A Microengineered Airway Lung Chip Models Key Features of Viral-induced Exacerbation of Asthma

Abstract

At a Glance Commentary. Scientific Knowledge on the Subject: New therapies for asthma exacerbations remain a significant unmet medical need. Development of human relevant preclinical models are needed to further elucidate the complex mechanisms underlying asthma exacerbation and investigate new therapeutic strategies.What This Study Adds to the Field: Using a human Airway Lung-Chip model, we show here for the first time a live human rhinovirus (HRV) infection of the asthmatic epithelium that recapitulates complex features of viral-induced asthma exacerbation. The dynamic microenvironment of the chip enables the real-time study of virus infection, epithelial response, and immune cell recruitment under healthy and asthmatic conditions. The model reproduces key endpoints that have been observed in asthmatics and individuals infected with rhinovirus including the ciliated cell sloughing, altered cilia beating frequency, goblet cell hyperplasia, increased expression of adhesion molecules in microvascular endothelial cells, and inflammatory mediator release. High-resolution temporal analysis of secreted inflammatory markers enabled by dynamic sampling revealed alteration of IL-6, IFN-λ1 and CXCL10 secretory phases after rhinovirus infection in an IL-13 high environment. Leveraging high-content imaging and analysis of circulating inflammatory cells, we demonstrated the efficacy of a CXCR2 antagonist to reduce adhesion, motility, and transmigration of perfused human neutrophils. Thus, this microengineered chip may offer a powerful addition to preclinical models for understanding mechanisms underlying asthma exacerbation pathology and developing new therapeutic strategies..

Soft matter science and the COVID-19 pandemic

“…Until recently, the only solution was to rely on ex vivo mucus samples obtained from relevant tissues. 12 The availability of mucus-secreting organs-on-a-chip 187,188 therefore may offer new opportunities for soft matter work on viruses embedded in realistic mucus droplets and films. SARS-CoV-2 and other enveloped respiratory viruses are highly infectious.…”

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

“…There is therefore an urgent need for a better understanding of the pathogenesis of SARS-CoV-2 in alveolar epithelial cells, especially in a more realistic model of the alveolar space that is vascularized. The lung-on-chip model is well-suited to this purpose because it includes a vascular compartment maintained under flow, and infection can occur at the air-liquid interface 19 , two key physiological features that are lacking in organoid models 20–22 . We therefore establish a human lung-on-chip model for SARS-CoV-2 infections, and probe the viral growth kinetics, cellular localization and responses to a low dose infection using qRT-PCR, ELISA, RNAScope, immunofluorescence and confocal imaging (Fig.…”

Refining Host-Pathogen Interactions: Organ-on-Chip Side of the Coin

“…More recently, microengineered airway chips were used to model key features of human rhinovirus 16 (HRV16)-induced exacerbations of asthma, and simultaneously assess the efficacy of immune modulators such as CXR2 antagonist during infection [56]. Furthermore, airway chips were employed to study viral replication by different strains of influenza virus, H1N1, H3N2, and H5N, responsible for outbreaks.…”