马链球菌兽疫亚种—猪链球菌2型基因工程疫苗的研究
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摘要
猪链球菌(Streptococcus suis, S. suis)是导致猪链球菌病主要的病原。该菌可分为33个血清型,其中猪2型链球菌(Streptococcus suis type 2, SS2)致病性强、流行最广泛。在临床上,该型亦是分离频率最高的血清型之一。SS2可引起猪的脑膜炎、化脓性肺炎和心肌炎等疾病。此菌亦可通过特定的传播途径感染人,是一种重要的人畜共患病病原。
马链球菌兽疫亚种(Streptococcus equi subsp. Zooepidemicus, SEZ)属于C群链球菌,可引起多种动物感染发病。临床症状主要表现为败血症、脑膜炎和关节炎等,一般呈地方性流行。人类可因摄取被该菌污染的牛奶等食品,或者与病猪或病马等动物接触,而引发该病。流行病学调查表明,在我国除新出现的猪链球菌2型外,马链球菌兽疫亚种仍是我国各地猪链球菌病的主要病原。
灭活疫苗对于预防猪链球菌病同种血清型的菌株有良好的保护力,但不同血清型之间的交叉保护力却很差,因此新型疫苗的研制成为研究的热点。随着新的毒力因子和免疫保护力蛋白的不断发现,为开发新型的基因工程疫苗的研究带来了新的希望,对防治猪链球菌病提供了新的前景。
为了解猪链球菌病,本实验室对四川分离株SC19菌株的特性进行了研究,为筛选疫苗候选株打下基础。在新型疫苗的研究中,以马链球菌兽疫亚种弱毒疫苗株ST171(在中国已使用达20年之久,对SEZ的防治起到了一定的作用。)作为出发菌株,表达猪2型链球菌的免疫原性蛋白,以期得到马链球菌兽疫亚种-猪链球菌2型二价弱毒活疫苗。现将主要研究结果报告如下：
1.猪链球菌2型SC-19中国流行株的特性研究
对中国分离株SC19的特性进行了研究,鉴定此菌株基因表型为mrp+epf+sly+,在绵阳血平板上是β溶血。可使Balb/c小鼠、昆明鼠、家兔和仔猪感染发病,对仔猪敏感。
感染猪链球菌2型SC19的仔猪多超急性死亡,症状以脑膜脑炎型和关节炎型为主,与北美株报道的临床及病理变化一致。细菌多分布于蛛网膜下腔的中性粒细胞的细胞浆中,对脑组织有组织嗜性,可推测细菌作用于中性粒细胞。溶血素作为链球菌的毒力因子,在猪体内被细菌高量的表达,说明溶血素的表达对于链球菌具有重要意义。溶血素单抗与组织的阳性结果也集中于中性粒细胞的细胞浆内,说明溶血素对于细菌粘附或入侵炎性细胞有一定的作用。
2.马链球菌兽疫亚种-猪链球菌2型弱毒活疫苗的研究
以马链球菌兽疫亚种弱毒疫苗株ST171为出发菌株,构建了可以表达猪2型链球菌免疫原性蛋白溶菌酶释放蛋白(MRP),表面蛋白1(SAO)和假设蛋白0197(HP0197)的重组菌ST171-MRP, ST171-SAO和ST171-HP0197。Western blot检测证明2型的免疫原性蛋白在ST171中有良好的表达。
小鼠免疫保护力试验证明这三组重组菌均能诱导产生特异的SEZ抗体,对SEZ致死剂量的攻击,均能提供良好的保护力。而且三组重组菌能诱导产生特异的SS2免疫原性蛋白的抗体和有效诱导细胞免疫应答,对SS2致死剂量的攻击,能提供部分保护力。仔猪免疫保护力试验证明2组重组菌ST171-SAO和ST171-HP0197能诱导产生特异的SEZ抗体,对SEZ致死剂量的攻击,均能提供良好的保护力。而且2组重组菌能诱导产生特异的SS2免疫原性蛋白的抗体和细胞免疫应答,对SS2致死剂量的攻击,能提供部分保护力。这些结果均证明ST171-MRP, ST171-SAO,ST171-0197有望被开发为马链球菌兽疫亚种-猪链球菌2型二价弱毒疫苗。
Streptococcus suis (S. suis) is an important swine pathogen that causes many pathological conditions, such as arthritis, endocarditis, meningitis, pneumonia, and septicemia. Thirty-three serotypes (types 1/2 and 1 to 31,33) have been described based on capsular polysaccharides. Most S. suis strains isolated from diseased pigs belong to a capsular type 2(SS2). SS2 is also an important zoonotic agent for people in contact with swine or their by-products and causes meningitis, permanent hearing loss, and septic shock.
