H1N2、H3N2及H5N1亚型猪流感病毒进化及致病性研究
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摘要
猪流感是引起猪的高度接触性病毒病,对感染畜群造成巨大的经济损失,并具有重要的公共卫生意义。猪流感病原主要包括H1N1,H1N2,H3N2等亚型A型流感病毒。猪作为流感病毒的中间宿主,具有混合器作用,人、禽流感病毒可以在其体内重组产生新病毒。开展猪流感流行病学检测及致病分离株的演化规律具有重要意义。
本研究先后在上海、河南、山东、湖北、江苏、广东等省市采集猪鼻拭子5886份和血清5788份。血清样品检测结果如下:H1阳性率40%(2323份),H3阳性率90%(5240份),H5阳性率0.086%(5份),H9阳性率0.138%(8份)。猪鼻拭子样品同时接种MDCK和SPF鸡胚进行病毒分离,共分离到4株H1N2,6株H3N2和1株H5N1流感病毒。结果表明当前我国不同地区猪群中普遍存在H1和H3亚型猪流感流行。
为了解我国猪流感病毒分子进化变异情况,本研究挑选H1N2代表毒株Swine/Guangdong/1/2006 (SwGD1/06)和H3N2代表毒株Swine/Guangdong/1/2006(SwGD1/05)进行基因组测定分析。结果表明SwGD1/06(H1N2)可能来源于北美猪群中流行的H1N2亚型猪流感病毒;而SwGD1/05(H3N2)可能能来源于在北美人群中流行的H3N2亚型流感病毒。分别用106 EID50剂量H1N2和H3N2分离病毒对H1、H3、H5、H9抗体皆为阴性的35日龄仔猪进行感染实验,结果是感染后第1、3、5、7d能从猪鼻拭子中重新分离到H1N2和H3N2病毒,其中第3d病毒含量最高;其它脏器没有分离到病毒。临床症状轻微,没有猪只死亡。结果表明单纯H1N2或H3N2流感病毒能在不引起临床症状的情况下感染易感猪只,这说明我国流行的H1和H3流感病毒对猪致病性不强。
为阐明H5N1亚型猪流感病毒跨种传播遗传基础,本研究筛选遗传关系相近(整个基因组只有23个氨基酸差异),对小鼠感染能力完全不同的的两株H5N1亚型流感病毒为模型病毒:DK/ZJ/52/00(DK52),对小鼠完全不感染;Swine/Fujian/1/04(FJ1),对小鼠有致病性且引起小鼠死亡。建立了FJ1和DK52的反向遗传操作系统,分别以FJ1和DK52为背景,利用反向遗传技术在293T细胞上救获单基因替换重组的16个病毒。这些病毒分别以106EID50剂量鼻腔感染小鼠,结果发现:DK52的PA和M基因分别替换FJ1相应基因,使RFJ1在小鼠肺脏感染能力降低103.21倍(病毒滴度(LgEID50)由原来的4.71变为1.5);反之FJ1的PA和M基因分别替换DK52的相应基因,使RDK52的致病性由不感染变为感染(肺脏病毒滴定结果为LgEID50,1.5)。其它单基因替换重组病毒没有改变这两株病毒对小鼠感染能力。结果表明M和PA基因影响FJ1和DK52在小鼠肺脏中的复制能力。
为进一步确定PA和M基因如何影响对FJ1和DK52对小鼠感染能力,我们把M和PA两个基因同时替换,发现以DK52的PA和M替换FJ1的PA和M基因后,使RFJ1/DK52PA+M不能在小鼠肺脏中复制;反之,以FJ1的PA和M替换DK52的PA和M基因后,导致RDK52/FJ1PA+M能感染小鼠并在肺脏中复制,病毒滴度达到2.5LgEID50。结果表明M和PA基因协同作用影响FJ1和DK52对小鼠感染能力。
在此基础上,我们分析FJ1和DK52两株病毒的PA和M基因氨基酸,发现PA(54、330,384,459)和M2(26)基因分别有4个和1个位点氨基酸不同。为进一步确定PA和M2的哪一个位点氨基酸对小鼠感染能力起作用,分别对PA和M2的两个位点进行点突变,利用反向遗传操作系统救获4个点突变病毒。突变病毒对小鼠感染结果发现:PAI54V(54位由I变为V)可使RFJ1在小鼠肺脏中复制能力降低103。21倍(LgEID50由原来的4.71变为1.5),反之,PAV54I(54位由V变为I)可使RDK52对小鼠由不感染变为感染(肺脏病毒滴定结果为LgEID50,1.5);同样,M2S26L(26位由S变为L)可以使FJ1感染小鼠能力降低103。21倍(LgEID50由原来的4.71变为1.5),反之M2L26S(26位由L变为S)可以可使RDK52对小鼠由不感染变为感染(肺脏病毒滴定结果为LgEID50,1.5)。但是PA的330,384,459位氨基酸的改变没有影响病毒致病性。结果表明PA基因的54位和M2基因的26位氨基酸协同作用影响FJ1和DK52对小鼠感染能力。
本研究系统研究了中国部分地区猪流感病毒流行的亚型和生物学特性,结果表明:中国目前猪群中主要流行H1和H3亚型流感毒株,而且H1和H3呈普遍感染状态;H1N2和H3N2可能分别来源于北美H1N2亚型猪流感病毒和北美H3N2亚型人流感病毒;H1N2和H3N2流感病毒可以在不引起临床症状情况下感染猪并且病毒能在上呼吸道中大量复制,这对阐明猪流感病毒感染致病机制具有一定的理论意义,同时对猪流感临床诊断具有一定的现实指导作用。利用反向遗传操作和定点突变技术发现PA的54位和M2的26位氨基酸协同影响FJ1和DK52对小鼠感染能力,这为阐明H5N1亚型流感病毒跨种间传播的分子遗传机制提供重要的理论和实验依据。因此本研究具有重要的兽医指导意义和重要的人类公共卫生意义。
