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

doi:10.1016/j.omtn.2024.102402

An mRNA vaccine induces antimycobacterial immunity by activating DNA damage repair and autophagy

Mol Ther Nucleic Acids. 2024 Nov 26;36(1):102402. doi: 10.1016/j.omtn.2024.102402. eCollection 2025 Mar 11.

Authors

Dan Chen¹, Weili Huang¹, Lifang Shen², Junli Zhang², Zhifen Pan³, Chen Zhang¹, Yuting Tang¹, Ziwei Zhou¹, Jie Tao⁴, Geyang Luo⁴, Shifeng Zhang¹, Jing Zhou⁴, Shuqin Xu², Meng Zhang¹, Yeyu Li¹, Yi Fang⁵, Fanfan Zhao⁵, Lei Huang⁵, Hangwen Li⁵, Hua Yang⁶, Hong Lv^{2

7}, Wei Sha⁶, Bo Yan⁴, Jun Liu⁸, Lu Zhang^{1

7

9}

Affiliations

¹ Department of Microbiology, School of Life Sciences, Fudan University, Shanghai 200438, China.
² State Key Laboratory of Genetic Engineering, Department of Genetics, School of Life Science, Fudan University, Shanghai 200438, China.
³ Department of Respiratory Medicine, The First Hospital of Jiaxing in Zhejiang Province, Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
⁴ Center for Tuberculosis Research, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.
⁵ Stemirna Therapeutics, Shanghai 201206, China.
⁶ Clinic and Research Centre of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University, Shanghai 200400, China.
⁷ Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai 200438, China.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁹ MOE Engineering Research Center of Gene Technology, Shanghai 200438, China.

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.

Keywords: DNA damage repair; MT: Oligonucleotides: Therapies and Applications; autophagy; granuloma; mRNA vaccine; tuberculosis.