Regulated delayed attenuation enhances the immunogenicity and protection provided by recombinant Salmonella enterica serovar Typhimurium vaccines expressing serovar Choleraesuis O-polysaccharides
Regulated delayed attenuation enhances the immunogenicity and protection provided by recombinant Salmonella enterica serovar Typhimurium vaccines expressing serovar Choleraesuis O-polysaccharides
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调节延迟减毒增强了表达猪霍乱 O-多糖血清型的重组肠沙门氏菌血清型鼠伤寒疫苗提供的免疫原性和保护作用
DOI：
10.1016/j.vaccine.2018.07.009
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发表时间：
2018
期刊：
影响因子：
5.5
通讯作者：
Zhang Ling
中科院分区：
文献类型：
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作者：
Zhao Xinxin;Jia Renyong;Zhu Dekang;Liu Mafeng;Wang Mingshu;Chen Shun;Yang Qiao;Wu Ying;Zhang Shaqiu;Zhang Ling;Liu Yunya;Yu Yanling;Cheng Anchun;Zhao Xinxin;Jia Renyong;Zhu Dekang;Liu Mafeng;Wang Mingshu;Chen Shun;Yang Qiao;Wu Ying;Zhang Shaqiu;Zhang Ling
调节性延迟减毒是一种保留沙门氏菌载体疫苗免疫原性的研究策略。在本研究中，该策略被用于优化先前构建的表达猪霍乱沙门氏菌O-多糖（OPS）的重组沙门氏菌肠溶型鼠伤寒沙门氏菌疫苗。通过用阿拉伯糖依赖性araCPBAD启动子替换天然ecrp启动子，构建了新型疫苗株SLT 31（Δ asd Δ rmlB-rfbP Δ Pcrp：：TaraCPBAD）和SLT 33（ΔasdΔrfbPΔpagL：：TaraCPBAD rfbP ΔPcrp：：TaraCPBAD）。作为对照，还构建了两个具有直接crp突变的疫苗株，即SLT 30（ΔasdΔrmlB-rfbPΔcrp）和SLT 32（ΔasdΔrfbPΔpagL：：TaraCPBADrfbPΔcrp）。然后，在具有或不具有调节的延迟减毒的菌株中评价将Asd+质粒pCZ 1上的异源猪霍乱沙门氏菌OPS递送至小鼠免疫系统的能力。SLT 30（pCZ 1）和SLT 31（pCZ 1）菌株仅表达异源OPS，而SLT 32（pCZ 1）和SLT 33（pCZ 1）菌株共表达同源和异源OPS。与SLT 30（pCZ 1）或SLT 32（pCZ 1）株相比，具有可调节的延迟减毒的菌株SLT 31（pCZ 1）或SLT 33（pCZ 1）在小鼠组织中的定殖率显著更好，并且在免疫后刺激了更强的抗猪霍乱沙门氏菌LPS的抗体应答。与SLT 30（pCZ 1）或SLT 32（pCZ 1）免疫后观察到的效果相比，用SLT 31（pCZ 1）或SLT 33（pCZ 1）免疫导致小鼠组织中细菌载量的显著降低，并且针对致死猪霍乱沙门氏菌剂量的保护程度更高（分别为100%对80%或70%对50%）。此外，所有四种疫苗均能提供完全的抗鼠伤寒沙门氏菌攻击保护。总之，我们的研究表明，通过一个araCPBAD调控的crp基因调控的延迟减毒可以增强表达异源OPS的沙门氏菌载体疫苗的交叉保护作用，并且菌株SLT 31（pCZ 1）是预防鼠伤寒沙门氏菌和猪霍乱沙门氏菌感染的良好候选疫苗。
Regulated delayed attenuation is a well-studied strategy for retaining the immunogenicity ofSalmonella-vectored vaccines. In this study, this strategy was used to optimize two previously constructed recombinantSalmonella entericaserovar Typhimurium vaccines expressingS.Choleraesuis O-polysaccharides (OPS). The novel vaccine strains SLT31 (ΔasdΔrmlB-rfbPΔPcrp::TaraCPBAD) and SLT33 (ΔasdΔrfbPΔpagL::TaraCPBADrfbPΔPcrp::TaraCPBAD) were constructed by replacement of the nativecrppromoter with the arabinose-dependentaraCPBADpromoter. As controls, two vaccine strains with directcrpmutations were also constructed, namely, SLT30 (ΔasdΔrmlB-rfbPΔcrp) and SLT32 (ΔasdΔrfbPΔpagL::TaraCPBADrfbPΔcrp). Then, the ability to deliver the heterologousS.Choleraesuis OPS on the Asd+plasmid pCZ1 to the mouse immune system was evaluated in the strains with or without regulated delayed attenuation. The SLT30 (pCZ1) and SLT31 (pCZ1) strains expressed only the heterologous OPS, while the SLT32 (pCZ1) and SLT33 (pCZ1) strains co-expressed the homologous and heterologous OPS. The strain SLT31 (pCZ1) or SLT33 (pCZ1), which exhibited regulated delayed attenuation, colonized mouse tissues significantly better and stimulated stronger antibody responses againstS.Choleraesuis LPS post immunization than the SLT30 (pCZ1) or SLT32 (pCZ1) strain. Immunization with SLT31 (pCZ1) or SLT33 (pCZ1) resulted in a significant reduction in bacterial loads in mouse tissues and a greater degree of protection against a lethalS.Choleraesuis dose compared with the effects observed after SLT30 (pCZ1) or SLT32 (pCZ1) immunization (100% vs. 80% or 70% vs. 50%, respectively). In addition, all four vaccines conferred complete protection againstS.Typhimurium challenge. Overall, our study demonstrates that regulated delayed attenuation via anaraCPBAD-regulatedcrpgene can enhance the cross-protection bySalmonella-vectored vaccines expressing heterologous OPS, and strain SLT31 (pCZ1) is a good candidate vaccine for preventing bothS.Typhimurium andS.Choleraesuis infections.