Dissecting the role of the airway epithelium in mycobacterial infections

Tuberculosis (TB) remains the world’s most lethal infectious disease, and there is an urgent need for a more detailed understanding of (early) infection events and the host factors involved in order to develop new strategies for TB treatment and infection prevention. Although most cases of TB are pulmonary, the role of the lung epithelium, particularly in the conducting airways, is understudied. The epithelium is able to sense invasion of the lung by mycobacteria responds via secretion of antimicrobials as well as cytokines and chemokines that attract innate and adaptive immune cells. As such, the lung epithelium is a critical first responder against airborne pathogens like Mycobacterium tuberculosis and related species. In this thesis, we aimed to dissect airway epithelial responses to various species of mycobacteria. Epithelial host responses induced by different mycobacterial species largely overlapped, and consisted mainly of increased inflammation and antimicrobial secretion. Continuous exposure of epithelial cells to mycobacteria induced partial cellular reprogramming towards a mesenchymal phenotype. Prior exposures to mycobacteria generally reduced the infection efficiency during a second exposure, also when exposed to different species sequentially. Acute smoke exposure had limited long-term effects on the epithelial host response to infection, but biofilm formation was increased. Finally, mycobacteria formed biofilms on airway epithelial cells, and infection with mycobacteria was detrimental to mucosal barrier integrity.