2. Academic Validation
  3. A CLOCK-targeting lncRNA induces trained immunity against tuberculosis

A CLOCK-targeting lncRNA induces trained immunity against tuberculosis

  • Cell Host Microbe. 2026 Jan 14;34(1):68-85.e13. doi: 10.1016/j.chom.2025.12.002.
Shanshan Yu 1,  Qiyao Chai 2,  Zhe Lu 3,  Changgen Qiu 3,  Yanzhao Zhong 3,  Yiru Wang 3,  Zehui Lei 3,  Lihua Qiang 4,  Yingxu Fang 3,  Xinwen Zhang 3,  Bingxi Li 5,  Mengqiu Gao 6,  Lingqiang Zhang 4,  Gong Cheng 7,  Jing Wang 5,  Cui Hua Liu 8,  Yu Pang 9
Affiliations

Affiliations

  • 1 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China; New Cornerstone Science Laboratory, Tsinghua University, Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 2 Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: [email protected].
  • 3 Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 101408, China.
  • 4 State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
  • 5 Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
  • 6 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.
  • 7 New Cornerstone Science Laboratory, Tsinghua University, Peking University Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
  • 8 Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Medical School, University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address: [email protected].
  • 9 Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China. Electronic address: [email protected].
PMID: 41475336 DOI: 10.1016/j.chom.2025.12.002
Abstract

Trained immunity confers innate immune memory via metabolic and epigenetic reprogramming, yet the intercellular mediators regulating this process in host defense remain largely elusive. Here, through plasma exosomal profiling of tuberculosis (TB)-resistant individuals, we identify a trained immunity-inducing long non-coding RNA (lncRNA), termed tuberculosisresister-derived CLOCK regulator 1 (TRCR1). Mechanistically, exosome-derived TRCR1 collaborates with the RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming lncRNA-protein-mRNA complexes in monocytes, thus enhancing circadian regulator CLOCK expression and promoting CLOCK-mediated histone H3 acetylation (K9/K14) at immune gene promoters, ultimately establishing epigenetic memory-mediated antimicrobial activity. We further reveal that Mycobacterium tuberculosis (Mtb)-secreted protein MPT53 induces lung epithelial cells to release TRCR1-enriched exosomes. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves Bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular TRCR1-FXR2-CLOCK axis driving trained immunity at the lung-systemic immune interface, providing a strategy for refining BCG vaccination and preventing infectious diseases.

Keywords

CLOCK; exosome; long non-coding RNA; resister; trained immunity; tuberculosis.

Figures
Products