2. Academic Validation
  3. Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival

Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival

  • Cell Host Microbe. 2023 Nov 8;31(11):1820-1836.e10. doi: 10.1016/j.chom.2023.09.010.
Shanshan Liu 1,  Liru Guan 1,  Cheng Peng 1,  Yuanna Cheng 1,  Hongyu Cheng 1,  Fei Wang 1,  Mingtong Ma 1,  Ruijuan Zheng 1,  Zhe Ji 2,  Pengfei Cui 1,  Yefei Ren 1,  Liru Li 1,  Chenyue Shi 1,  Jie Wang 3,  Xiaochen Huang 3,  Xia Cai 4,  Di Qu 4,  Haiping Zhang 5,  Zhiyong Mao 5,  Haipeng Liu 6,  Peng Wang 7,  Wei Sha 7,  Hua Yang 8,  Lin Wang 9,  Baoxue Ge 10
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai 200433, P.R. China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China.
  • 2 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China.
  • 3 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai 200433, P.R. China.
  • 4 Biosafety Level 3 Laboratory, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
  • 5 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, P.R. China.
  • 6 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
  • 7 Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China.
  • 8 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai 200433, P.R. China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China. Electronic address: yanghua97065@163.com.
  • 9 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai 200433, P.R. China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China. Electronic address: 651377481@qq.com.
  • 10 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Key Laboratory of Pathogen-Host Interaction, Ministry of Education, Tongji University School of Medicine, Shanghai 200433, P.R. China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, P.R. China; Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China; Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, P.R. China. Electronic address: gebaoxue@sibs.ac.cn.
PMID: 37848028 DOI: 10.1016/j.chom.2023.09.010
Abstract

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the Cyclic GMP-AMP Synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated activation of the IFN-β pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and in vivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.

Keywords

Mycobacterium tuberculosis; host DNA repair; interferon-β; intracellular survival; lipid droplets; scavenger receptor-A; urease C.

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