Molecular Therapy: Nucleic Acids (Mar 2025)
An mRNA vaccine induces antimycobacterial immunity by activating DNA damage repair and autophagy
- Dan Chen,
- Weili Huang,
- Lifang Shen,
- Junli Zhang,
- Zhifen Pan,
- Chen Zhang,
- Yuting Tang,
- Ziwei Zhou,
- Jie Tao,
- Geyang Luo,
- Shifeng Zhang,
- Jing Zhou,
- Shuqin Xu,
- Meng Zhang,
- Yeyu Li,
- Yi Fang,
- Fanfan Zhao,
- Lei Huang,
- Hangwen Li,
- Hua Yang,
- Hong Lv,
- Wei Sha,
- Bo Yan,
- Jun Liu,
- Lu Zhang
Affiliations
- Dan Chen
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Weili Huang
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Lifang Shen
- State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Science, Fudan University, Shanghai 200438, China
- Junli Zhang
- State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Science, Fudan University, Shanghai 200438, China
- Zhifen Pan
- Department of Respiratory Medicine, The First Hospital of Jiaxing in Zhejiang Province, Affiliated Hospital of Jiaxing University, Jiaxing 314000, China
- Chen Zhang
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Yuting Tang
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Ziwei Zhou
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Jie Tao
- Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- Geyang Luo
- Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- Shifeng Zhang
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Jing Zhou
- Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China
- Shuqin Xu
- State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Science, Fudan University, Shanghai 200438, China
- Meng Zhang
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Yeyu Li
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China
- Yi Fang
- Stemirna Therapeutics, Shanghai 201206, China
- Fanfan Zhao
- Stemirna Therapeutics, Shanghai 201206, China
- Lei Huang
- Stemirna Therapeutics, Shanghai 201206, China
- Hangwen Li
- Stemirna Therapeutics, Shanghai 201206, China
- Hua Yang
- Clinic and Research Centre of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200400, China
- Hong Lv
- State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Science, Fudan University, Shanghai 200438, China; Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai 200438, China
- Wei Sha
- Clinic and Research Centre of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200400, China
- Bo Yan
- Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China; Corresponding author: Bo Yan, Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
- Jun Liu
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Corresponding author: Jun Liu, Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Lu Zhang
- Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China; Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai 200438, China; MOE Engineering Research Center of Gene Technology, Shanghai 200438, China; Corresponding author: Lu Zhang, Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China.
- Journal volume & issue
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Vol. 36,
no. 1
p. 102402
Abstract
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 Mycobacterium marinum 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.