Streptococcus equi subsp. Zooepidemicus (SEZ) made lead to substantial economic losses for pig industry and became a substantial serous threat to human health especially whome involved in pig industry. It infects a wide range of animals, causing septicemia, meningitis, endocarditis, arthritis and mastitis. To date, the pig industry is still suffering from this disease in China.
Though conventional inactivated vaccine has played a key role in protection against homologous bacteria infection, but the results were inconsistent when it was used to protect against heterologous bacteria infection. The study of novel genetically engineering vaccine would become the focus against the SS infection.
To know the characteristics of Chinese popular strain SC19, a series of experiments were done for the goal of understanding this disease and the vaccinal study.
For prevent SS2 and SEZ, in the present study, strain ST171 was used as a vector to express protective proteins of SS2. The recombinant strains ST171-MRP, ST171-SAO and ST171-HP0197 were constructed and its potential as a bivalent vaccine against both SEZ and SS2 infection was examined in mouse and pig model. The principal results were described as the following:
1. The study of the characteristics of Chinese popular strain SC19
A strain named SC19 was isolated from Sichuan province in 2005. SC19 was belong to SS2 and the genotype was mrp+epf+sly+. It has the haemolytic activity and could infect Balb/c, km, rabbit and pig.
In this paper, the lesions following experimental infection of pigs with S. suis 2 were studied. The important clinical symptoms were nerval symptom and arthritis. Histopathologically, the infected pigs exhibited typical meningoencephalitis symptoms. Immunohistochemistry identified bacteria within the cytoplasm of neutrophils and macrophages localized in meningeal lesions. The brain is easy to be disoperation by the bacteria. The secreted suilysin protein showed a similar localization within the cytoplasm of inflammatory cells, indicating that suilysin had high expression by bacteria when the bateria went into in vivo of pig and may contribute to the pathogenesis of streptococcal meningoencephalitis.
2. The potential as a live attenuated vaccine of the recombinant of streptococcus equi ssp.zooepidemicus expressing the recombinant immunogenic protein of streptococcus suis type 2
In the present study, SEZ strain ST171, which is a live attenuated vaccine strain used widely in china for many years, was used as a source strain to develop a bivalent live vaccine. Muramidase-released protein (MRP), surface protein SP1 (SAO), hypothetical protein SSU98_0197 (HP0197) of SS2 which were proved to have the effective protetive efficacy were inserted into the genome of ST171 and gave rise to the recombinant strains ST171-MRP, ST171-SAO and ST171-HP0197. The proteins were expressed successfully in ST171-MRP, ST171-SAO and ST171-HP0197 as determined by western blot assay.
The further protective efficacy of recombinant strains as live vaccine was evaluated in mouse and pig model. The inserted gene did not influence the virulence of strain ST171, and the 3 recombinant strains induced obvious SEZ-specific humoral immune responses and provided conspicuous protection against a lethal SEZ challenge, which is similar to vaccine ST171. Most importantly, the recombinant could induce detectable protein-specific IgG antibody and celular immunological response, and provide partial protect of mice against a lethal SS2 challenge. The further protective efficacy in pig model was done. The 2 recombinant strains ST171-SAO and ST171-HP0197, like ST171, induced obvious SEZ-specific humoral immune responses and provided conspicuous protection against a lethal SEZ challenge. Simultaneously, the recombinant strains could induce detectable protein-specific IgG antibody and celular immunological response, and provide partial protect of pig against a lethal SS2 challenge. These results indicate that ST171-MRP, ST171-SAO and ST171-HP0197 were the potential candidate for development of bivalent vaccine against both SEZ and SS2 infections.