Swine influenza is a highly infectious viral disease of pigs causing considerable economic impact. Three different subtypes-H1N1, H3N2 and H1N2 are circulating in swine worldwide. Pig as an intermediate host posed significance in producing a new viruses. Therefore, it has great significance to make clear which subtypes of influenza are ciculating and its pathgencity in China.
To learn about regularity of veterinary epidemiology and pathogenicity of SIV, Firstly, we collected 5886 nasal swabs and 5788 serum samples of pigs in part of China, including Shanghai、Henan、Shandong、hubei、Jiangsu、Guangdong province. The result of antibody titers of 5788 serum samples was as follows: H1 positive percentage was 40%, H3 positive percentage was 90%, H5 positive percentage was 0.086%, H9 positive percentage was 0.138%. Four H1N2 subtype, six H3N2 subtype and one H5N1 subtype influenza isolates were isolated by inoculation of Madin-Darby canine kidney(MDCK) cells with nasal swabs, and no viruse isolated in SPF embryonated eggs, this results demonstrated that MDCK cell line was more sensitive than SPF embryonated eggs on isolating SIV; The results demonstrated that H1 and H3 subtype is the primary circulating isolates among pigs in China. And then swine/Guangdong/1/2006(H1N2)(SwGD1/06)and Swine/Guangdong/1/2005(H3N2)(SwGD1/05)were selected to be sequenced and compared with sequences available in GenBank, and making phylogenetic trees of the complete genes. The results of analysis indicated that SwGD1/06 (H1N2) probably origins from H1N2 swine influenza viruses circulated in North America, while SwGD1/05(H3N2) probably come from H3N2 human influenza viruses circulated in North America. Finally , to study the pathogencity of the two viruses to pigs, we selected pigs whose antibody was negative to H1、H3、H5、H9 standard antigens as experiment animal. Challenged with 106EID50 H1N2 and H3N2 viruses respectively, we could reisolate viruses from nasal swabs on first、third、fifth、seventh day post infection, respectively, and the viruses titer was highest on the third day post infection, but we could not reisolate viruses from any other organs of infected pigs. The results indicated that H1N2 and H3N2 viruses could replicate in pig’s upper respiratory tract without clinical symptoms.
