Journal Article

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

Shroff, Tanvi, Karalis, Katia, Cheng, Deion, Shukla, Abhishek, Villenave, Remi, Alves, Stephen, Salmon, Michael, Lee, Hyun-Hee, Lucchesi, Carolina, Ngyuen, Justin, Nawroth, Janna C., Hamilton, Geraldine A., Varone, Antonio

2020

Overview

Viral-induced exacerbation of asthma remains 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 and neutrophil transepithelial migration, and enables evaluation of immunomodulatory therapy. Specifically, a microengineered model of fully differentiated human mucociliary airway epithelium was stimulated with IL-13 to induce a T-helper cell type 2 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 T-helper cell type 2 microenvironment through exogenous IL-13 stimulation induced features of asthmatic 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 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, whereas treatment with MK-7123, a CXCR2 antagonist, reduced neutrophil diapedesis in all conditions. In conclusion, our microengineered 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.

• Publisher: Oxford University Press
• Subject: Airway management / Asthma / Asthma - virology / Bioengineering / Cell Movement / Cells, Cultured / Cytopathogenic Effect, Viral / Disease Progression / Hospitalization / Humans / Lab-On-A-Chip Devices / Lung - pathology / Lung - virology / Medical treatment / Microtechnology / Models, Biological / Mortality / Neutrophil Infiltration / Receptors, Interleukin-8B - antagonists & inhibitors / Receptors, Interleukin-8B - metabolism / Respiratory tract / Rhinovirus