马链球菌兽疫亚种(Streptococcus equi subsp. Zooepidemicus, SEZ)属于C群链球菌,可引起多种动物感染发病。临床症状主要表现为败血症、脑膜炎和关节炎等,一般呈地方性流行。人类可因摄取被该菌污染的牛奶等食品,或者与病猪或病马等动物接触,而引发该病。流行病学调查表明,在我国除新出现的猪链球菌2型外,马链球菌兽疫亚种仍是我国各地猪链球菌病的主要病原。
灭活疫苗对于预防猪链球菌病同种血清型的菌株有良好的保护力,但不同血清型之间的交叉保护力却很差,因此新型疫苗的研制成为研究的热点。随着新的毒力因子和免疫保护力蛋白的不断发现,为开发新型的基因工程疫苗的研究带来了新的希望,对防治猪链球菌病提供了新的前景。
为了解猪链球菌病,本实验室对四川分离株SC19菌株的特性进行了研究,为筛选疫苗候选株打下基础。在新型疫苗的研究中,以马链球菌兽疫亚种弱毒疫苗株ST171(在中国已使用达20年之久,对SEZ的防治起到了一定的作用。)作为出发菌株,表达猪2型链球菌的免疫原性蛋白,以期得到马链球菌兽疫亚种-猪链球菌2型二价弱毒活疫苗。现将主要研究结果报告如下：
1.猪链球菌2型SC-19中国流行株的特性研究
对中国分离株SC19的特性进行了研究,鉴定此菌株基因表型为mrp+epf+sly+,在绵阳血平板上是β溶血。可使Balb/c小鼠、昆明鼠、家兔和仔猪感染发病,对仔猪敏感。
感染猪链球菌2型SC19的仔猪多超急性死亡,症状以脑膜脑炎型和关节炎型为主,与北美株报道的临床及病理变化一致。细菌多分布于蛛网膜下腔的中性粒细胞的细胞浆中,对脑组织有组织嗜性,可推测细菌作用于中性粒细胞。溶血素作为链球菌的毒力因子,在猪体内被细菌高量的表达,说明溶血素的表达对于链球菌具有重要意义。溶血素单抗与组织的阳性结果也集中于中性粒细胞的细胞浆内,说明溶血素对于细菌粘附或入侵炎性细胞有一定的作用。
2.马链球菌兽疫亚种-猪链球菌2型弱毒活疫苗的研究
以马链球菌兽疫亚种弱毒疫苗株ST171为出发菌株,构建了可以表达猪2型链球菌免疫原性蛋白溶菌酶释放蛋白(MRP),表面蛋白1(SAO)和假设蛋白0197(HP0197)的重组菌ST171-MRP, ST171-SAO和ST171-HP0197。Western blot检测证明2型的免疫原性蛋白在ST171中有良好的表达。
小鼠免疫保护力试验证明这三组重组菌均能诱导产生特异的SEZ抗体,对SEZ致死剂量的攻击,均能提供良好的保护力。而且三组重组菌能诱导产生特异的SS2免疫原性蛋白的抗体和有效诱导细胞免疫应答,对SS2致死剂量的攻击,能提供部分保护力。仔猪免疫保护力试验证明2组重组菌ST171-SAO和ST171-HP0197能诱导产生特异的SEZ抗体,对SEZ致死剂量的攻击,均能提供良好的保护力。而且2组重组菌能诱导产生特异的SS2免疫原性蛋白的抗体和细胞免疫应答,对SS2致死剂量的攻击,能提供部分保护力。这些结果均证明ST171-MRP, ST171-SAO,ST171-0197有望被开发为马链球菌兽疫亚种-猪链球菌2型二价弱毒疫苗。
Streptococcus suis (S. suis) is an important swine pathogen that causes many pathological conditions, such as arthritis, endocarditis, meningitis, pneumonia, and septicemia. Thirty-three serotypes (types 1/2 and 1 to 31,33) have been described based on capsular polysaccharides. Most S. suis strains isolated from diseased pigs belong to a capsular type 2(SS2). SS2 is also an important zoonotic agent for people in contact with swine or their by-products and causes meningitis, permanent hearing loss, and septic shock.
