马耳他型布氏杆菌弱毒疫苗株M5-90致弱分子机制的研究
摘要
布病尤其是由B. melitensis感染所致,仍然是目前世界上最重要的种人畜共患病,每年大约有50多万病例报道。迄今为止,采用多种方法开发和研究防控布病的疫苗,但是还没有种安全有效的疫苗能应用于人的布病防控,当前的主要疫苗均对人有定致病性。B. melitensis M5-90系我国自行分离培养的弱毒疫苗株,具有较好的安全性及免疫保护力,为我国布病防控发挥了重要作用,但其致弱的分子机制还不甚清楚。为研制更加安全、有效的布氏杆菌疫苗,迫切需要加强对布氏杆菌病病原致病分子机制与免疫机制的基础研究。
I.马耳他布氏杆菌疫苗株M5-90致弱分子机制的研究
在完成M5-90及其亲本强毒株M28的全基因组测序基础上,通过系统基因组比对,并结合比对亲缘关系最近的强毒国际参考株B. melitensis 16M和ATCC23457,共筛选到23个毒力相关基因(OCDs)。其中差异最显著的是延伸因子EF-Tu(BM28_A1261),在M5-90编码区出现50处SNPs和9处Indels,占整个基因组差异的30%。2-D DIGE分析实验室条件下培养的M28和M5-90全细菌蛋白(pH范围4.0-7.0)表达差异,共鉴定到24个差异显著蛋白,7个为M5-90高表达,其余17个为M28高表达。这是第次关于人工致弱的强、弱亲本毒株间基因组学和比较蛋白组学分析。结果发现, DNA/RNA合成代谢,营养吸收利用和细胞外膜合成或外膜蛋白等相关基因变异在M5-90的致弱过程中起到了重要作用。在此基础上,首先选择基因组上突变最为集中的tuf-2(BM28_A1261)基因作为重组靶位点,以M28和M5-90为亲本,以卡那霉素抗性基因(Kan~r)作为筛选标记,构建tuf基因缺失突变株;成功构建了突变株M28-tuf1、M28-tuf2和M90-tuf2。M90-tuf2和亲本株M5-90不论在生长特性还是对小鼠毒力上都无显著差异;M28-tuf1、M28-tuf2对小鼠致病力明显减弱(p<0.01),但仍比疫苗株强(p<0.01)。M28-tuf1致病力略高于M28-tuf2,差异不显著;通过小鼠感染模型证实tuf是M5-90致弱的重要基因,但不是唯因素,tuf-2在M5-90致弱中的起到重要作用。
II.马耳他布氏杆菌疫苗株M5-90致弱免疫机制研究
布氏杆菌是种胞内寄生菌,巨噬细胞是布氏杆菌体内侵袭的主要目标细胞。M5-90及其强毒亲本株M28致病力显著差异,研究二者与宿主相互作用差异,有助于与理解M5-90致弱的免疫机制。本研究,利用数字表达谱DGE技术分析鼠腹膜巨噬细胞感染M28和M5-90 4 h后转录组的变化,共计鉴定出1019个DEGs。发现多个显著性差异信号通路,如溶酶体和SNARE胞内运输通路。首次分析了强弱毒布氏杆菌感染组间DEGs,并对显著性差异代谢通路DEGs构建蛋白相互作用网络(Singal-Net)。网络中关键基因多为细胞凋亡相关基因,如Mapk3、Traf6、Chuk、Kras、Jak1和Ptpn6等。这些基因及其参与的信号转导过程体现了强弱菌株侵染宿主细胞的主要差别,其结果是弱毒株M5-90抗溶酶体消化及抗细胞凋亡能力弱于强毒株M28,导致宿主细胞内生存能力的下降或存活时间的缩短。这些数据有利于深入理解M5-90的致弱分子免疫机制。
Brucella melitensis is a Gram-negative coccobacillus bacteria belonging to theα-Proteobacteria subclass. It is an important zoonotic pathogen that causes brucellosis, a disease affecting sheep, cattle, and sometimes humans. So far, no satisfactory vaccine has been discovered to fight the disease in humans, while animal vaccines are pathogenic to humans. Therefore, we should venture deeper in the study of the pathogenic and attenuation mechanism of Brucella as well as the development of new types of Brucella vaccines.
