptide in the N-terminal segment which was composition of 20 amino acids residues, and had four structural domains: a short N-terminal segment, a collagen-like region (CLR), a neck region, and a C-terminal carbohydrate recognition domain (CRD) by bioinformatics. Then the full-length DNA sequences of porcine SP-A was obtained by comparative genomics and primer walking. The results showed SP-A gene spanned about 4 229 bp which composed of 4 exons and 3 introns.
②The experiment group 1 was composition of 361 Large White pigs (LW) and 132 Songliao Black pigs (SB) which were reared in the same conditions and period. Thirty-three single nucleotide polymorphisms (SNPs) were found by PCR-SSCP. There were five SNPs in exon, three of them were same-sense mutation, and two of them were missense mutation resulted in alanine changed to threonine, and phenylalanine changed to tyrosine. The results showed that the SNPs which we found in LW and SB were whole linkage disequilibrium, and there wasⅠhaplotype,Ⅱhaplotype andⅢhaplotype. A chi-square analysis suggested that the allele frequencies and genotype frequencies of SP-A were in Hardy-Weinberg equilibrium (P>0.05) in LW, but were in disequilibrium (P<0.01) in SB. And the SP-A gene had intermediate polymorphism in LW and SB.
The frequencies of the SP-A haplotypes in different sex were not statistiatics difference (P>0.05) in LW and SB. The pigs of SP-AⅡhaplotype had the highest incidence of PRD which was 33.67%, and there was exceeding significant difference between incidence of PRD and different haplotypes (P<0.01) in LW. The pigs of SP-AⅡhaplotype had the highest incidence of PRD which was 10.53%, and there was significant difference between the incidence of PRD and different haplotypes (P<0.05) in SB. It indicated there was a certain association extent between haplotype and the incidence of PRD. And the SP-AⅠhaplotype was anti-PRD haplotype. It’s predicted the pigs of SP-AⅠhaplotype had higher pulmonary immune defence function.
③It was successful to establish the model of acute lung injure (ALI) in pigs via intravenous injection of 0.05 ml/kg avoirdupois oleic acid (OA) by a few each time and more times. It contributes to the further study on ALI and innate immune of the lung.
④The experiment group 2 was composition of 54 pigs which containedⅠ,ⅡandⅢhaplotypes. They were established the model of OA-ALI in 50±1 day-old, and the level of lung water content was taken as marker of the degree of lung injury. The SP-A mRNA expression quantity in lung tissue and the SP-A content in BALF were determined with FQ-PCR and western blot method, respectively. The results showed: with the lung water content increasing, the SP-A mRNA expression quantity and the SP-A content decreased at 1h time point. Comparing to the 1h, 3h and 6h, the lung water content increased to the highest, and the SP-A mRNA expression quantity and the SP-A content decreased to the lowest at 3h time point. Comparing to the 1h time point, the lung water content decreased, the SP-A mRNA expression quantity exceeding significant increased (P<0.01), and the SP-A content significant increased (P<0.05) at 6h time point. Moreover, comparing to theⅡandⅢhaplotype, the lung water content of SP-AⅠhaplotype heightened smallest, the SP-A content of SP-AⅠhaplotype was higher, and was closed to the control group; at 1h and 3h time point, SP-A mRNA expression quantity of SP-AⅠhaplotype was also higher, and was also closed to the control group, and at 6h time point, mRNA expression quantity of SP-AⅠhaplotype was higher thanⅡandⅢhaplotype significantly. These results indicated: the SP-A mRNA expression quantity in lung tissue and the SP-A content in BALF had the reverse trend with the level of lung water content, and the same with the degree of lung injury. In the condition of the same etiological agent damage, pigs of SP-AⅠhaplotype could recover SP-A of pigs with SP-AⅠhaplotype in shorter time, which was profit to relieving etiological agent damage to the lung as soon as possible。So, it’s predicted pigs with SP-AⅠhaplotype had higher ability to coping etiological agent damage.
The above findings indicated, the same to human and mouse, porcine SP-A also had function of pulmonary immune defence. There were association between haplotypes and the incidence of PRD. The pigs of SP-AⅠhaplotype had higer ability of pulmonary immune defence, which could make the degree and time of injury by etiological agent the lowest, and made the possibility of secondary infection decrease, so the incidence of PRD was lower in pigs of SP-AⅠhaplotype.
Results of this study revealed the function of pulmonary immune defence of porcine SP-A in all-around for first time. Furthermore, this work contributes to judgement the degree of lung injury during the PRD, and clinical diagnosis of PRD and exploitation of newtype medicine of prevention and cure PRD, and selection the pigs which had higher pulmonary immune defence.
引文
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