副溶血弧菌VI型分泌系统功能及其调控
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摘要
副溶血弧菌(Vibrio parahaemolyticus)是一种重要的食源性人兽共患病原菌,广泛存在于海洋环境,能够引起人急性肠胃炎、伤口感染和败血症,对动物主要引起水生动物疾病,如海鲷、对虾、九孔鲍、文蛤等。
耐热直接溶血毒素(thermostable direct hemolysin, TDH)、耐热直接溶血相关毒素(TDH-related hemolysin, TRH)、Ⅲ型分泌系统1(T3SS1)和Ⅲ型分泌系统2(T3SS2)被认为是副溶血弧菌的主要致病因子。对实验室近年来保存的33株临床分离株和511株环境分离株进行tdh, trh, vcrD1(T3SS1结构蛋白基因)和vcrD2(T3SS2结构蛋白基因)的PCR检测发现它们在临床分离株中的阳性率分别为100%、9.1%、100%和87.9%,在环境分离株中的分离率分别为11.2%、19.4%、100%和1.2%。T3SS1存在于所有副溶血弧菌分离株中,这与报道相一致。tdh和T3SS2在临床分离株中的阳性率均高于环境分离株,符合致病因子的一般特征。
Ⅵ型分泌系统(T6SS)是近年来新发现的一种分泌系统,广泛存在于革兰氏阴性菌变形菌门细菌中,能够增强细菌对外界环境的适应性,介导细菌对宿主细胞的致病力。对副溶血弧菌全基因组序列RIMD2210633分析发现,副溶血弧菌中存在两套T6SS,分别位于染色体1(T6SS1)和染色体2(T6SS2)上。T6SS1基因簇结构与霍乱弧菌的T6SS同源性较高,其结构蛋白基因icmF1在副溶血弧菌临床分离株和环境分离株中的携带率分别为90.9%和25.0%,提示T6SS1可能与副溶血弧菌的致病力密切相关;T6SS2与一些海洋细菌的T6SS具有较高的同源性,其结构蛋白基因icmF2在副溶血弧菌临床分离株和环境分离株中均为100%。
为了验证T6SS1和T6SS2是否具有转位和分泌蛋白的功能,本研究选取副溶血弧菌临床分离株HZ为亲本菌株,构建了结构蛋白基因icmF1和icmF2,转位蛋白基因hcpl和hcp2的缺失突变株和回复突变株,并用Hcp1和Hcp2多克隆抗体检测亲本株和T6SS相关基因缺失株中Hcp1和Hcp2的表达和转位情况。缺失icmF2后,Hcp2只能在菌体沉淀中被检测到,而在培养上清中未能检出,说明T6SS2在体外培养条件下是一个功能性的分泌系统,介导蛋白转位和分泌。而Hcp1在亲本株、△icmF1和△Ahcp1的菌体沉淀和培养上清中均检测不到；互补表达的Hcp1能在菌体沉淀中被检测到,但也不存在于培养上清中；荧光定量PCR检测亲本株中icmF1、icmF2、hcp1和hcp2的基因转录水平发现,icmF1和hcpl的转录量仅为icmF2和hcp2的十七分之一和十分之一。说明T6SS1在体外是一个非活化的分泌系统,相关基因处于低表达和低转录状态。
为了研究T6SS的生物学功能,本研究首先构建了缺失副溶血弧菌主要致病因子TDH,T3SS1和T3SS2相关基因的三缺失突变株DTTT,并以DTTT菌株为亲本,进一步缺失icmF1、icmF2、hcp1或hcp2基因,从细菌对宿主细胞的感染生物学(细胞粘附、细胞毒性、细胞自噬、细胞凋亡和红细胞溶血能力)和细菌对环境的适应性(生长特性,抗酸应激和形成生物被膜能力)两大方面展开副溶血弧菌两套T6SS的生物学活性研究。
副溶血弧菌T6SS1和T6SS2均具有细胞粘附能力。缺失了T6SS1结构蛋白就因icmF1和转位蛋白基因hcp1的细菌,对Caco-2和HeLa细胞的粘附能力显著降低,而缺失了T6SS2结构蛋白基因icmF2和转位蛋白基因hcp2的细菌只对HeLa细胞粘附能力降低。T6SS1在体外培养条件下处于低表达和低转录状态,但在细胞粘附试验中呈现一定的活性,且该活性能被Hcpl抗体阻断。
副溶血弧菌T6SS2具有促细胞自噬的能力。△icmF2、△hcp2和△vgrG2缺失株与小鼠巨噬细胞RAW264.7共培养4h后,细胞中LC3-Ⅰ转化为LC3-Ⅱ的量要显著低于亲本株DTTT,而△icmF1菌株与亲本株相比差异不显著。说明T6SS2可能促进RAW264.7发生自噬。副溶血弧菌感染稳定表达LC3-GFP的RAW264.7细胞,△icmF2缺失株感染的细胞中LC3-GFP的荧光斑点要显著低于亲本株DTTT,进一步证明了T6SS2促进RAW264.7自噬。
