Airway immune signatures of protection and disease progression in recent human tuberculosis household contacts [bulk RNA-seq]

The local early immune factors dictating whether individuals who have been infected with Mycobacterium tuberculosis remain healthy or progress to active TB have not been defined. We interrogated the airway immune response at single cell resolution in bronchoalveolar lavage (BAL) from PET-CT characterised recent TB household contacts, who either controlled the infection or progressed to TB disease, as well as of active TB patients at diagnosis. Single cell RNA-sequencing revealed type I IFN-dependent and -independent neutrophil signatures in BAL from active TB patients 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 active TB patients with a neutrophil dominated airway profile. Conversely, we identified T cell signatures of protection in non-progressor contacts dominated by genes related to regulation, quiescence and a stem-like profile. Both the signature of TB progression and the stem-like T cell signature of non-progressors from human airways were recapitulated in scRNA-seq data from non-human primate (NHP) granulomas, associated with disease or immune protection, respectively. 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.