A Micro-Engineered Airway Lung-Chip Models Key Features of Viral-Induced Exacerbation of Asthma

Abstract

Viral-induced exacerbation of asthma remain a major cause of hospitalization and mortality. New human relevant models of the airways are urgently needed to understand how respiratory infections may trigger asthma attacks, and to advance treatment development. Here, we describe a new human relevant model of rhinovirus-induced asthma exacerbation that recapitulates viral infection of asthmatic airway epithelium, neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Specifically, a micro-engineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a Th2-type asthmatic phenotype and infected with live human rhinovirus 16 (HRV16) to reproduce key features of viral-induced asthma exacerbation.

We observed that the infection with HRV16 replicated key hallmarks of the cytopathology and inflammatory responses observed in human airways. Generation of a Th2 microenvironment through exogenous IL-13 stimulation induced features of asthmatics airways, including goblet cell hyperplasia, reduction of cilia beating frequency, and endothelial activation, but did not alter rhinovirus infectivity or replication. High resolution kinetic analysis of secreted inflammatory markers revealed that IL-13 treatment altered the IL-6, IFN-λ1, and CXCL10 secretion in response to HRV16. Neutrophil transepithelial migration was greatest when viral infection was combined with IL-13 treatment, while treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions.

In conclusion, our micro-engineered Airway Lung-Chip provides a novel human-relevant platform for exploring the complex mechanisms underlying viral-induced asthma exacerbation. Our data suggest that IL-13 may impair the hosts’ ability to mount an appropriate and coordinated immune response to rhinovirus infection. We also show that the Airway Lung-Chip can be used to assess the efficacy of modulators of the immune response.