I. molecular basis of Attenuation of Brucella melitensis strain M5-90
B. melitensis vaccine strain M5-90 (identified as biovar 1) originated after a virulent B. melitensis (M28) isolation from a sheep was serially-passaged through chickens, treated with acriflavine and passaged for 90 generations in chicken embryo fibroblasts. This attenuated vaccine is considered to be one of the key factors that led to a rapid decline in the incidence of brucellosis in animals and humans in China during the 1970s to 1990s. Understanding the genetic similarities and differences between the vaccine strain and wild virulent strain will provide clues as to how the vaccine provides protection. To that end, we sequenced the B. melitensis parent strain M28 and the M5-90 strain using a whole-genome shotgun sequencing strategy. The main goal of this study is to identify candidate virulence genes by systematic comparative analysis of the attenuated strain with virulent strain M28 and other published genome sequences of two closely related strains B. melitensis 16M and ATCC 23457. We found 23 OCDs (ORFs with consistent differences) were different between the attenuated strains but they were identical amongst the virulent strains. A proteome study based on 2-D DIGE was performed in order to analyze the proteome difference between M28 and M5-90, which were grown under identical laboratory conditions. The majority of the 24 proteins heavily regulated at this stage were involved in bacterial metabolism, amino acid transportation, cell envelope and outer membrane biogenesis. This is the first genomic and proteomic analysis of an artificially attenuated Brucella strain. The results suggest that inactivation of genes involved in DNA/RNA metabolism, nutrient acquisition and utilization, and cell envelope or outer membrane proteins biogenesis may have played a role in the attenuation of M5-90.
Compared with the M28 EF-Tu gene (BM28_A1261), M5-90 had one combined EF-Tu pseudogene with 50 SNPs and nine gaps (eight single nucleotide additions and one nucleotide deletion). To evaluate the potential role of EF-Tu in pathogenesis, the mutant tuf gene of B.melitensis (M28-tuf1, M28-tuf2 and M90-tuf2) was constructed by replacing the tuf gene of M28 and its attenuated M5-90 strain with kanamycin resistance gene. Double mutation recombinant was selected by adding kanamycin and ampicillin in the culture, and confirmed by PCR. The M28-tuf1 and M28-tuf2 mutant strains exhibited significant attenuation compared to M28 in mice infection model and still more pathogenically significant than M5-90. M28-tuf2 attenuation was compared to M28-tuf1, but the difference between the two groups is not considered statistically significant. These results indicated that the tuf-2 gene play an important role in the attenuation of M5-90.
II. Immunologic mechanism of attenuation of M5-90 (murine transcriptome DGE analysis)
Brucella species (spp.) reside in professional and non-professional phagocytes; in particular, macrophages are a major target in infected mammals. In comparison with other pathogenic bacteria, Brucella lack classical virulence factors, and their virulence is associated with their capacity to invade and propagate within host cells. The molecular mechanisms that cause M5-90 attenuation, particularly the alterations in pathogenicity between virulent strains of B. melitensis, remain poorly understood. In this study, we employed the Illumina Genome Analyzer platform to perform Digital Gene Expression (DGE) analysis of the peritoneal macrophage genome-wide transcriptome response to B. melitensis infection. A total of 1019 differentially expressed transcripts were identified in the macrophages four hours after infection with the different B. melitensis strains, with genes involved in the lysosome and SNARE interactions in vesicular transport being highly represented. Many proteins of the MAPK, Jak–STAT and TLR signaling pathways, along with the renal cell carcinoma and some other associated signaling pathways, were built in the protein–protein interaction networks (Signal-net). The key genes were some apoptosis-related genes, like Mapk3, Traf6, Chuk, Kras, Jak1 and Ptpn6. The regulation of these genes resulted in anti-apoptotic effects, especially M5-90 with weaker anti-apoptotic ability than M28. Our data provide new insight into the molecular attenuation mechanism of strain M5-90 and may enable vaccine residual virulence to be reduced, enhancing vaccine efficacy.
