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

The local immune factors dictating whether individuals who have been infected with Mycobacterium tuberculosis remain healthy or progress to active tuberculosis (TB) have not been defined. Here we interrogated the airway immune response at single-cell resolution in bronchoalveolar lavage from positron emission and computed tomography-characterized recent TB household contacts, who either controlled the infection or progressed to TB disease, as well as of patients with active TB at diagnosis. Single-cell RNA sequencing revealed type I IFN-dependent and IFN-independent neutrophil signatures in bronchoalveolar lavage from patients with active TB and TB progressors. We report an inverse relationship between airway neutrophils and T cells, with T cells showing signatures of exhaustion, cytotoxicity and cell death in progressors and patients with active TB with a neutrophil-dominated airway profile. Conversely, we identified T cell signatures of protection in nonprogressor contacts dominated by genes related to regulation, quiescence and a stem-like profile. Our findings from early human airway responses in TB contacts reveal genes, pathways and cell states that may dictate infection outcome and inform strategies for developing effective host-directed therapies and vaccines.