Abstract
Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1β and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100-family members and epithelial-myeloid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb.
Highlights
The first interactions between Mycobacterium tuberculosis (Mtb) and its human host occur in the lungs after inhalation of aerosolised bacteria
Through in vitro infection and transwell co-culture models, we identified primary bronchial epithelial cells to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1 β and type I IFN, with the capacity to shape the local antimicrobial and immunological environment
Epithelial cells were the major cell type lining the respiratory tract and harboured less than 10% of leukocyte subsets (Fig 1A), of which macrophages, lymphocytes and neutrophils contributed on average 86.4%, 12.5% and 1.1%, respectively
Summary
The first interactions between Mycobacterium tuberculosis (Mtb) and its human host occur in the lungs after inhalation of aerosolised bacteria. Fifty percent of individuals exposed to Mtb remain uninfected [1] and host-determinants have been associated with this resistance to or clearance of infection in humans [2]. The majority of cells in the airway lining are epithelial which constitute a surface of approximately 70 m2 [4] and are likely to be the first point of contact for Mtb in the human host. Epithelial cells are known to significantly contribute to the immune responses in the lungs and can sense intra- and extracellular pathogens, such as viruses and bacteria, via a wide range of pattern recognition receptors (PRR) [5]. Their responses in tuberculosis (TB) are poorly defined and little investigated, which presents a surprising knowledge gap
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