Airway immune signatures of protection and disease progression in recent human tuberculosis household contacts.

Summary

Single-cell RNA-seq of bronchoalveolar lavage from recent TB contacts identified neutrophil-dominant, type I IFN–linked programs and inverse T-cell abundance with exhaustion in progressors, whereas nonprogressors displayed regulatory, quiescent, stem-like T-cell states. These airway programs delineate early human responses that may determine infection outcomes.

Key Findings

• Single-cell RNA-seq of BAL identified type I IFN–dependent and IFN-independent neutrophil signatures in active TB and progressors.
• An inverse relationship existed between airway neutrophils and T cells; progressors showed T-cell exhaustion, cytotoxicity, and cell death signatures.
• Nonprogressors exhibited protective T-cell programs enriched for regulation, quiescence, and stem-like states, suggesting mechanisms of natural control.

Clinical Implications

Airway neutrophil dominance with T-cell exhaustion may serve as early biomarkers to risk-stratify recent contacts and to prioritize host-directed interventions restoring T-cell function or tempering type I IFN–neutrophil axes.

Limitations

• Observational design without interventional validation of pathways
• Sample size and generalisability not detailed; causality cannot be inferred

Future Directions

Longitudinal validation in larger, diverse cohorts; interventional studies testing host-directed agents targeting neutrophil–IFN axes and T-cell exhaustion programs; integration with mucosal vaccine strategies.