Abstract
We inhale respiratory pathogens continuously, and the subsequent signaling events between host and microbe are complex, ultimately resulting in clearance of the microbe, stable colonization of the host, or active disease. Traditional in vitro methods are ill-equipped to study these critical events in the context of the lung microenvironment. Here we introduce a microscale organotypic model of the human bronchiole for studying pulmonary infection. By leveraging microscale techniques, the model is designed to approximate the structure of the human bronchiole, containing airway, vascular, and extracellular matrix compartments. To complement direct infection of the organotypic bronchiole, we present a clickable extension that facilitates volatile compound communication between microbial populations and the host model. Using Aspergillus fumigatus, a respiratory pathogen, we characterize the inflammatory response of the organotypic bronchiole to infection. Finally, we demonstrate multikingdom, volatile-mediated communication between the organotypic bronchiole and cultures of Aspergillus fumigatus and Pseudomonas aeruginosa.
Highlights
We inhale respiratory pathogens continuously, and the subsequent signaling events between host and microbe are complex, resulting in clearance of the microbe, stable colonization of the host, or active disease
We describe a modular multikingdom culture method that enables volatile communication between the bronchiole model and cultures of two other microbes. This platform extends our ability to understand multikingdom interactions, and we report that volatile communication between the human bronchiole model and the fungus A. fumigatus is modulated by volatile contact with Pseudomonas aeruginosa, an often co-inhabiting bacterium in patients with cystic fibrosis
The center lumen is lined with primary human bronchial epithelial cells and can be filled with air to form an air–liquid interface (ALI) culture representing the in vivo airway (Fig. 1b, c)
Summary
We inhale respiratory pathogens continuously, and the subsequent signaling events between host and microbe are complex, resulting in clearance of the microbe, stable colonization of the host, or active disease. Many in vitro models of pulmonary infection represent infection by placing pathogens directly atop the air-exposed apical surface of a monolayer culture of pulmonary epithelial cells, investigating the effects of direct communication between respiratory epithelium and pathogen[5], and migration through the epithelial layer[6] This approach is appealing and achieved in Transwell systems or more recently in micro-engineered lung-ona-chip systems, both of which utilize a microporous membrane as a support for the epithelial layer, and do not integrate fibroblasts or supporting matrix[7, 8]. We present a microscale in vitro platform that models the structure of the human terminal bronchiole, the narrowest conducting airway in the lung, and that can be used to investigate both physical contact and volatile communication between host and pathogen(s) at this level of the respiratory tree. This platform extends our ability to understand multikingdom interactions, and we report that volatile communication between the human bronchiole model and the fungus A. fumigatus is modulated by volatile contact with Pseudomonas aeruginosa, an often co-inhabiting bacterium in patients with cystic fibrosis
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