布鲁氏菌LS蛋白(BLS)研究进展
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摘要
LS蛋白(2,4-二氧四氢蝶啶合成酶)广泛存在于动物、植物和微生物中,是催化核黄素生物合成的重要合成酶之一。该酶最显著的特征之一是其在不同物种中具有空间结构差异。布鲁氏菌LS蛋白(BLS)是布鲁氏菌的一种优势抗原,是由两个五聚体组成的结构稳定的十聚体。BLS是光滑型和粗糙型布鲁氏菌所共有的抗原,用于布鲁氏菌病的诊断可提高其敏感性;BLS可以激发抗原特异性细胞应答产生IFN-γ,从而对宿主产生保护力,是一种理想的布鲁氏菌病亚单位疫苗的候选蛋白。本文综述了BLS的结构特性及应用研究进展,旨在为BLS的深入研究和开发应用提供参考。
Lumazine synthase(LS) is widely distributed in animals, plants and microbes, and is one of the important synthesizing enzymes that catalyze the biosynthesis of riboflavin. One of the most remarkable characteristics of LS is that it has different spatial structures in different species. Brucella lumazine synthase(BLS), which has a stable structure of decamer consisting of two pentamers, is a dominant antigen of Brucella. BLS is a common antigen existing in both smooth type and rough type Brucella, and it can improve the sensitivity of diagnostic assays for Brucellosis; BLS is capable of stimulating antigen-specific cellular responses, resulting in production of IFN-γ, which consequently provides protection for the host. Therefore, BLS is an ideal candidate protein for development of subunit vaccine against Brucellosis. In this paper, the structural features of BLS protein and its application are reviewed,aiming at providing reference for in-depth studies and application of BLS.
Lumazine synthase(LS) is widely distributed in animals, plants and microbes, and is one of the important synthesizing enzymes that catalyze the biosynthesis of riboflavin. One of the most remarkable characteristics of LS is that it has different spatial structures in different species. Brucella lumazine synthase(BLS), which has a stable structure of decamer consisting of two pentamers, is a dominant antigen of Brucella. BLS is a common antigen existing in both smooth type and rough type Brucella, and it can improve the sensitivity of diagnostic assays for Brucellosis; BLS is capable of stimulating antigen-specific cellular responses, resulting in production of IFN-γ, which consequently provides protection for the host. Therefore, BLS is an ideal candidate protein for development of subunit vaccine against Brucellosis. In this paper, the structural features of BLS protein and its application are reviewed,aiming at providing reference for in-depth studies and application of BLS.
引文
[1]Goldbaum FA,Leoni J,Wallach JC,et al.Characterization of an18-kilodalton Brucella cytoplasmic protein which appears to be a serological marker of active infection of both human and bovine brucellosis[J].Journal of Clinical Microbiology,1993,31(8):2141-2145
[2]Goldbaum FA,Velikovsky CA,Baldi PC,et al.The 18-kDa cytoplasmic protein of Brucella species-an antigen useful for diagnosis-is a lumazine synthase[J].Journal of Medical Microbiology,1999,48(9):833-839
[3]Zylberman V,Craig PO,Klinke S,et al.High order quaternary arrangement confers increased structural stability to Brucella sp.lumazine synthase[J].The Journal of Biological Chemistry,2004,279(9):8093-8101
[4]Wu YK.Expression and antigenic study of a fusion protein originated from Brucella ribosomal protein L7/L12 and BLS[D].Baotou:Master’s Thesis of Inner Mongolia University of Science&Technology,2014(in Chinese)吴亚坤.布鲁氏菌核糖体蛋白L7/L12与BLS蛋白的融合表达及免疫原性研究[D].包头:内蒙古科技大学硕士学位论文,2014