To demonstrate the molecular basis of cross-species transmission of H5N1 swine influenza viruses, we selected two isolates DK/ZJ/52/00(DK52)、Sw/FJ/1/01(FJ1)as model viruses, whose inheritance was closest, there were only 23 amimo acids difference between the complete genomes of the two strains: DK52 viruses could not replicate in the lungs of mice, however FJ1 viruses could replicate in the lungs of mice and also led mice to die. We established eight-plasmid reverse genetics system of the two viruses(RDK52、RFJ1) to evaluate the pathogenicity differences of the two viruses by BALB/C mice model. We rescued 16 single gene reassortant viruses by transfected 293 Tcell on the background of FJ1 and DK52, respectively. The results of infection of mice with 106EID50 18 viruses respectively was that PA and M gene of DK52 viruses dramatically attenuated the RFJ1(Lg EID50, 4.71 versus 1.5 ), respectively, and making RFJ1/DK52PA and RFJ1/DK52M couldnot kill mice ; on the other hand, PA and M gene of FJ1 viruses causes RDK52 viruses to replicate in the lungs of mice (LgEID50, 0, versus1.5), respectively. And other genes could not change the pathogenicity of the reassortmant viruses. This result indicated that PA and M genes could affect the replication ability of FJ1 and DK52 viruses in mice.
Furtherly, we replaced M and PA genes at the same reassorments viruses using an eight-plasmid reverse genetics system, results of infection with PA and M genes substitutation viruses had shown that M and PA gene of DK52 viruses together can completely change the pathogenicity of the RFJ1 viruses, making RFJ1 could not replicate in the lungs of mice at all; on the other hand, M and PA gene of FJ1 viruses together could make RDK52 viruses replicate in the lungs of mice(LgEID50, 2.5), therefore it was concluded that M and PA gene cooperate to affect the replication ability of FJ1 and DK52 viruses in mice.
Comparing Amino acid sequence of PA and M genes between FJ1 and DK52 viruses, we finded that there were only four and one amino acids differences in PA(54,330,384,459) and M2(26) genes, respectively.To elucidate the molecular basis of the virulence and replication discrepancy between the FJ1 and DK52 viruses, we generated four mutant viruses. A I-to-V (PAI54V) substitution at position 54 in PA resulted in marked attenuation of RFJ1 virus (LgEID50,4.71 versus 1.5); However, a V-to-I (PAV54I) substitution at position 54 in PA enabled DK52 to replicate in lungs of mice, although viruses titer was very low (Lg EID50, 1.5). M gene acted as PA, a P-to-L (M2S26L) substitution at position 26 in M2 resulted in marked attenuation of RFJ1 virus (LgEID50,4.71 versus 1.5); a L-to-S (M2L26S) substitution at position 26 in M2 enabled DK52 to replicate in lungs of mice, although viruses titer is very low (Lg EID50, 1.5). However, changes of amino acids in position 330,384,459 of PA gene couldnot affect the the pathogenicity of FJ1 and DK52 viruses in mice. It was clear that amino acids at position 54 of PA and position 26 of M2 cooperate to affect the pathogenicity of FJ1 and DK52 viruses in mice.
In summary, we investigate the epidemiology of swine influenza viruses among pigs in part of China, the results indicated that H1 and H3 subtype was currently the primary circulating isolates among pigs in China; the results of pigs challenged with H1N2 and H3N2 virusses demonstrated that H1N2 and H3N2 virusses could replicate in pig’s upper respiratory tract without clinical symptoms, therefore this study possesed great significance in veterinary epidemiology and pathogenicity of H1N2 viruses in pigs. Using reverse genetics, we demonstrated that amino acids at position 54 of PA gene and at position 26 of M2 gene cooperate to affect the pathogenicity of FJ1 and DK52 viruses in mice, this result can provided powerful proof to explain why H5N1 influenza viruses acrossed species transmiting to human. Therefore this study posed significance in human public health.