I.马耳他布氏杆菌疫苗株M5-90致弱分子机制的研究
在完成M5-90及其亲本强毒株M28的全基因组测序基础上,通过系统基因组比对,并结合比对亲缘关系最近的强毒国际参考株B. melitensis 16M和ATCC23457,共筛选到23个毒力相关基因(OCDs)。其中差异最显著的是延伸因子EF-Tu(BM28_A1261),在M5-90编码区出现50处SNPs和9处Indels,占整个基因组差异的30%。2-D DIGE分析实验室条件下培养的M28和M5-90全细菌蛋白(pH范围4.0-7.0)表达差异,共鉴定到24个差异显著蛋白,7个为M5-90高表达,其余17个为M28高表达。这是第次关于人工致弱的强、弱亲本毒株间基因组学和比较蛋白组学分析。结果发现, DNA/RNA合成代谢,营养吸收利用和细胞外膜合成或外膜蛋白等相关基因变异在M5-90的致弱过程中起到了重要作用。在此基础上,首先选择基因组上突变最为集中的tuf-2(BM28_A1261)基因作为重组靶位点,以M28和M5-90为亲本,以卡那霉素抗性基因(Kan~r)作为筛选标记,构建tuf基因缺失突变株;成功构建了突变株M28-tuf1、M28-tuf2和M90-tuf2。M90-tuf2和亲本株M5-90不论在生长特性还是对小鼠毒力上都无显著差异;M28-tuf1、M28-tuf2对小鼠致病力明显减弱(p<0.01),但仍比疫苗株强(p<0.01)。M28-tuf1致病力略高于M28-tuf2,差异不显著;通过小鼠感染模型证实tuf是M5-90致弱的重要基因,但不是唯因素,tuf-2在M5-90致弱中的起到重要作用。
II.马耳他布氏杆菌疫苗株M5-90致弱免疫机制研究
布氏杆菌是种胞内寄生菌,巨噬细胞是布氏杆菌体内侵袭的主要目标细胞。M5-90及其强毒亲本株M28致病力显著差异,研究二者与宿主相互作用差异,有助于与理解M5-90致弱的免疫机制。本研究,利用数字表达谱DGE技术分析鼠腹膜巨噬细胞感染M28和M5-90 4 h后转录组的变化,共计鉴定出1019个DEGs。发现多个显著性差异信号通路,如溶酶体和SNARE胞内运输通路。首次分析了强弱毒布氏杆菌感染组间DEGs,并对显著性差异代谢通路DEGs构建蛋白相互作用网络(Singal-Net)。网络中关键基因多为细胞凋亡相关基因,如Mapk3、Traf6、Chuk、Kras、Jak1和Ptpn6等。这些基因及其参与的信号转导过程体现了强弱菌株侵染宿主细胞的主要差别,其结果是弱毒株M5-90抗溶酶体消化及抗细胞凋亡能力弱于强毒株M28,导致宿主细胞内生存能力的下降或存活时间的缩短。这些数据有利于深入理解M5-90的致弱分子免疫机制。
Brucella melitensis is a Gram-negative coccobacillus bacteria belonging to theα-Proteobacteria subclass. It is an important zoonotic pathogen that causes brucellosis, a disease affecting sheep, cattle, and sometimes humans. So far, no satisfactory vaccine has been discovered to fight the disease in humans, while animal vaccines are pathogenic to humans. Therefore, we should venture deeper in the study of the pathogenic and attenuation mechanism of Brucella as well as the development of new types of Brucella vaccines.