[5]Bonomi HR,Marchesini MI,Klinke S,et al.An atypical riboflavin pathway is essential for Brucella abortus virulence[J].PLoS One,2010,5(2):e9435
[6]Zylberman V,Klinke S,Haase I,et al.Evolution of vitamin B2biosynthesis:6,7-Dimethyl-8-Ribityllumazine synthases of Brucella[J].Journal of Bacteriology,2006,188(17):6135-6142
[7]Klinke S,Zylberman V,Vega DR,et al.Crystallographic studies on decameric Brucella spp.Lumazine synthase:a novel quaternary arrangement evolved for a new function?[J].Journal of Molecular Biology,2005,353(1):124-137
[8]Braden BC,Velikovsky CA,Cauerhff AA,et al.Divergence in macromolecular assembly:X-ray crystallographic structure analysis of lumazine synthase from Brucella abortus[J].Journal of Molecular Biology,2000,297(5):1031-1036
[9]Hiriart Y,Rossi AH,Biedma ME,et al.Characterization of structural and immunological properties of a fusion protein between flagellin from Salmonella and lumazine synthase from Brucella[J].Protein Science,2017,26(5):1049-1059
[10]Cassataro J,Delpino MV,Velikovsky CA,et al.Diagnostic usefulness of antibodies against ribosome recycling factor from Brucella melitensis in human or canine brucellosis[J].Clinical and Diagnostic Laboratory Immunology,2002,9(2):366-369
[11]Wanke MM,Delpino MV,Baldi PC.Comparative performance of tests using cytosolic or outer membrane antigens of Brucella for the serodiagnosis of canine brucellosis[J].Veterinary Microbiology,2002,88(4):367-375
[12]Thepsuriyanont P,Intarapuk A,Chanket P,et al.ELISA for brucellosis detection based on three Brucella recombinant proteins[J].Southeast Asian Journal of Tropical Medicine and Public Health,2014,45(1):130-141
[13]Velikovsky CA,Goldbaum FA,Cassataro J,et al.Brucella lumazine synthase elicits a mixed Th1-Th2 immune response and reduces infection in mice challenged with Brucella abortus 544independently of the adjuvant formulation used[J].Infection and Immunity,2003,71(10):5750-5755
[14]Velikovsky CA,Cassataro J,Giambartolomei GH,et al.A DNAvaccine encoding lumazine synthase from Brucella abortus induces protective immunity in BALB/c mice[J].Infection and Immunity,2002,70(5):2507-2511
[15]Shan SM,Wang JY,Du ZQ.The enhancement of immunostimulatory ability of antigen Omp31 by Brucella lumazine synthase[J].Science&Technology Vision,2014(6):112(in Chinese)单生苗,王建英,杜志强.布鲁菌BLS分子增强抗原分子Omp31免疫刺激能力的研究[J].科技视界,2014(6):112
[16]Estein SM,Fiorentino MA,Paolicchi FA,et al.The polymeric antigen BLSOmp31 confers protection against Brucella ovis infection in rams[J].Vaccine,2009,27(48):6704-6711
[17]Cassataro J,Pasquevich KA,Estein SM,et al.A recombinant subunit vaccine based on the insertion of 27 amino acids from Omp31 to the N-terminus of BLS induced a similar degree of protection against B.ovis than Rev.1 vaccination[J].Vaccine,2007,25(22):4437-4446
[18]Du ZQ,Wang JY.A novel lumazine synthase molecule from Brucella significantly promotes the immune-stimulation effects of antigenic protein[J].Genetics and Molecular Research,2015,14(4):13084-13095
[19]Zhou LL.Preliminary study on brucella BLS-L7/L12recombinant subunit vaccine[D].Beijing:Master’s Thesis of Academy of Military Medical Sciences,2007(in Chinese)周丽丽.布鲁氏菌BLS-L7/L12重组亚单位疫苗的初步研究[D].北京:中国人民解放军军事医学科学院硕士学位论文,2007
