Evaluation of Francisella tularensis ΔpdpC as a candidate live attenuated vaccine against respiratory challenge by a virulent SCHU P9 strain of Francisella tularensis in a C57BL/6J mouse model
Evaluation of Francisella tularensis ΔpdpC as a candidate live attenuated vaccine against respiratory challenge by a virulent SCHU P9 strain of Francisella tularensis in a C57BL/6J mouse model
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在 C57BL/6J 小鼠模型中评估土拉弗朗西斯菌 ΔpdpC 作为候选减毒活疫苗针对土拉弗朗西斯菌 SCHU P9 毒株引起的呼吸道攻击
DOI：
10.1111/1348-0421.12555
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发表时间：
2018
影响因子：
2.6
通讯作者：
Morikawa Shigeru
中科院分区：
文献类型：
--
作者：
Tian Deyu;Uda Akihiko;Park Eun-sil;Hotta Akitoyo;Fujita Osamu;Yamada Akio;Hirayama Kazuhiro;Hotta Kozue;Koyama Yuuki;Azaki Mika;Morikawa Shigeru
引起土拉菌病的土拉弗朗西斯菌是一种细胞内革兰氏阴性菌。图拉伦希沙斯由于其作为生物武器的历史而在近几十年来受到极大关注。因此，开发针对兔热病的新型疫苗已成为一个重要目标。衰减的F.本研究利用TargeTron诱变技术对土拉菌ΔpdpC株的致病性决定簇蛋白C（pdpC）基因进行了突变，并对其作为土拉菌疫苗候选株的可能性进行了研究。C57 BL/6 J小鼠皮下免疫免疫后21天，用100×半数致死量（LD_（50））的强毒SCHUP 9株鼻内攻击1 × 106 CFU Δ pdpC。免疫的C57 BL/6 J小鼠经100 LD 50的该菌株接种后，38%的小鼠获得了抗该攻击的保护。相反，所有未免疫的小鼠在攻击后6天死亡。免疫小鼠的存活率显著高于未免疫小鼠。此外，Δ pdpC在小鼠中连续传代以确认其稳定减毒。在第1至第10代期间，小鼠脾脏中持续存在低细菌负荷。在ΔpdpC的体内传代过程中未观察到CFU数量的统计学显著变化。插入的破坏pdpC的内含子序列在小鼠中甚至在第10代后仍完全保持。考虑到Δ pdpC具有稳定的减毒作用和内含子序列，它有望成为兔热病疫苗的候选基因。
Francisella tularensis, which causes tularemia, is an intracellular gram‐negative bacterium.F. tularensishas received significant attention in recent decades because of its history as a biological weapon. Thus, development of novel vaccines against tularemia has been an important goal. The attenuatedF. tularensisstrain ΔpdpC, in which the pathogenicity determinant protein C gene (pdpC) has been disrupted by TargeTron mutagenesis, was investigated as a potential vaccine candidate for tularemia in the present study. C57BL/6J mice immunized s.c. with 1 × 106CFUs of ΔpdpCwere challenged intranasally with 100× the median lethal dose (LD50) of a virulent SCHU P9 strain 21 days post immunization. Protection against this challenge was achieved in 38% of immunized C57BL/6J mice administered 100 LD50of this strain. Conversely, all unimmunized mice succumbed to death 6 days post challenge. Survival rates were significantly higher in vaccinated than in unimmunized mice. In addition, ΔpdpCwas passaged serially in mice to confirm its stable attenuation. Low bacterial loads persisted in mouse spleens during the first to tenth passages. No statistically significant changes in the number of CFUs were observed duringin vivopassage of ΔpdpC. The inserted intron sequences for disruptingpdpCwere completely maintained even after the tenth passage in mice. Considering the stable attenuation and intron sequences, it is suggested that ΔpdpCis a promising tularemia vaccine candidate.