A lung-on-chip model reveals an essential role for alveolar epithelial cells in controlling bacterial growth during early tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is spread via aerosolized droplets and makes 'first contact' with a new host in the alveolar space, an interaction largely inaccessible to experimental observation. We establish a lung-on-chip as an infection model for early tuberculosis, where time-lapse imaging at an air-liquid interface reveals the dynamics of early host-Mtb interactions 15 with a spatiotemporal resolution unattainable in animal models. Pulmonary surfactant mediates a non-growing Mtb population in both alveolar epithelial cells (AECs) and macrophages, although AECs are more permissive to Mtb growth. Defective surfactant production leads to uncontrolled rapid Mtb growth in both cell types which can be partially rescued by formulations containing

Rapid endothelial infection, endothelialitis and vascular damage characterise SARS-CoV-2 infection in a human lung-on-chip model

“…We first characterized the progression of infection by measuring the release of viral progeny and intracellular viral RNA loads. Infected LoCs were monitored daily for the release of infected viral progeny (1) apically -on the epithelial layer and (2) basolaterally -in the cell culture media flowed through the vascular channel ('apical wash' and 'vascular effluent' in Fig. 1A).…”

“…Organ-on-chip technologies recreate key aspects of human physiology in a bottom-up and modular manner 1 . In the context of infectious diseases, this allows for studies of cell dynamics 2,3 , infection tropism 4 , and the role of physiological factors in disease pathogenesis in more native settings 5 . This is particularly relevant for the study of respiratory infectious diseases 6 , where the vast surface area of the alveoli poses a challenge to direct experimental observation.…”

Mechanical Stimulation: A Crucial Element of Organ-on-Chip Models

“…This biomechanical input is essential for the replication of lung function and results in a 10-fold enhancement of the uptake of nano particulates into the alveolar epithelium over static conditions dramatically increasing reactive oxygen species production and promoting neutrophil capture and transmigration ( Huh et al, 2010 ). Pulmonary surfactant production is enhanced within the chip further promoting epithelium integrity and barrier function while functioning as an important defense mechanism against bacterial infection ( Thacker et al, 2020 ). Several commercial systems have been used to generate lung-on-a-chip models that mimic the complex solid and fluid microenvironment of the airway epithelium such as SynVivo’s SynALI lung model which comprises an apical channel functionalized with lung epithelial cells and surrounded by “vasculature” comprised of endothelial cells separated by a porous scaffold ( Kolhar et al, 2013 ; Liu et al, 2019 ; Soroush et al, 2020 ).…”

Volatile metabolites differentiate air–liquid interface cultures after infection with Staphylococcus aureus

“…Cultures can be further enhanced to develop a true lung infection model to include bronchial epithelial cells for cilia, goblet cells for mucus production, and include inflammatory cells for host response to xenobiotics. 36…”