T6SS2促进RAW264.7自噬的活性可能是通过其转位蛋白和分泌蛋白来实现的。目前T6SS2还未有分泌蛋白发现,因此我们怀疑T6SS2可能通过转位蛋白Hcp2和VgrG2介导细菌的自噬。在RAW264.7中真核表达GFP-Hcp2和口GFP-VgrG2蛋白,发现表达GFP-VgrG2的细胞LC3-Ⅱ的量要显著高于对照组(表达GFP),而表达GFP-Hcp2的细胞与对照组相比无显著差异。向培养RAW264.7的培养基中添加原核表达的Hcp2和VgrG2蛋白,也呈现类似结果：添加VgrG2蛋白后,细胞LC3-Ⅱ的量要高于对照组,添加Hcp2蛋白则变化不显著。说明T6SS2对RAW264.7细胞的自噬作用是通过其转位蛋白VgrG2来实现的。不论是细胞内源性的VgrG2,还是外源添加的VgrG2均能引起细胞自噬,推测VgrG2引起细胞自噬可能在其刺穿宿主细胞膜并进入宿主细胞的过程中,引起自噬途径相关信号的改变。
无论是T6SS1还是T6SS2,都不具有细胞毒性和溶血活性,不诱导宿主细胞凋亡。T6SS1和T6SS2也不贡献副溶血弧菌对抗酸应激和形成生物被膜的能力。
在T6SS2基因簇的下游,存在两个二元调控因子VPA1045和VPA1049,具有反应调节因子典型的Che-Y结构域。Vpa1045和Vpa1049基因缺失后,hcp2转录水平与亲本相比均差异不显著。免疫印迹分析发现在细菌培养上清中的Hcp2转位量显著下降,而菌体沉淀中Hcp2表达量与亲本相比均差异不显著。进一步的细胞试验发现,Vpa1045和Vpa1049的缺失也降低细菌对HeLa细胞的粘附能力。
Vibrio parahaemolyticus, a halophilic bacterium in marine environments, is a most important foodbrone pathogen in the world. It causes wound infectious, septicemia and most commonly acute gastroenteritis in humans, it also causes disease in invertebrates, including abalone, Haliotis diversicolor supertexta and shrimp.
The major virulence factors of V. parahaemolyticus include thermostable direct hemolysin (TDH), TDH related hemolysin (TRH) and two sets of type III secretion system (T3SS). PCR identification of tdh, trh, vcrDl (structure gene of T3SS1) and vcrD2(structure gene of T3SS2) in33clinical isolates of V. parahaemolyticus and511environmental isolates stored in our lab found that the fraction of these genes were100%,9.1%,100%and87.9%respectively in clinical strains and11.2%,19.4%,100%,1.2%in environmental strains. T3SS1was present in all V. parahaemolyticus. which is consisted with previous reports.tdh and T3SS2exist higher in clinical strains than in environmental strains, which was one feather of pathogenic factors.
