A CLOCK-targeting lncRNA induces trained immunity against tuberculosis

Area of Science:

• Immunology
• Molecular Biology
• Epigenetics

Background:

• Trained immunity involves innate immune memory through metabolic and epigenetic changes.
• Intercellular mediators of trained immunity are not fully understood.
• Tuberculosis (TB) poses a significant global health challenge.

Purpose of the Study:

• Identify intercellular mediators of trained immunity in tuberculosis resistance.
• Elucidate the mechanism by which these mediators establish epigenetic memory.
• Evaluate the therapeutic potential of identified mediators in host defense against TB.

Main Methods:

• Plasma exosomal profiling of TB-resistant individuals.
• Identification and characterization of a novel long non-coding RNA (lncRNA), TRCR1.
• Investigation of TRCR1's interaction with FXR2 and CLOCK mRNA in monocytes.
• Analysis of CLOCK-mediated histone acetylation at immune gene promoters.
• In vivo studies using mouse models of TB infection and BCG vaccination.

Main Results:

• TRCR1, an exosome-derived lncRNA, was identified as a key inducer of trained immunity.
• TRCR1, via FXR2, stabilizes CLOCK mRNA, enhancing CLOCK expression and histone acetylation.
• This epigenetic reprogramming establishes antimicrobial activity and host defense.
• Mycobacterium tuberculosis (Mtb) protein MPT53 induces TRCR1 release from lung epithelial cells.
• TRCR1 administration in mice enhanced anti-Mtb immunity and BCG vaccine efficacy.

Conclusions:

• An intercellular TRCR1-FXR2-CLOCK axis drives trained immunity at the lung-systemic interface.
• TRCR1 represents a novel therapeutic target for enhancing host defense against infectious diseases.
• TRCR1 holds potential for refining BCG vaccination strategies.