Innate activation of human primary epithelial cells broadens the host response to Mycobacterium tuberculosis in the airways

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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. Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which remains a major public health burden today. In the majority of cases, infection is acquired by inhalation of aerosolised bacteria. Mtb is thought to target alveolar macrophages in the lower airways to establish infection. However, the cells predominantly lining the respiratory tract are epithelial cells and thus are likely crucial during the early host-pathogen interactions. We recovered primary human bronchial epithelial cells from healthy volunteers to assess their global transcriptomic response to direct Mtb-exposure and exposure to Mtb-infected myeloid cells. Our analysis revealed that, while being inert to direct Mtb-infection, epithelial cells were highly responsive to soluble mediators released by infected macrophages. The epithelial response induced by this cellular cross-talk, promoted neutrophil influx in vitro as well as the increase of antimycobaterial host responses. Our data provide novel and unexpected insights into the role of the primary human airway epithelium and define a non-redundant role for epithelial cells in shaping the local immunological environment at the site of initial Mtb infection.

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