Type VI secretion system, a new secretion only found in proteobacteria, devotes environment adapting and pathogenicity of bacteria. Bioinformatic analysis of whole genome of V. parahaemolyticus RIMD2210633reveals two clusters of T6SS. One is on Chromosone I, which is called T6SS1; the other is on Chromosome II, which is named T6SS2. T6SS1is identical to T6SS in Vibrio cholerae, which has90.9%possession in clinical isolates and25%in environment isolates. T6SS2, however, is identical to T6SS in those marine bacteria, which exists in all the V. parahaemolyticus isolates.
To confirm if both T6SS1and T6SS2can translocate and secrete proteins in vitro, a lot of mutant strains target on structure proteins icmF1and icmF2, as well as translocons hcpl and hcp2was made. Hcpl and Hcp2polyclonal antibody were immunized using V. parahaemolyticus clinical strain HZ as background strain. Western blot was performed to analysis the expression and translocation of Hcpl and Hcp2in pellets and supernatants of HZ and its mutants. We found that Hcp2can only be detected in pellet, but not in supernatant after deleting icmF2, the structure gene of T6SS2. However, Hcpl can not be detected neither in pellet nor in supernatant in HZ and all its mutants. When expressed using plasmid, Hcpl can be detected in pellet but not in supernatant even in the wild-type strain. The result of real-time RT PCR revealed that the transcription of hcpl was10times lower than hcp2, and icmF1was about17times lower than icmF2. These results highly show that T6SS2is an active secretion system in vitro, which can translocate and secrete proteins. However, T6SS1is an inactive secretion system in vitro, and hcp1, even the whole genes of T6SS1cluster were in a low transcriptional and expressional level.
To investigate the function of T6SS, icmF1, icmF2, hcp1or hcp2mutants were made based on DTTT background, a triple mutant strain void of tdh, vcrDl and vcrD2. Functional analysis targets two major parts. One is about bacteria infection, including cell adherence, cytotoxicity, autophagy, apoptosis and hemolysis. The other is about environment adapt, including growth further, acid tolerance and biofilm.
Both T6SS1and T6SS2devote cell adherence. After deleting icmF1and hcp1, the adherence to Caco-2and HeLa cell were both decreased. However, deleting icmF2and hcp2only lead cell adherence decreasing to HeLa cell. T6SS1do play functions in cell assay, and Hcp1antibody in cell culture can decrease adherence of wild-type strain to Caco-2.
T6SS2induces autophagy. When autophagy happened, cytosolic LC3-Ⅰ converted to membrane associated LC3-Ⅱ. In our experiment, LC3-Ⅱ was decreased when macrophage RAW264.7was infected with△icmF2,△hcp2and△vgrG2mutant strains for4h. No significant change of LC3-Ⅱ was seen when infected with△icmF1. In a cell line stably expressing a GFP-tagged LC3, LC3-Ⅱ accumulates slowly when infected with△icmF2, compared to DTTT and adding2μmol/mL Rapamycin. These results indicated that T6SS2induces autophagy of RAW264.7.
T6SS2induces autophagy of RAW264.7through VgrG2protein, a translocon of T6SS2. In a cell line expressing GFP-tagged VgrG2, LC3-Ⅱ increased obviously in western blot. Further in a cell cultured with prokaryotic VgrG2protein, LC3-Ⅱ also accumulated quickly. No matter intracellular or extrinsic VgrG2induce autophagy, indicating that the autophagy pass-way might change in the process of the phage tail-associated protein VgrG2across into host membrane.
Neither T6SS1nor T6SS2induce cytotoxicity, hemolysin and apoptosis. And both T6SS1and T6SS2were not involved in acid tolerance and biofilm of V. parahaemolyticus.
In T6SS2cluster, VPA1045and VPA1049were found to contain the Che-Y domain, belonging to response regulate family of two-component regulators. Deletion of either Vpa1045or Vpa1049did not affect expression and transcription of Hcp2, but decreased translocation of Hcp2in the supernatant of V. parahaemotycus. Bacterial adherence to the HeLa monolayer was also significantly reduced infected with△Vpa1045or△Vpa1049mutant strain comparing to their parent strain. So we concluded that the two-component regulators VPA1045and VPA1049might regulate T6SS2of V. parahaemolyticus.