[20]Du ZQ,Li X,Wang JY.Immunogenicity analysis of a novel subunit vaccine candidate molecule-recombinant L7/L12ribosomal protein of Brucella suis[J].Applied Biochemistry and Biotechnology,2016,179(8):1445-1455
[21]Mejias MP,Cabrera G,Fernández-Brando RJ,et al.Protection of mice against Shiga toxin 2(Stx2)-associated damage by maternal immunization with a Brucella Lumazine synthase-Stx2 B subunit chimera[J].Infection&Immunity,2014,82(4):1491-1499
[22]Sacerdoti F,Mejías MP,Bruballa AC,et al.Immunization with BLS-Stx2B chimera totally protects dams from early pregnancy loss induced by Shiga toxin type 2(Stx2)and confers anti-Stx2immunity to the offspring[J].Vaccine,2016,34(39):4732-4737
[23]Martorelli L,Garbaccio S,Vilte DA,et al.Immune response in calves vaccinated with type three secretion system antigens and Shiga toxin 2B subunit of Escherichia coli O157:H7[J].PLoSOne,2017,12(1):e0169422
[24]Mejias MP,Ghersi G,Craig PO,et al.Immunization with a chimera consisting of the B subunit of Shiga toxin type 2 and Brucella lumazine synthase confers total protection against Shiga toxins in mice[J].The Journal of Immunology,2013,191(5):2403-2411
[25]Bellido D,Craig PO,Mozgovoj MV,et al.Brucella spp.lumazine synthase as a bovine rotavirus antigen delivery system[J].Vaccine,2009,27(1):136-145
[26]Alfano EF,Lentz EM,Bellido D,et al.Expression of the multimeric and highly immunogenic Brucella spp.Lumazine synthase fused to bovine rotavirus VP8d as a scaffold for antigen production in tobacco chloroplasts[J].Frontiers in Plant Science,2015,6:1170
[27]Alvarez P,Zylberman V,Ghersi G,et al.Tandem repeats of the extracellular domain of Matrix 2 influenza protein exposed in Brucella lumazine synthase decameric carrier molecule induce protection in mice[J].Vaccine,2013,31(5):806-812
[28]Fragoso G,Esquivel-Guadarrama F,Santana MA,et al.Heterologous prime-boost oral immunization with GK-1 peptide from Taenia crassiceps cysticerci induces protective immunity[J].Clinical and Vaccine Immunology,2011,18(7):1067-1076
[29]Cruz-Revilla C,Toledo A,Rosas G,et al.Effective protection against experimental Taenia solium tapeworm infection in hamsters by primo-infection and by vaccination with recombinant or synthetic heterologous antigens[J].Journal of Parasitology,2006,92(4):864-868
[30]Berguer PM,Alzogaray VA,Rossi AH,et al.A polymeric protein induces specific cytotoxicity in a TLR4 dependent manner in the absence of adjuvants[J].PLoS One,2012,7(9):e45705
[31]Rossi AH,Farias A,Fernández JE,et al.Brucella spp.Lumazine synthase induces a TLR4-mediated protective response against B16 melanoma in mice[J].PLoS One,2015,10(5):e0126827
[32]Jiang H,Dong H,Peng XW,et al.Transcriptome analysis of gene expression profiling of infected macrophages between Brucella suis 1330 and live attenuated vaccine strain S2 displays mechanistic implication for regulation of virulence[J].Microbial Pathogenesis,2018,119:241-247
[2]Goldbaum FA,Velikovsky CA,Baldi PC,et al.The 18-kDa cytoplasmic protein of Brucella species-an antigen useful for diagnosis-is a lumazine synthase[J].Journal of Medical Microbiology,1999,48(9):833-839
[3]Zylberman V,Craig PO,Klinke S,et al.High order quaternary arrangement confers increased structural stability to Brucella sp.lumazine synthase[J].The Journal of Biological Chemistry,2004,279(9):8093-8101
