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

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 abscessus—Bronchial Epithelial Cells Cross-Talk Through Type I Interferon Signaling

“…Mycobacterial cell walls contain multiple peptidoglycans including D-glucosamine and a mycolic acid layer (5) that initiate the interaction between bacteria and host upon inhalation (6). Macrophages are a critical immune cell in combatting mycobacterial infections with a significant proportion of their response dependent on type I IFN signaling (7,8).…”

Spreading of a mycobacterial cell surface lipid into host epithelial membranes promotes infectivity

“…In zebrafish these responses result in bacterial clearance (Cambier et al, 2014b), highlighting this pathway as a conserved response to infection. In contrast, human epithelial cells infected by mycobacteria have no significant change in global transcription, suggesting minimal immune detection (Reuschl et al, 2017). Our data now demonstrate that PDIM plays a role in silencing epithelial cell responses, promoting uptake by non-activated macrophages.…”

Epithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway

“…Of note, the epithelial cell-mediated attenuation of Mtb -induced TLR-mediated inflammatory responses in U937 macrophage-like cells was cell contact independent, suggesting that the contact-independent communication between alveolar epithelial cells reduced immune responses of macrophages to Mtb in an early stage of infections. Indeed, such an early immune interaction of epithelial cells and macrophages was recently confirmed in another study by using a coculture model of human primary bronchial epithelial cells (PBECs) and THP-1 monocytes, in which the epithelial cells were found to express the same transcriptomic pattern in response to Mtb infection to that of alveolar macrophages or THP-1 cells [ 28 ]. By using this novel model, the authors demonstrated that PBECs were inert to direct Mtb -infection and not potent responders in an IL-1 β - and type I interferon- (IFN-) mediated Mtb -activated immune network.…”

“…Indeed, there is a substantial evidence for interactions between alveolar epithelial cells and macrophages in alveolar sacs [ 2 ]. In this respect, alveolar epithelial cells are an important source of cytokines and mediators modulating the phenotype or activation of alveolar macrophages in response to an external stimulus, including the Mtb [ 2 , 5 , 10 , 28 ]. A previous coculture study using Mono-Mac-6 Mphis (MM6-Mphis) macrophages and epithelial A549 cells demonstrated that a direct cell contact between epithelial cells and macrophages led a decreased intracellular growth of Mtb in infected macrophages, despite that the bacterial growth in A549 cells was not affected [ 29 ].…”