Inflammasome activation differences underpin different Mycobacterium tuberculosis infection outcomes

Area of Science:

• Immunology
• Microbiology
• Cell Biology

Background:

• The clinical outcomes of Mycobacterium tuberculosis (Mtb) infection vary, ranging from latent to active tuberculosis (TB).
• The specific cellular mechanisms driving these divergent TB outcomes remain poorly understood.

Purpose of the Study:

• To investigate the cellular pathways, including guanylate-binding protein-1 (GBP1), hypoxia-inducible factor 1α (HIF-1α), and NLRP3 inflammasome activation, that differentiate progressive from non-progressive Mtb infections.
• To elucidate the role of these pathways in determining the clinical outcome of Mtb infection.

Main Methods:

• Infection of rabbit lungs, primary rabbit and human macrophages, and THP-1 cell-derived macrophages with virulent (HN878) and less virulent (CDC1551) Mtb strains.
• Analysis of GBP1, HIF-1α, and NLRP3 inflammasome activation pathways.
• Assessment of mitochondrial stress, apoptosis, and necrosis.
• Validation using macrophages with knocked-down HIF-1α or GBP1 expression.

Main Results:

• Progressive Mtb infection (HN878) correlated with upregulated GBP1, HIF-1α, and NLRP3 inflammasome activation.
• NLRP3 inflammasome activation, mediated by HIF-1α and GBP1, resulted in increased mitochondrial stress, apoptosis, and necrosis during progressive infection.
• These pathways were less active during non-progressive Mtb infection (CDC1551).
• Knockdown of HIF-1α or GBP1 confirmed their role in influencing Mtb infection outcomes.

Conclusions:

• Differential activation of the HIF-1α- and GBP1-mediated NLRP3 inflammasome pathway is a key determinant of Mtb infection outcomes.
• This pathway influences the transition from latent to active tuberculosis.