耐热直接溶血毒素(thermostable direct hemolysin, TDH)、耐热直接溶血相关毒素(TDH-related hemolysin, TRH)、Ⅲ型分泌系统1(T3SS1)和Ⅲ型分泌系统2(T3SS2)被认为是副溶血弧菌的主要致病因子。对实验室近年来保存的33株临床分离株和511株环境分离株进行tdh, trh, vcrD1(T3SS1结构蛋白基因)和vcrD2(T3SS2结构蛋白基因)的PCR检测发现它们在临床分离株中的阳性率分别为100%、9.1%、100%和87.9%,在环境分离株中的分离率分别为11.2%、19.4%、100%和1.2%。T3SS1存在于所有副溶血弧菌分离株中,这与报道相一致。tdh和T3SS2在临床分离株中的阳性率均高于环境分离株,符合致病因子的一般特征。
Ⅵ型分泌系统(T6SS)是近年来新发现的一种分泌系统,广泛存在于革兰氏阴性菌变形菌门细菌中,能够增强细菌对外界环境的适应性,介导细菌对宿主细胞的致病力。对副溶血弧菌全基因组序列RIMD2210633分析发现,副溶血弧菌中存在两套T6SS,分别位于染色体1(T6SS1)和染色体2(T6SS2)上。T6SS1基因簇结构与霍乱弧菌的T6SS同源性较高,其结构蛋白基因icmF1在副溶血弧菌临床分离株和环境分离株中的携带率分别为90.9%和25.0%,提示T6SS1可能与副溶血弧菌的致病力密切相关;T6SS2与一些海洋细菌的T6SS具有较高的同源性,其结构蛋白基因icmF2在副溶血弧菌临床分离株和环境分离株中均为100%。
为了验证T6SS1和T6SS2是否具有转位和分泌蛋白的功能,本研究选取副溶血弧菌临床分离株HZ为亲本菌株,构建了结构蛋白基因icmF1和icmF2,转位蛋白基因hcpl和hcp2的缺失突变株和回复突变株,并用Hcp1和Hcp2多克隆抗体检测亲本株和T6SS相关基因缺失株中Hcp1和Hcp2的表达和转位情况。缺失icmF2后,Hcp2只能在菌体沉淀中被检测到,而在培养上清中未能检出,说明T6SS2在体外培养条件下是一个功能性的分泌系统,介导蛋白转位和分泌。而Hcp1在亲本株、△icmF1和△Ahcp1的菌体沉淀和培养上清中均检测不到；互补表达的Hcp1能在菌体沉淀中被检测到,但也不存在于培养上清中；荧光定量PCR检测亲本株中icmF1、icmF2、hcp1和hcp2的基因转录水平发现,icmF1和hcpl的转录量仅为icmF2和hcp2的十七分之一和十分之一。说明T6SS1在体外是一个非活化的分泌系统,相关基因处于低表达和低转录状态。
为了研究T6SS的生物学功能,本研究首先构建了缺失副溶血弧菌主要致病因子TDH,T3SS1和T3SS2相关基因的三缺失突变株DTTT,并以DTTT菌株为亲本,进一步缺失icmF1、icmF2、hcp1或hcp2基因,从细菌对宿主细胞的感染生物学(细胞粘附、细胞毒性、细胞自噬、细胞凋亡和红细胞溶血能力)和细菌对环境的适应性(生长特性,抗酸应激和形成生物被膜能力)两大方面展开副溶血弧菌两套T6SS的生物学活性研究。
副溶血弧菌T6SS1和T6SS2均具有细胞粘附能力。缺失了T6SS1结构蛋白就因icmF1和转位蛋白基因hcp1的细菌,对Caco-2和HeLa细胞的粘附能力显著降低,而缺失了T6SS2结构蛋白基因icmF2和转位蛋白基因hcp2的细菌只对HeLa细胞粘附能力降低。T6SS1在体外培养条件下处于低表达和低转录状态,但在细胞粘附试验中呈现一定的活性,且该活性能被Hcpl抗体阻断。
副溶血弧菌T6SS2具有促细胞自噬的能力。△icmF2、△hcp2和△vgrG2缺失株与小鼠巨噬细胞RAW264.7共培养4h后,细胞中LC3-Ⅰ转化为LC3-Ⅱ的量要显著低于亲本株DTTT,而△icmF1菌株与亲本株相比差异不显著。说明T6SS2可能促进RAW264.7发生自噬。副溶血弧菌感染稳定表达LC3-GFP的RAW264.7细胞,△icmF2缺失株感染的细胞中LC3-GFP的荧光斑点要显著低于亲本株DTTT,进一步证明了T6SS2促进RAW264.7自噬。