[4]Wu YK.Expression and antigenic study of a fusion protein originated from Brucella ribosomal protein L7/L12 and BLS[D].Baotou:Master’s Thesis of Inner Mongolia University of Science&Technology,2014(in Chinese)吴亚坤.布鲁氏菌核糖体蛋白L7/L12与BLS蛋白的融合表达及免疫原性研究[D].包头:内蒙古科技大学硕士学位论文,2014
[5]Bonomi HR,Marchesini MI,Klinke S,et al.An atypical riboflavin pathway is essential for Brucella abortus virulence[J].PLoS One,2010,5(2):e9435
[6]Zylberman V,Klinke S,Haase I,et al.Evolution of vitamin B2biosynthesis:6,7-Dimethyl-8-Ribityllumazine synthases of Brucella[J].Journal of Bacteriology,2006,188(17):6135-6142
[7]Klinke S,Zylberman V,Vega DR,et al.Crystallographic studies on decameric Brucella spp.Lumazine synthase:a novel quaternary arrangement evolved for a new function?[J].Journal of Molecular Biology,2005,353(1):124-137
[8]Braden BC,Velikovsky CA,Cauerhff AA,et al.Divergence in macromolecular assembly:X-ray crystallographic structure analysis of lumazine synthase from Brucella abortus[J].Journal of Molecular Biology,2000,297(5):1031-1036
[9]Hiriart Y,Rossi AH,Biedma ME,et al.Characterization of structural and immunological properties of a fusion protein between flagellin from Salmonella and lumazine synthase from Brucella[J].Protein Science,2017,26(5):1049-1059
[10]Cassataro J,Delpino MV,Velikovsky CA,et al.Diagnostic usefulness of antibodies against ribosome recycling factor from Brucella melitensis in human or canine brucellosis[J].Clinical and Diagnostic Laboratory Immunology,2002,9(2):366-369
[11]Wanke MM,Delpino MV,Baldi PC.Comparative performance of tests using cytosolic or outer membrane antigens of Brucella for the serodiagnosis of canine brucellosis[J].Veterinary Microbiology,2002,88(4):367-375
[12]Thepsuriyanont P,Intarapuk A,Chanket P,et al.ELISA for brucellosis detection based on three Brucella recombinant proteins[J].Southeast Asian Journal of Tropical Medicine and Public Health,2014,45(1):130-141
[13]Velikovsky CA,Goldbaum FA,Cassataro J,et al.Brucella lumazine synthase elicits a mixed Th1-Th2 immune response and reduces infection in mice challenged with Brucella abortus 544independently of the adjuvant formulation used[J].Infection and Immunity,2003,71(10):5750-5755
[14]Velikovsky CA,Cassataro J,Giambartolomei GH,et al.A DNAvaccine encoding lumazine synthase from Brucella abortus induces protective immunity in BALB/c mice[J].Infection and Immunity,2002,70(5):2507-2511
[15]Shan SM,Wang JY,Du ZQ.The enhancement of immunostimulatory ability of antigen Omp31 by Brucella lumazine synthase[J].Science&Technology Vision,2014(6):112(in Chinese)单生苗,王建英,杜志强.布鲁菌BLS分子增强抗原分子Omp31免疫刺激能力的研究[J].科技视界,2014(6):112
[16]Estein SM,Fiorentino MA,Paolicchi FA,et al.The polymeric antigen BLSOmp31 confers protection against Brucella ovis infection in rams[J].Vaccine,2009,27(48):6704-6711
[17]Cassataro J,Pasquevich KA,Estein SM,et al.A recombinant subunit vaccine based on the insertion of 27 amino acids from Omp31 to the N-terminus of BLS induced a similar degree of protection against B.ovis than Rev.1 vaccination[J].Vaccine,2007,25(22):4437-4446
