The human lung mucosa determines Mycobacterium tuberculosis infection outcome in the alveolar epithelium

Abstract

Abstract Mycobacterium tuberculosis (M.tb) deposited into the alveolar space encounters the human lung mucosa, i.e. alveolar lining fluid, or ALF. We have shown that M.tb exposure to ALF alters the M.tb cell wall surface and subsequently its interactions with human phagocytes, allowing these cells to control better the infection. Understudied host cells in M.tb pathogenesis are alveolar epithelial cells (ATs), nonprofessional phagocytes which are thought to participate in the initial phase and subsequent outcome of M.tb infection. Based on our previous results with phagocytes, we hypothesized that exposure of M.tb to human ALF will allow ATs to control better the infection. However, our results show that exposure of M.tb to ALF drives highly variable rates of bacterial uptake by ATs. Furthermore, independently of this uptake variability, M.tb exposure to ALF resulted in significant differences in M.tb intracellular growth in ATs. Based on these results, we defined two different types of human ALFs: Low-ALF (L-ALF, upon exposure allows better control of the M.tb infection) and High-ALF (H-ALF, upon exposure exacerbates M.tb infection). We further show that H-ALF exposed M.tb reduces the ATs release of pro-inflammatory cytokines and chemoattractants, as well as reduces ATs cytotoxicity. Moreover, H-ALF exposed M.tb affects the crosstalk between infected ATs and phagocytes by downregulating their inflammatory response. These results suggest a novel role for human ALF, where exposure of M.tb to ALF during infection defines ATs as potential M.tb stable reservoirs promoting intracellular bacterial replication and growth, while limiting local inflammation, and phagocyte infiltration and activation.