T6SS2促进RAW264.7自噬的活性可能是通过其转位蛋白和分泌蛋白来实现的。目前T6SS2还未有分泌蛋白发现,因此我们怀疑T6SS2可能通过转位蛋白Hcp2和VgrG2介导细菌的自噬。在RAW264.7中真核表达GFP-Hcp2和口GFP-VgrG2蛋白,发现表达GFP-VgrG2的细胞LC3-Ⅱ的量要显著高于对照组(表达GFP),而表达GFP-Hcp2的细胞与对照组相比无显著差异。向培养RAW264.7的培养基中添加原核表达的Hcp2和VgrG2蛋白,也呈现类似结果：添加VgrG2蛋白后,细胞LC3-Ⅱ的量要高于对照组,添加Hcp2蛋白则变化不显著。说明T6SS2对RAW264.7细胞的自噬作用是通过其转位蛋白VgrG2来实现的。不论是细胞内源性的VgrG2,还是外源添加的VgrG2均能引起细胞自噬,推测VgrG2引起细胞自噬可能在其刺穿宿主细胞膜并进入宿主细胞的过程中,引起自噬途径相关信号的改变。
无论是T6SS1还是T6SS2,都不具有细胞毒性和溶血活性,不诱导宿主细胞凋亡。T6SS1和T6SS2也不贡献副溶血弧菌对抗酸应激和形成生物被膜的能力。
在T6SS2基因簇的下游,存在两个二元调控因子VPA1045和VPA1049,具有反应调节因子典型的Che-Y结构域。Vpa1045和Vpa1049基因缺失后,hcp2转录水平与亲本相比均差异不显著。免疫印迹分析发现在细菌培养上清中的Hcp2转位量显著下降,而菌体沉淀中Hcp2表达量与亲本相比均差异不显著。进一步的细胞试验发现,Vpa1045和Vpa1049的缺失也降低细菌对HeLa细胞的粘附能力。
Vibrio parahaemolyticus, a halophilic bacterium in marine environments, is a most important foodbrone pathogen in the world. It causes wound infectious, septicemia and most commonly acute gastroenteritis in humans, it also causes disease in invertebrates, including abalone, Haliotis diversicolor supertexta and shrimp.
The major virulence factors of V. parahaemolyticus include thermostable direct hemolysin (TDH), TDH related hemolysin (TRH) and two sets of type III secretion system (T3SS). PCR identification of tdh, trh, vcrDl (structure gene of T3SS1) and vcrD2(structure gene of T3SS2) in33clinical isolates of V. parahaemolyticus and511environmental isolates stored in our lab found that the fraction of these genes were100%,9.1%,100%and87.9%respectively in clinical strains and11.2%,19.4%,100%,1.2%in environmental strains. T3SS1was present in all V. parahaemolyticus. which is consisted with previous reports.tdh and T3SS2exist higher in clinical strains than in environmental strains, which was one feather of pathogenic factors.
