A lung-on-chip infection model reveals protective and permissive roles of alveolar epithelial cells in 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 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 surfactant phospholipids. AECs thus have both host-protective and pathogen-permissive roles during first contact, which may explain the full spectrum of human disease and inform new therapeutic interventions.