Remodeling of bronchial epithelium caused by asthmatic inflammation affects its response to rhinovirus infection

Bogdan Jakiela,Grazyna Bochenek,Stanislawa Bazan-Socha,Hanna Plutecka,Marek Sanak,Ana Rebane,Jerzy Soja,Marcin Surmiak,Krzysztof Sladek,Anet Laanesoo

doi:10.1038/s41598-021-92252-6

Bogdan Jakiela, Grazyna Bochenek + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-92252-6

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Journal: Scientific Reports	Publication Date: Jun 17, 2021
Citations: 16	License type: open-access

Affiliation: Jagiellonian University, University of Tartu

Abstract

Human rhinoviruses (HRV) are frequent cause of asthma exacerbations, however the influence of airway inflammation on the severity of viral infection is poorly understood. Here, we investigated how cytokine-induced remodeling of airway epithelium modulates antiviral response. We analyzed gene expression response in in vitro differentiated bronchial epithelium exposed to cytokines and next infected with HRV16. IL-13-induced mucous cell metaplasia (MCM) was associated with impaired ciliogenesis and induction of antiviral genes, resulting in lower susceptibility to HRV. Epithelial-mesenchymal transition caused by TGF-β was associated with increased virus replication and boosted innate response. Moreover, HRV infection per se caused transient upregulation of MCM markers and growth factors, followed by low-level virus replication and shedding. Our data suggest that the outcome of HRV infection depends on the type of lower airway inflammation and the extent of epithelial damage. Type-2 inflammation (eosinophilic asthma) may induce antiviral state of epithelium and decrease virus sensitivity, while growth factor exposure during epithelial repair may facilitate virus replication and inflammatory response. Additionally, responses to HRV were similar in cells obtained from asthma patients and control subjects, which implicates that antiviral mechanisms are not intrinsically impaired in asthma, but may develop in the presence of uncontrolled airway inflammation.

Highlights

Human rhinoviruses (HRV) are frequent cause of asthma exacerbations, the influence of airway inflammation on the severity of viral infection is poorly understood
To investigate how asthmatic inflammation affects epithelial structure and antiviral responses, we introduced an in vitro model of cytokine-induced remodeling using human bronchial epithelial cells (HBECs) isolated from airway biopsies sampled in asthma patients and control subjects (n = 40; Supplementary Table S1 and Fig. S1)
HBECs were mucociliary differentiated at the air–liquid interface (ALI) and chronically exposed to IL-13, IL-17A or transforming growth factor-β (TGF-β) (Fig. 1a)

Summary

Introduction

Human rhinoviruses (HRV) are frequent cause of asthma exacerbations, the influence of airway inflammation on the severity of viral infection is poorly understood. Type-2 inflammation (eosinophilic asthma) may induce antiviral state of epithelium and decrease virus sensitivity, while growth factor exposure during epithelial repair may facilitate virus replication and inflammatory response. Mediators secreted by inflammatory cells may modify those processes, altering the epithelial phenotype itself An example of such a change is mucous cell metaplasia (MCM), a type of epithelial remodeling commonly seen in asthma, characterized by an increase in goblet cell number usually induced by chronic exposure to T2-cytokines (e.g., IL-13)[7, 8]. IFN signaling results in a downstream expression of antiviral effector proteins called IFN-stimulated genes (ISGs) which act synergistically by inhibiting virus replication and mounting an ‘antiviral state’ in the host and surrounding cells[16] This complex system of innate defense is critical for limiting the infection of airway epithelium. Little is known how exposure of mucociliary epithelium to TGF-β modulates the viral response, the relatively high sensitivity of primary HBECs to HRV suggests that regenerating cells could be an easy target for the virus

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