[18]Du ZQ,Wang JY.A novel lumazine synthase molecule from Brucella significantly promotes the immune-stimulation effects of antigenic protein[J].Genetics and Molecular Research,2015,14(4):13084-13095
[19]Zhou LL.Preliminary study on brucella BLS-L7/L12recombinant subunit vaccine[D].Beijing:Master’s Thesis of Academy of Military Medical Sciences,2007(in Chinese)周丽丽.布鲁氏菌BLS-L7/L12重组亚单位疫苗的初步研究[D].北京:中国人民解放军军事医学科学院硕士学位论文,2007
[20]Du ZQ,Li X,Wang JY.Immunogenicity analysis of a novel subunit vaccine candidate molecule-recombinant L7/L12ribosomal protein of Brucella suis[J].Applied Biochemistry and Biotechnology,2016,179(8):1445-1455
[21]Mejias MP,Cabrera G,Fernández-Brando RJ,et al.Protection of mice against Shiga toxin 2(Stx2)-associated damage by maternal immunization with a Brucella Lumazine synthase-Stx2 B subunit chimera[J].Infection&Immunity,2014,82(4):1491-1499
[22]Sacerdoti F,Mejías MP,Bruballa AC,et al.Immunization with BLS-Stx2B chimera totally protects dams from early pregnancy loss induced by Shiga toxin type 2(Stx2)and confers anti-Stx2immunity to the offspring[J].Vaccine,2016,34(39):4732-4737
[23]Martorelli L,Garbaccio S,Vilte DA,et al.Immune response in calves vaccinated with type three secretion system antigens and Shiga toxin 2B subunit of Escherichia coli O157:H7[J].PLoSOne,2017,12(1):e0169422
[24]Mejias MP,Ghersi G,Craig PO,et al.Immunization with a chimera consisting of the B subunit of Shiga toxin type 2 and Brucella lumazine synthase confers total protection against Shiga toxins in mice[J].The Journal of Immunology,2013,191(5):2403-2411
[25]Bellido D,Craig PO,Mozgovoj MV,et al.Brucella spp.lumazine synthase as a bovine rotavirus antigen delivery system[J].Vaccine,2009,27(1):136-145
[26]Alfano EF,Lentz EM,Bellido D,et al.Expression of the multimeric and highly immunogenic Brucella spp.Lumazine synthase fused to bovine rotavirus VP8d as a scaffold for antigen production in tobacco chloroplasts[J].Frontiers in Plant Science,2015,6:1170
[27]Alvarez P,Zylberman V,Ghersi G,et al.Tandem repeats of the extracellular domain of Matrix 2 influenza protein exposed in Brucella lumazine synthase decameric carrier molecule induce protection in mice[J].Vaccine,2013,31(5):806-812
[28]Fragoso G,Esquivel-Guadarrama F,Santana MA,et al.Heterologous prime-boost oral immunization with GK-1 peptide from Taenia crassiceps cysticerci induces protective immunity[J].Clinical and Vaccine Immunology,2011,18(7):1067-1076
[29]Cruz-Revilla C,Toledo A,Rosas G,et al.Effective protection against experimental Taenia solium tapeworm infection in hamsters by primo-infection and by vaccination with recombinant or synthetic heterologous antigens[J].Journal of Parasitology,2006,92(4):864-868
[30]Berguer PM,Alzogaray VA,Rossi AH,et al.A polymeric protein induces specific cytotoxicity in a TLR4 dependent manner in the absence of adjuvants[J].PLoS One,2012,7(9):e45705
[31]Rossi AH,Farias A,Fernández JE,et al.Brucella spp.Lumazine synthase induces a TLR4-mediated protective response against B16 melanoma in mice[J].PLoS One,2015,10(5):e0126827
[32]Jiang H,Dong H,Peng XW,et al.Transcriptome analysis of gene expression profiling of infected macrophages between Brucella suis 1330 and live attenuated vaccine strain S2 displays mechanistic implication for regulation of virulence[J].Microbial Pathogenesis,2018,119:241-247