Tobacco smoke exposure results in recruitment of inflammatory airspace monocytes and accelerated growth of Mycobacterium tuberculosis

Tobacco smoking doubles the risk of active tuberculosis (TB) and accounts for up to 20% of all active TB cases globally. How smoking promotes lung microenvironments permissive to Mycobacterium tuberculosis (Mtb) growth remains incompletely understood. We investigated primary bronchoalveolar lavage cells from current- and never-smokers by performing single-cell RNA-sequencing (scRNA-seq), flow cytometry, and functional assays. We observed enrichment of immature inflammatory monocytes in the lungs of smokers compared to non-smokers. These monocytes exhibited phenotypes consistent with recent recruitment from blood, ongoing differentiation, increased activation, and states similar to those with chronic obstructive pulmonary disease (COPD). Using integrative scRNA-seq and flow cytometry, we identify CD93 as a marker for a subset of these newly recruited smoking-associated lung monocytes and further provide evidence that recruitment of monocytes into the lung is mediated by CCL11 binding to CCR2. We also show that these cells exhibit elevated inflammatory responses upon exposure to Mtb and accelerated intracellular growth of Mtb compared to mature macrophages. This elevated Mtb growth could be inhibited with an anti-inflammatory small molecule, providing a direct connection between smoking-induced pro-inflammatory states and permissiveness to Mtb growth. Our findings suggest a model in which smoking leads to recruitment of immature inflammatory monocytes from the periphery to the lung via CCL11-CCR2 interactions, which results in the accumulation of these Mtb permissive cells in the airway. This work defines how smoking may lead to increased susceptibility to Mtb and identifies novel host-directed therapies to reduce the burden of TB among those who smoke. One Sentence Summary Inflammatory monocytes are recruited to the airways of smokers where they may contribute to more rapid growth of Mycobacterium tuberculosis in the lungs.