Type VI secretion system, a new secretion only found in proteobacteria, devotes environment adapting and pathogenicity of bacteria. Bioinformatic analysis of whole genome of V. parahaemolyticus RIMD2210633reveals two clusters of T6SS. One is on Chromosone I, which is called T6SS1; the other is on Chromosome II, which is named T6SS2. T6SS1is identical to T6SS in Vibrio cholerae, which has90.9%possession in clinical isolates and25%in environment isolates. T6SS2, however, is identical to T6SS in those marine bacteria, which exists in all the V. parahaemolyticus isolates.
To confirm if both T6SS1and T6SS2can translocate and secrete proteins in vitro, a lot of mutant strains target on structure proteins icmF1and icmF2, as well as translocons hcpl and hcp2was made. Hcpl and Hcp2polyclonal antibody were immunized using V. parahaemolyticus clinical strain HZ as background strain. Western blot was performed to analysis the expression and translocation of Hcpl and Hcp2in pellets and supernatants of HZ and its mutants. We found that Hcp2can only be detected in pellet, but not in supernatant after deleting icmF2, the structure gene of T6SS2. However, Hcpl can not be detected neither in pellet nor in supernatant in HZ and all its mutants. When expressed using plasmid, Hcpl can be detected in pellet but not in supernatant even in the wild-type strain. The result of real-time RT PCR revealed that the transcription of hcpl was10times lower than hcp2, and icmF1was about17times lower than icmF2. These results highly show that T6SS2is an active secretion system in vitro, which can translocate and secrete proteins. However, T6SS1is an inactive secretion system in vitro, and hcp1, even the whole genes of T6SS1cluster were in a low transcriptional and expressional level.
To investigate the function of T6SS, icmF1, icmF2, hcp1or hcp2mutants were made based on DTTT background, a triple mutant strain void of tdh, vcrDl and vcrD2. Functional analysis targets two major parts. One is about bacteria infection, including cell adherence, cytotoxicity, autophagy, apoptosis and hemolysis. The other is about environment adapt, including growth further, acid tolerance and biofilm.
Both T6SS1and T6SS2devote cell adherence. After deleting icmF1and hcp1, the adherence to Caco-2and HeLa cell were both decreased. However, deleting icmF2and hcp2only lead cell adherence decreasing to HeLa cell. T6SS1do play functions in cell assay, and Hcp1antibody in cell culture can decrease adherence of wild-type strain to Caco-2.
T6SS2induces autophagy. When autophagy happened, cytosolic LC3-Ⅰ converted to membrane associated LC3-Ⅱ. In our experiment, LC3-Ⅱ was decreased when macrophage RAW264.7was infected with△icmF2,△hcp2and△vgrG2mutant strains for4h. No significant change of LC3-Ⅱ was seen when infected with△icmF1. In a cell line stably expressing a GFP-tagged LC3, LC3-Ⅱ accumulates slowly when infected with△icmF2, compared to DTTT and adding2μmol/mL Rapamycin. These results indicated that T6SS2induces autophagy of RAW264.7.
T6SS2induces autophagy of RAW264.7through VgrG2protein, a translocon of T6SS2. In a cell line expressing GFP-tagged VgrG2, LC3-Ⅱ increased obviously in western blot. Further in a cell cultured with prokaryotic VgrG2protein, LC3-Ⅱ also accumulated quickly. No matter intracellular or extrinsic VgrG2induce autophagy, indicating that the autophagy pass-way might change in the process of the phage tail-associated protein VgrG2across into host membrane.
Neither T6SS1nor T6SS2induce cytotoxicity, hemolysin and apoptosis. And both T6SS1and T6SS2were not involved in acid tolerance and biofilm of V. parahaemolyticus.
In T6SS2cluster, VPA1045and VPA1049were found to contain the Che-Y domain, belonging to response regulate family of two-component regulators. Deletion of either Vpa1045or Vpa1049did not affect expression and transcription of Hcp2, but decreased translocation of Hcp2in the supernatant of V. parahaemotycus. Bacterial adherence to the HeLa monolayer was also significantly reduced infected with△Vpa1045or△Vpa1049mutant strain comparing to their parent strain. So we concluded that the two-component regulators VPA1045and VPA1049might regulate T6SS2of V. parahaemolyticus.
引文
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