Immunomodulatory Agents Combat Multidrug-Resistant Tuberculosis by Improving Antimicrobial Immunity

Area of Science:

• Immunology
• Microbiology
• Pharmacology

Background:

• Multidrug-resistant tuberculosis (MDR TB) presents significant treatment challenges due to low success rates.
• Novel therapeutic strategies are crucial for combating MDR TB effectively.

Purpose of the Study:

• To investigate the potential of active vitamin D3 (vitD) and phenylbutyrate (PBA) as adjuncts to conventional chemotherapy for MDR TB.
• To determine if vitD and PBA can enhance immune-mediated eradication of Mycobacterium tuberculosis.

Main Methods:

• Utilized a human macrophage model infected with MDR TB isolates.
• Assessed the antimicrobial effects of vitD+PBA combined with rifampicin or isoniazid.
• Employed colony-forming unit counts, gene expression analysis (LL-37, defensins, NOS, DUOX2), RNA interference, Western blotting, and confocal microscopy.

Main Results:

• VitD+PBA inhibited MDR TB growth in macrophages and potentiated the effects of rifampicin and isoniazid.
• The combination induced the antimicrobial peptide LL-37 and LC3-dependent autophagy, crucial for bacterial clearance.
• LL-37 silencing diminished the efficacy of vitD+PBA, confirming its role. The combination with isoniazid showed potent additive effects.

Conclusions:

• Immunomodulatory agents like vitD and PBA can augment standard MDR TB treatment.
• These agents activate multiple immune pathways, supporting the development of next-generation individualized therapies for challenging pulmonary TB cases.