Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease

Area of Science:

• Immunology
• Infectious Diseases
• Genomics

Background:

• Mechanisms of Mycobacterium tuberculosis infection progressing to active tuberculosis disease are not fully understood.
• Longitudinal studies are crucial for defining the timeline of immune events preceding disease onset.

Purpose of the Study:

• To define the immunological mechanisms and temporal dynamics underlying the progression from Mycobacterium tuberculosis infection to pulmonary tuberculosis disease.
• To identify biomarkers indicative of tuberculosis disease progression in adolescents.

Main Methods:

• Longitudinal whole blood transcriptomic analysis (RNA sequencing) and plasma proteome analysis in adolescents who progressed to tuberculosis disease versus healthy controls.
• Analysis of gene expression in purified T cells and validation in an independent adult cohort receiving BCG re-vaccination.

Main Results:

• Tuberculosis progression was associated with sequential immune modulation, including early elevation of Type I/II interferon and complement cascade signaling (18 months pre-diagnosis).
• Changes in myeloid inflammation, lymphoid, monocyte, and neutrophil gene modules occurred closer to disease diagnosis.
• Early suppression of Th17 responses was observed in progressors, confirmed by reduced IL-17 expression post-BCG vaccination in an independent cohort.

Conclusions:

• A timeline of distinct immunological stages preceding tuberculosis disease manifestation and diagnosis has been established.
• Findings highlight sequential inflammatory dynamics and immune alterations crucial for understanding tuberculosis pathogenesis.
• These insights have significant implications for developing novel diagnostics, vaccines, and host-directed therapies for tuberculosis.