BCG-Derived Outer Membrane Vesicles Induce TLR2-Dependent Trained Immunity to Protect Against Polymicrobial Sepsis

Area of Science:

• Immunology
• Infectious Diseases
• Vaccinology

Background:

• Sepsis is a critical care mortality cause, necessitating novel host defense strategies.
• Trained immunity offers innate immune memory to bolster host defense.
• Bacillus Calmette-Guérin (BCG) induces trained immunity but has adverse reactions.

Purpose of the Study:

• To investigate BCG-derived outer membrane vesicles (B-OMVs) as a safe and effective inducer of trained immunity against sepsis.
• To evaluate the safety and efficacy of B-OMVs compared to conventional vaccines.
• To elucidate the underlying mechanisms of B-OMV-mediated trained immunity.

Main Methods:

• Characterization and safety assessments of B-OMVs.
• Experimental polymicrobial sepsis models.
• Analysis of hematopoietic stem cell expansion and myelopoiesis.
• Toll-like receptor 2 (TLR2) pathway activation studies, including aerobic glycolysis and epigenetic reprogramming.
• Assessment of bone marrow-derived macrophage phagocytic activity.

Main Results:

• B-OMVs effectively triggered trained immunity and protected against experimental sepsis.
• B-OMVs demonstrated no significant toxicity or pathological effects.
• Mechanisms involved TLR2-dependent activation of aerobic glycolysis and epigenetic reprogramming, promoting myelopoiesis.
• Enhanced immune response and phagocytic activity in macrophages were observed.

Conclusions:

• B-OMVs represent a novel, safe, and effective immunomodulatory agent for combating sepsis-induced immune dysfunction.
• B-OMVs show translational potential as an alternative to BCG vaccines for inducing trained immunity.
• This study highlights B-OMVs as a promising strategy to enhance host defense against sepsis.