Taking control of a volatile situation

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Science Translational Medicine  06 Dec 2017:
Vol. 9, Issue 419, eaar4431
DOI: 10.1126/scitranslmed.aar4431


A 3D microscale model of the human bronchiole reveals volatile-mediated communication between Aspergillus, Pseudomonas, and host.

The lung is a complex cellular environment under constant threat from airborne microbes. Healthy lungs contain a resident microbiome, and respiratory tract infections are common and often polymicrobial. People can be infected or colonized with multiple different viruses, bacteria, or fungi at the same time. While reductionist approaches to study these host-pathogen interactions have been informative, it has been difficult to capture the complexity of respiratory infections with ex vivo models.

Barkal and colleagues have made important strides in modeling the complexity of the human terminal bronchiole, the narrowest conducting airway in the lung. Their platform contains the vasculature and airways of a bronchiole embedded within a matrix of collagen and pulmonary fibroblasts. The airway is composed of human bronchial epithelial cells with a central air-liquid interface, and the vascular lumen is lined with primary lung microvascular cells. They designed luminal diameters to match average human measurements. To minimize the number of primary human cells needed, the entire microscale configuration is constructed atop a glass coverslip. Microbes and immune cells can be added to the airway and vascular lumens, and each compartment can be independently sampled. Although small in size, it is amenable to analysis by bead-based ELISA, histology, and time-lapse imaging.

To model human infection, they added the spores of the fungal pathogen Aspergillus fumigatus to the airway and found it germinated and extended hyphae through the epithelial barrier. An attenuated Aspergillus mutant (ΔlaeA) induced a more robust inflammatory cytokine response than the wild-type fungus and caused neutrophils added to the vascular lumen to migrate more robustly to infected airways. To expand the platform, they engineered an extension that allows communication of volatile compounds between microbial populations and the lung tissue. Since patients with cystic fibrosis are often colonized with both Aspergillus and Pseudomonas, they examined cytokine responses of the bronchiole exposed to volatiles released by A. fumigatus, Pseudomonas aeruginosa, or both. Overall, there was a greater response when the bronchiole was subjected to volatiles from both organisms compared to monomicrobial volatile exposure.

Thus, the investigators provide a biologically complex, structurally accurate organotypic model of the human terminal bronchiole. The model is amenable to controlled interrogation by genetically or chemically altering any of the three host cell populations in the bronchiole, introducing distinct immune effectors into the vasculature, and applying a range of pathogens to the airway. The versatility of the model allows for unprecedented insight into multikingdom host-pathogen interactions.

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