本研究先后在上海、河南、山东、湖北、江苏、广东等省市采集猪鼻拭子5886份和血清5788份。血清样品检测结果如下:H1阳性率40%(2323份),H3阳性率90%(5240份),H5阳性率0.086%(5份),H9阳性率0.138%(8份)。猪鼻拭子样品同时接种MDCK和SPF鸡胚进行病毒分离,共分离到4株H1N2,6株H3N2和1株H5N1流感病毒。结果表明当前我国不同地区猪群中普遍存在H1和H3亚型猪流感流行。
为了解我国猪流感病毒分子进化变异情况,本研究挑选H1N2代表毒株Swine/Guangdong/1/2006 (SwGD1/06)和H3N2代表毒株Swine/Guangdong/1/2006(SwGD1/05)进行基因组测定分析。结果表明SwGD1/06(H1N2)可能来源于北美猪群中流行的H1N2亚型猪流感病毒;而SwGD1/05(H3N2)可能能来源于在北美人群中流行的H3N2亚型流感病毒。分别用106 EID50剂量H1N2和H3N2分离病毒对H1、H3、H5、H9抗体皆为阴性的35日龄仔猪进行感染实验,结果是感染后第1、3、5、7d能从猪鼻拭子中重新分离到H1N2和H3N2病毒,其中第3d病毒含量最高;其它脏器没有分离到病毒。临床症状轻微,没有猪只死亡。结果表明单纯H1N2或H3N2流感病毒能在不引起临床症状的情况下感染易感猪只,这说明我国流行的H1和H3流感病毒对猪致病性不强。
为阐明H5N1亚型猪流感病毒跨种传播遗传基础,本研究筛选遗传关系相近(整个基因组只有23个氨基酸差异),对小鼠感染能力完全不同的的两株H5N1亚型流感病毒为模型病毒:DK/ZJ/52/00(DK52),对小鼠完全不感染;Swine/Fujian/1/04(FJ1),对小鼠有致病性且引起小鼠死亡。建立了FJ1和DK52的反向遗传操作系统,分别以FJ1和DK52为背景,利用反向遗传技术在293T细胞上救获单基因替换重组的16个病毒。这些病毒分别以106EID50剂量鼻腔感染小鼠,结果发现:DK52的PA和M基因分别替换FJ1相应基因,使RFJ1在小鼠肺脏感染能力降低103.21倍(病毒滴度(LgEID50)由原来的4.71变为1.5);反之FJ1的PA和M基因分别替换DK52的相应基因,使RDK52的致病性由不感染变为感染(肺脏病毒滴定结果为LgEID50,1.5)。其它单基因替换重组病毒没有改变这两株病毒对小鼠感染能力。结果表明M和PA基因影响FJ1和DK52在小鼠肺脏中的复制能力。
为进一步确定PA和M基因如何影响对FJ1和DK52对小鼠感染能力,我们把M和PA两个基因同时替换,发现以DK52的PA和M替换FJ1的PA和M基因后,使RFJ1/DK52PA+M不能在小鼠肺脏中复制;反之,以FJ1的PA和M替换DK52的PA和M基因后,导致RDK52/FJ1PA+M能感染小鼠并在肺脏中复制,病毒滴度达到2.5LgEID50。结果表明M和PA基因协同作用影响FJ1和DK52对小鼠感染能力。
在此基础上,我们分析FJ1和DK52两株病毒的PA和M基因氨基酸,发现PA(54、330,384,459)和M2(26)基因分别有4个和1个位点氨基酸不同。为进一步确定PA和M2的哪一个位点氨基酸对小鼠感染能力起作用,分别对PA和M2的两个位点进行点突变,利用反向遗传操作系统救获4个点突变病毒。突变病毒对小鼠感染结果发现:PAI54V(54位由I变为V)可使RFJ1在小鼠肺脏中复制能力降低103。21倍(LgEID50由原来的4.71变为1.5),反之,PAV54I(54位由V变为I)可使RDK52对小鼠由不感染变为感染(肺脏病毒滴定结果为LgEID50,1.5);同样,M2S26L(26位由S变为L)可以使FJ1感染小鼠能力降低103。21倍(LgEID50由原来的4.71变为1.5),反之M2L26S(26位由L变为S)可以可使RDK52对小鼠由不感染变为感染(肺脏病毒滴定结果为LgEID50,1.5)。但是PA的330,384,459位氨基酸的改变没有影响病毒致病性。结果表明PA基因的54位和M2基因的26位氨基酸协同作用影响FJ1和DK52对小鼠感染能力。
本研究系统研究了中国部分地区猪流感病毒流行的亚型和生物学特性,结果表明:中国目前猪群中主要流行H1和H3亚型流感毒株,而且H1和H3呈普遍感染状态;H1N2和H3N2可能分别来源于北美H1N2亚型猪流感病毒和北美H3N2亚型人流感病毒;H1N2和H3N2流感病毒可以在不引起临床症状情况下感染猪并且病毒能在上呼吸道中大量复制,这对阐明猪流感病毒感染致病机制具有一定的理论意义,同时对猪流感临床诊断具有一定的现实指导作用。利用反向遗传操作和定点突变技术发现PA的54位和M2的26位氨基酸协同影响FJ1和DK52对小鼠感染能力,这为阐明H5N1亚型流感病毒跨种间传播的分子遗传机制提供重要的理论和实验依据。因此本研究具有重要的兽医指导意义和重要的人类公共卫生意义。
