BCG‐Derived Outer Membrane Vesicles Induce TLR2‐Dependent Trained Immunity to Protect Against Polymicrobial Sepsis
Trained immunity, an innate immune memory, has emerged as a promising strategy to enhance host defense against sepsis, a leading cause of mortality in critical care. While Bacillus Calmette-Guérin (BCG) is the most widely used vaccine for tuberculosis prevention, its broader use as an inducer of trained immunity is limited by adverse reactions. Here, it is reported that BCG-derived outer membrane vesicles (B-OMVs) effectively trigger trained immunity to protect against experimental polymicrobial sepsis. Comprehensive characterization and safety assessments confirmed that B-OMVs exhibited no significant toxicity or pathological effects, positioning them as a promising alternative to conventional BCG vaccines and E. coli-derived outer membrane vesicles (E-OMVs) in terms of both efficacy and safety. Mechanistically, B-OMVs enhanced trained immunity by promoting hematopoietic stem cell expansion and myelopoiesis via toll like receptor 2 (TLR2)-dependent activation of aerobic glycolysis and epigenetic reprogramming. This led to an amplified immune response and enhanced phagocytic activity in bone marrow-derived macrophages. Together, these findings establish B-OMVs as a novel immunomodulatory agent against sepsis-induced immune dysfunction, with translational potential.
Authors
- Yingyi Yang
- Peng Pan (ORCID: https://orcid.org/0000-0002-5023-7570)
- Zijian Zhou (ORCID: https://orcid.org/0000-0003-2383-8490)
- Lingqi Xu
- Wenyan Hao (ORCID: https://orcid.org/0000-0003-1430-6003)
- Jin Zhu
- Huiting Zhou (ORCID: https://orcid.org/0000-0003-1218-5391)
- Yuan Gong (ORCID: https://orcid.org/0000-0001-6819-8402)
- Qiang Shan (ORCID: https://orcid.org/0000-0002-7089-0278)
- Zhenzhen Dong (ORCID: https://orcid.org/0000-0003-2000-727X)
- Daolin Tang (ORCID: https://orcid.org/0000-0002-1903-6180)
- Ke Yang (ORCID: https://orcid.org/0000-0002-7696-9227)
- J.H. Wang
- Rui Kang (ORCID: https://orcid.org/0000-0003-2725-1574)
- Jian Wang (ORCID: https://orcid.org/0000-0002-9482-5227)
- Jie Huang (ORCID: https://orcid.org/0000-0001-5815-190X)
- Zhenjiang Bai (ORCID: https://orcid.org/0000-0002-9404-7058)
Institutions
- Zunyi Medical University (CN)
- Xiamen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- University College Cork (IE)
- Cork University Hospital (IE)
- Soochow University (CN)
- Suzhou Institute of Systems Medicine (CN)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-06-24
- DOI
- https://doi.org/10.1002/advs.202504101
- Citations
- 7
- Primary Topic
- Immune responses and vaccinations
- Type
- article
- Field-Weighted Citation Impact
- 5.58
Funders
- National Natural Science Foundation of China
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province