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

• Published in: eLife Vol. 9
• Main Authors: Thacker, Vivek V, Dhar, Neeraj, Sharma, Kunal, Barrile, Riccardo, Karalis, Katia, McKinney, John D
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications, Ltd 24.11.2020; eLife Sciences Publications Ltd
• Subjects: Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - microbiology; Animals; Bacterial Load; Bacterial Proteins - genetics; Cells, Cultured; disease models; Disease Models, Animal; Female; Host-Pathogen Interactions; Lab-On-A-Chip Devices; Macrophages, Alveolar - metabolism; Macrophages, Alveolar - microbiology; Mice, Inbred C57BL; Mice, Transgenic; Microbial Viability; Microbiology and Infectious Disease; Microfluidic Analytical Techniques - instrumentation; Microscopy, Video; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - pathogenicity; organ-on-chip; Physics of Living Systems; pulmonary surfactant; Pulmonary Surfactant-Associated Proteins - genetics; Pulmonary Surfactant-Associated Proteins - metabolism; Time Factors; Time-Lapse Imaging; time-lapse microscopy; Tools and Resources; Tuberculosis, Pulmonary - genetics; Tuberculosis, Pulmonary - metabolism; Tuberculosis, Pulmonary - microbiology; Virulence; mouse; host-pathogen interactions; Mycobacterium tuberculosis; infectious disease; time-lapse microscopy; microbiology; disease models; physics of living systems; organ-on-chip; pulmonary surfactant
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.59961

We establish a murine lung-on-chip infection model and use time-lapse imaging to reveal the dynamics of host- interactions at an air-liquid interface with a spatiotemporal resolution unattainable in animal models and to probe the direct role of pulmonary surfactant in early infection. Surfactant deficiency results in rapid and uncontrolled bacterial growth in both macrophages and alveolar epithelial cells. In contrast, under normal surfactant levels, a significant fraction of intracellular bacteria are non-growing. The surfactant-deficient phenotype is rescued by exogenous addition of surfactant replacement formulations, which have no effect on bacterial viability in the absence of host cells. Surfactant partially removes virulence-associated lipids and proteins from the bacterial cell surface. Consistent with this mechanism, the attenuation of bacteria lacking the ESX-1 secretion system is independent of surfactant levels. These findings may partly explain why smokers and elderly persons with compromised surfactant function are at increased risk of developing active tuberculosis.