Disease progression is associated with differential neutrophil maturation in Mycobacterium tuberculosis-infected...

Area of Science:

• Immunology
• Infectious Diseases
• Microbiology

Background:

• Tuberculosis (TB) pathogenesis involves complex host-pathogen interactions, with innate immunity's role, particularly neutrophils, remaining incompletely understood.
• Neutrophils exhibit dual roles in TB, potentially contributing to both host defense and disease exacerbation.
• Understanding neutrophil dynamics is crucial for elucidating TB progression from latent to active disease.

Purpose of the Study:

• To investigate changes in neutrophil phenotype and function during Mycobacterium tuberculosis (Mtb) infection in cynomolgus macaques.
• To identify specific neutrophil subpopulations and molecular signatures associated with rapid versus slow progression of active TB.
• To explore the capacity of neutrophils to modulate T cell responses in the context of TB.

Main Methods:

• Stratification of Mtb-infected macaques into fast and slow progressors based on clinical, bacteriological, and PET/CT imaging data.
• Transcriptomic analysis to identify differential gene expression signatures.
• Mass cytometry (CyTOF) to analyze neutrophil subpopulations and phenotypes in blood and lung granulomas.
• In vitro assays to assess neutrophil-mediated modulation of CD8 T cell function.

Main Results:

• Fast progressors exhibited transcriptomic signatures of type I interferons and neutrophil degranulation.
• Emergence of immature blood neutrophils (CD101+ CD10-) was observed in fast-progressing animals.
• Neutrophils demonstrated contact-dependent modulation of TNF-α production and CD8 T cell cytotoxicity.
• Tissue-specific neutrophil phenotypes (CD101- CD10+) were found in lung granulomas, with increased infiltration in active TB.

Conclusions:

• Neutrophil subpopulations and their functional states are associated with TB disease progression.
• Immature neutrophils and altered degranulation patterns may indicate rapid TB advancement.
• Neutrophils can modulate CD8 T cell responses, potentially influencing TB pathogenesis.
• These findings highlight neutrophils as key players in TB progression and potential therapeutic targets.