Streptococcus equi subsp. Zooepidemicus (SEZ) made lead to substantial economic losses for pig industry and became a substantial serous threat to human health especially whome involved in pig industry. It infects a wide range of animals, causing septicemia, meningitis, endocarditis, arthritis and mastitis. To date, the pig industry is still suffering from this disease in China.
Though conventional inactivated vaccine has played a key role in protection against homologous bacteria infection, but the results were inconsistent when it was used to protect against heterologous bacteria infection. The study of novel genetically engineering vaccine would become the focus against the SS infection.
To know the characteristics of Chinese popular strain SC19, a series of experiments were done for the goal of understanding this disease and the vaccinal study.
For prevent SS2 and SEZ, in the present study, strain ST171 was used as a vector to express protective proteins of SS2. The recombinant strains ST171-MRP, ST171-SAO and ST171-HP0197 were constructed and its potential as a bivalent vaccine against both SEZ and SS2 infection was examined in mouse and pig model. The principal results were described as the following:
1. The study of the characteristics of Chinese popular strain SC19
A strain named SC19 was isolated from Sichuan province in 2005. SC19 was belong to SS2 and the genotype was mrp+epf+sly+. It has the haemolytic activity and could infect Balb/c, km, rabbit and pig.
In this paper, the lesions following experimental infection of pigs with S. suis 2 were studied. The important clinical symptoms were nerval symptom and arthritis. Histopathologically, the infected pigs exhibited typical meningoencephalitis symptoms. Immunohistochemistry identified bacteria within the cytoplasm of neutrophils and macrophages localized in meningeal lesions. The brain is easy to be disoperation by the bacteria. The secreted suilysin protein showed a similar localization within the cytoplasm of inflammatory cells, indicating that suilysin had high expression by bacteria when the bateria went into in vivo of pig and may contribute to the pathogenesis of streptococcal meningoencephalitis.
2. The potential as a live attenuated vaccine of the recombinant of streptococcus equi ssp.zooepidemicus expressing the recombinant immunogenic protein of streptococcus suis type 2
In the present study, SEZ strain ST171, which is a live attenuated vaccine strain used widely in china for many years, was used as a source strain to develop a bivalent live vaccine. Muramidase-released protein (MRP), surface protein SP1 (SAO), hypothetical protein SSU98_0197 (HP0197) of SS2 which were proved to have the effective protetive efficacy were inserted into the genome of ST171 and gave rise to the recombinant strains ST171-MRP, ST171-SAO and ST171-HP0197. The proteins were expressed successfully in ST171-MRP, ST171-SAO and ST171-HP0197 as determined by western blot assay.
The further protective efficacy of recombinant strains as live vaccine was evaluated in mouse and pig model. The inserted gene did not influence the virulence of strain ST171, and the 3 recombinant strains induced obvious SEZ-specific humoral immune responses and provided conspicuous protection against a lethal SEZ challenge, which is similar to vaccine ST171. Most importantly, the recombinant could induce detectable protein-specific IgG antibody and celular immunological response, and provide partial protect of mice against a lethal SS2 challenge. The further protective efficacy in pig model was done. The 2 recombinant strains ST171-SAO and ST171-HP0197, like ST171, induced obvious SEZ-specific humoral immune responses and provided conspicuous protection against a lethal SEZ challenge. Simultaneously, the recombinant strains could induce detectable protein-specific IgG antibody and celular immunological response, and provide partial protect of pig against a lethal SS2 challenge. These results indicate that ST171-MRP, ST171-SAO and ST171-HP0197 were the potential candidate for development of bivalent vaccine against both SEZ and SS2 infections.
引文
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