I. molecular basis of Attenuation of Brucella melitensis strain M5-90
B. melitensis vaccine strain M5-90 (identified as biovar 1) originated after a virulent B. melitensis (M28) isolation from a sheep was serially-passaged through chickens, treated with acriflavine and passaged for 90 generations in chicken embryo fibroblasts. This attenuated vaccine is considered to be one of the key factors that led to a rapid decline in the incidence of brucellosis in animals and humans in China during the 1970s to 1990s. Understanding the genetic similarities and differences between the vaccine strain and wild virulent strain will provide clues as to how the vaccine provides protection. To that end, we sequenced the B. melitensis parent strain M28 and the M5-90 strain using a whole-genome shotgun sequencing strategy. The main goal of this study is to identify candidate virulence genes by systematic comparative analysis of the attenuated strain with virulent strain M28 and other published genome sequences of two closely related strains B. melitensis 16M and ATCC 23457. We found 23 OCDs (ORFs with consistent differences) were different between the attenuated strains but they were identical amongst the virulent strains. A proteome study based on 2-D DIGE was performed in order to analyze the proteome difference between M28 and M5-90, which were grown under identical laboratory conditions. The majority of the 24 proteins heavily regulated at this stage were involved in bacterial metabolism, amino acid transportation, cell envelope and outer membrane biogenesis. This is the first genomic and proteomic analysis of an artificially attenuated Brucella strain. The results suggest that inactivation of genes involved in DNA/RNA metabolism, nutrient acquisition and utilization, and cell envelope or outer membrane proteins biogenesis may have played a role in the attenuation of M5-90.
Compared with the M28 EF-Tu gene (BM28_A1261), M5-90 had one combined EF-Tu pseudogene with 50 SNPs and nine gaps (eight single nucleotide additions and one nucleotide deletion). To evaluate the potential role of EF-Tu in pathogenesis, the mutant tuf gene of B.melitensis (M28-tuf1, M28-tuf2 and M90-tuf2) was constructed by replacing the tuf gene of M28 and its attenuated M5-90 strain with kanamycin resistance gene. Double mutation recombinant was selected by adding kanamycin and ampicillin in the culture, and confirmed by PCR. The M28-tuf1 and M28-tuf2 mutant strains exhibited significant attenuation compared to M28 in mice infection model and still more pathogenically significant than M5-90. M28-tuf2 attenuation was compared to M28-tuf1, but the difference between the two groups is not considered statistically significant. These results indicated that the tuf-2 gene play an important role in the attenuation of M5-90.
II. Immunologic mechanism of attenuation of M5-90 (murine transcriptome DGE analysis)
Brucella species (spp.) reside in professional and non-professional phagocytes; in particular, macrophages are a major target in infected mammals. In comparison with other pathogenic bacteria, Brucella lack classical virulence factors, and their virulence is associated with their capacity to invade and propagate within host cells. The molecular mechanisms that cause M5-90 attenuation, particularly the alterations in pathogenicity between virulent strains of B. melitensis, remain poorly understood. In this study, we employed the Illumina Genome Analyzer platform to perform Digital Gene Expression (DGE) analysis of the peritoneal macrophage genome-wide transcriptome response to B. melitensis infection. A total of 1019 differentially expressed transcripts were identified in the macrophages four hours after infection with the different B. melitensis strains, with genes involved in the lysosome and SNARE interactions in vesicular transport being highly represented. Many proteins of the MAPK, Jak–STAT and TLR signaling pathways, along with the renal cell carcinoma and some other associated signaling pathways, were built in the protein–protein interaction networks (Signal-net). The key genes were some apoptosis-related genes, like Mapk3, Traf6, Chuk, Kras, Jak1 and Ptpn6. The regulation of these genes resulted in anti-apoptotic effects, especially M5-90 with weaker anti-apoptotic ability than M28. Our data provide new insight into the molecular attenuation mechanism of strain M5-90 and may enable vaccine residual virulence to be reduced, enhancing vaccine efficacy.
引文
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