Live Attenuated Salmonella Vaccines against Mycobacterium tuberculosis with Antigen Delivery via the Type III Secretion System
Live Attenuated Salmonella Vaccines against Mycobacterium tuberculosis with Antigen Delivery via the Type III Secretion System
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DOI：
10.1128/iai.05525-11
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发表时间：
2012-02-01
影响因子：
3.1
通讯作者：
Clark-Curtiss, Josephine E.
中科院分区：
文献类型：
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作者：
Dolores Juarez-Rodriguez, Maria;Arteaga-Cortes, Lourdes T.;Clark-Curtiss, Josephine E.
结核病仍然是一个全球性的健康威胁，迫切需要开发一种安全、有效并能提供长期保护的疫苗。在这项研究中，我们构建了重组减毒沙门氏菌疫苗（RASV）菌株与表达融合蛋白的质粒，融合蛋白由沙门氏菌3型分泌系统效应子SopE的80个氨基末端氨基酸和结核分枝杆菌抗原早期分泌抗原靶6-kDa（ESAT-6）蛋白和培养滤液蛋白10（CFP-10）组成。我们证明，在细胞培养试验中，SopE-分枝杆菌抗原融合蛋白易位到INT-407细胞的细胞质中。用合成SopE-ESAT-6- CFP-10融合蛋白的RASV株口服免疫小鼠，导致小鼠对M.结核病H37 Rv的免疫保护，这与皮下施用的牛分枝杆菌卡介苗（BCG）免疫所提供的保护相似。此外，用指定这些分枝杆菌抗原的RASV菌株进行口服免疫引起产生针对ESAT-6的显著抗体滴度，并产生分泌ESAT-6或CFP-10特异性γ干扰素（IFN-γ）和分泌肿瘤坏死因子α（TNF-α）的脾细胞。
Tuberculosis remains a global health threat, and there is dire need to develop a vaccine that is safe and efficacious and confers long-lasting protection. In this study, we constructed recombinant attenuated Salmonella vaccine (RASV) strains with plasmids expressing fusion proteins consisting of the 80 amino-terminal amino acids of the type 3 secretion system effector SopE of Salmonella and the Mycobacterium tuberculosis antigens early secreted antigenic target 6-kDa (ESAT-6) protein and culture filtrate protein 10 (CFP-10). We demonstrated that the SopE-mycobacterial antigen fusion proteins were translocated into the cytoplasm of INT-407 cells in cell culture assays. Oral immunization of mice with RASV strains synthesizing SopE-ESAT-6- CFP-10 fusion proteins resulted in significant protection of the mice against aerosol challenge with M. tuberculosis H37Rv that was similar to the protection afforded by immunization with Mycobacterium bovis bacillus Calmette-Guerin (BCG) administered subcutaneously. In addition, oral immunization with the RASV strains specifying these mycobacterial antigens elicited production of significant antibody titers to ESAT-6 and production of ESAT-6- or CFP-10-specific gamma interferon (IFN-gamma)-secreting and tumor necrosis factor alpha (TNF-alpha)-secreting splenocytes.