Swine influenza is a highly infectious viral disease of pigs causing considerable economic impact. Three different subtypes-H1N1, H3N2 and H1N2 are circulating in swine worldwide. Pig as an intermediate host posed significance in producing a new viruses. Therefore, it has great significance to make clear which subtypes of influenza are ciculating and its pathgencity in China.
To learn about regularity of veterinary epidemiology and pathogenicity of SIV, Firstly, we collected 5886 nasal swabs and 5788 serum samples of pigs in part of China, including Shanghai、Henan、Shandong、hubei、Jiangsu、Guangdong province. The result of antibody titers of 5788 serum samples was as follows: H1 positive percentage was 40%, H3 positive percentage was 90%, H5 positive percentage was 0.086%, H9 positive percentage was 0.138%. Four H1N2 subtype, six H3N2 subtype and one H5N1 subtype influenza isolates were isolated by inoculation of Madin-Darby canine kidney(MDCK) cells with nasal swabs, and no viruse isolated in SPF embryonated eggs, this results demonstrated that MDCK cell line was more sensitive than SPF embryonated eggs on isolating SIV; The results demonstrated that H1 and H3 subtype is the primary circulating isolates among pigs in China. And then swine/Guangdong/1/2006(H1N2)(SwGD1/06)and Swine/Guangdong/1/2005(H3N2)(SwGD1/05)were selected to be sequenced and compared with sequences available in GenBank, and making phylogenetic trees of the complete genes. The results of analysis indicated that SwGD1/06 (H1N2) probably origins from H1N2 swine influenza viruses circulated in North America, while SwGD1/05(H3N2) probably come from H3N2 human influenza viruses circulated in North America. Finally , to study the pathogencity of the two viruses to pigs, we selected pigs whose antibody was negative to H1、H3、H5、H9 standard antigens as experiment animal. Challenged with 106EID50 H1N2 and H3N2 viruses respectively, we could reisolate viruses from nasal swabs on first、third、fifth、seventh day post infection, respectively, and the viruses titer was highest on the third day post infection, but we could not reisolate viruses from any other organs of infected pigs. The results indicated that H1N2 and H3N2 viruses could replicate in pig’s upper respiratory tract without clinical symptoms.
