Chen Dan, Huang Weili, Shen Lifang, Zhang Junli, Pan Zhifen, Zhang Chen, Tang Yuting, Zhou Ziwei, Tao Jie, Luo Geyang, Zhang Shifeng, Zhou Jing, Xu Shuqin, Zhang Meng, Li Yeyu, Fang Yi, Zhao Fanfan, Huang Lei, Li Hangwen, Yang Hua, Lv Hong, Sha Wei, Yan Bo, Liu Jun, Zhang Lu
Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China.
State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Science, Fudan University, Shanghai 200438, China.
Mol Ther Nucleic Acids. 2024 Nov 26;36(1):102402. doi: 10.1016/j.omtn.2024.102402. eCollection 2025 Mar 11.
Effective vaccines are urgently needed for the control of tuberculosis (TB). Here, we report that an mRNA TB vaccine is highly effective and exhibits both prophylactic and therapeutic activity in the zebrafish model of TB. Adult zebrafish immunized with the mRNA vaccine survived significantly longer after challenge compared to those immunized with the DNA vaccine. Furthermore, post-infection treatment with the mRNA vaccine drastically reduced the bacterial burden. The mRNA vaccine activated multiple DNA break repair systems that are essential for the normal development and function of adaptive immunity, but did not activate the canonical DNA damage responses that promote cell death. This highlights a profound connection between DNA damage repair and the activation of immune responses under physiological processes of immunization. Remarkably, the mRNA vaccine induced autophagy in granulomas, coinciding with bacterial killing and cell survival. Collectively, these findings demonstrate that the mRNA vaccine elicits potent innate and adaptive immunity, providing effective host protection against mycobacterial challenge.
控制结核病（TB）迫切需要有效的疫苗。在此，我们报告一种mRNA结核病疫苗非常有效，并且在斑马鱼结核病模型中展现出预防和治疗活性。与用DNA疫苗免疫的成年斑马鱼相比，用mRNA疫苗免疫的成年斑马鱼在受到攻击后存活时间显著更长。此外，用mRNA疫苗进行感染后治疗可大幅降低细菌负荷。mRNA疫苗激活了多个对适应性免疫的正常发育和功能至关重要的DNA断裂修复系统，但未激活促进细胞死亡的经典DNA损伤反应。这突出了DNA损伤修复与免疫生理过程中免疫反应激活之间的深刻联系。值得注意的是，mRNA疫苗在肉芽肿中诱导自噬，这与细菌杀伤和细胞存活相吻合。总体而言，这些发现表明mRNA疫苗可引发强大的先天性和适应性免疫，为宿主提供有效的保护以抵御分枝杆菌攻击。