To demonstrate the molecular basis of cross-species transmission of H5N1 swine influenza viruses, we selected two isolates DK/ZJ/52/00(DK52)、Sw/FJ/1/01(FJ1)as model viruses, whose inheritance was closest, there were only 23 amimo acids difference between the complete genomes of the two strains: DK52 viruses could not replicate in the lungs of mice, however FJ1 viruses could replicate in the lungs of mice and also led mice to die. We established eight-plasmid reverse genetics system of the two viruses(RDK52、RFJ1) to evaluate the pathogenicity differences of the two viruses by BALB/C mice model. We rescued 16 single gene reassortant viruses by transfected 293 Tcell on the background of FJ1 and DK52, respectively. The results of infection of mice with 106EID50 18 viruses respectively was that PA and M gene of DK52 viruses dramatically attenuated the RFJ1(Lg EID50, 4.71 versus 1.5 ), respectively, and making RFJ1/DK52PA and RFJ1/DK52M couldnot kill mice ; on the other hand, PA and M gene of FJ1 viruses causes RDK52 viruses to replicate in the lungs of mice (LgEID50, 0, versus1.5), respectively. And other genes could not change the pathogenicity of the reassortmant viruses. This result indicated that PA and M genes could affect the replication ability of FJ1 and DK52 viruses in mice.
Furtherly, we replaced M and PA genes at the same reassorments viruses using an eight-plasmid reverse genetics system, results of infection with PA and M genes substitutation viruses had shown that M and PA gene of DK52 viruses together can completely change the pathogenicity of the RFJ1 viruses, making RFJ1 could not replicate in the lungs of mice at all; on the other hand, M and PA gene of FJ1 viruses together could make RDK52 viruses replicate in the lungs of mice(LgEID50, 2.5), therefore it was concluded that M and PA gene cooperate to affect the replication ability of FJ1 and DK52 viruses in mice.
Comparing Amino acid sequence of PA and M genes between FJ1 and DK52 viruses, we finded that there were only four and one amino acids differences in PA(54,330,384,459) and M2(26) genes, respectively.To elucidate the molecular basis of the virulence and replication discrepancy between the FJ1 and DK52 viruses, we generated four mutant viruses. A I-to-V (PAI54V) substitution at position 54 in PA resulted in marked attenuation of RFJ1 virus (LgEID50,4.71 versus 1.5); However, a V-to-I (PAV54I) substitution at position 54 in PA enabled DK52 to replicate in lungs of mice, although viruses titer was very low (Lg EID50, 1.5). M gene acted as PA, a P-to-L (M2S26L) substitution at position 26 in M2 resulted in marked attenuation of RFJ1 virus (LgEID50,4.71 versus 1.5); a L-to-S (M2L26S) substitution at position 26 in M2 enabled DK52 to replicate in lungs of mice, although viruses titer is very low (Lg EID50, 1.5). However, changes of amino acids in position 330,384,459 of PA gene couldnot affect the the pathogenicity of FJ1 and DK52 viruses in mice. It was clear that amino acids at position 54 of PA and position 26 of M2 cooperate to affect the pathogenicity of FJ1 and DK52 viruses in mice.
In summary, we investigate the epidemiology of swine influenza viruses among pigs in part of China, the results indicated that H1 and H3 subtype was currently the primary circulating isolates among pigs in China; the results of pigs challenged with H1N2 and H3N2 virusses demonstrated that H1N2 and H3N2 virusses could replicate in pig’s upper respiratory tract without clinical symptoms, therefore this study possesed great significance in veterinary epidemiology and pathogenicity of H1N2 viruses in pigs. Using reverse genetics, we demonstrated that amino acids at position 54 of PA gene and at position 26 of M2 gene cooperate to affect the pathogenicity of FJ1 and DK52 viruses in mice, this result can provided powerful proof to explain why H5N1 influenza viruses acrossed species transmiting to human. Therefore this study posed significance in human public health.
引文
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