An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5 responsive mouse model

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Title: An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5 responsive mouse model
Authors: Ravanetti, L
Dijkhuis, A
Sabogal Pineros, YS
Bal, SM
Dierdorp, BS
Dekker, T
Logiantara, A
Adcock, IM
Rao, NL
Boon, L
Villetti, G
Sterk, PJ
Facchinetti, F
Lutter, R
U-BIOPRED Study Group.
Item Type: Journal Article
Abstract: BACKGROUND: Acute worsening of asthma symptoms (exacerbation) is predominantly triggered by respiratory viruses, with influenza causing the most severe exacerbations. The lack of an adequate animal model hampers mechanistic insight and the development of new therapeutics. AIM: We developed and characterized a robust, consistent and reproducible mouse model of severe exacerbation of chronic allergic asthma. METHODS: Chronic allergic airway inflammation was induced following a house dust mite (HDM)-sensitization protocol. HDM-sensitized mice and controls were infected with influenza virus A/X31 H3N2 and either or not treated with inhaled Fluticasone Propionate (FP), systemic corticosteroids (Pred) or anti-IL5. Mice were sacrificed at different time points after infection: cellular accumulation and cytokines levels in the airways; PenH as a measure of airway hyperresponsiveness (AHR); lung histology and viral replication were assessed. RESULTS: Infection with low dose A/X31 H3N2 led to prolonged deterioration of lung function, aggravated mucus production, peri-vascular, peri-bronchial and allergic inflammation that was unresponsive to inhaled corticosteroids, but responsive to systemic corticosteroids. The exacerbation was preceded at 14h after virus exposure by a marked innate, but no Th2 and Th1 response, subsequently followed by enhanced numbers of eosinophils, neutrophils, dendritic and T cells into the lung lumen, parenchyma and draining lymph nodes in HDM-sensitized mice. Anti-IL-5 treatment attenuated eosinophils and prevented the X31-induced exacerbation. CONCLUSIONS: Together these findings indicate that an early innate response that involves eosinophils underlies the exacerbation. This model recapitulates all major features of severe asthma exacerbations and can serve to discern driving mechanisms and promote development of novel therapeutics. This article is protected by copyright. All rights reserved.
Issue Date: 3-Oct-2016
Date of Acceptance: 21-Sep-2016
URI: http://hdl.handle.net/10044/1/41464
DOI: https://dx.doi.org/10.1111/all.13057
ISSN: 1398-9995
Publisher: Wiley
Start Page: 737
End Page: 753
Volume: 72
Issue: 5
Copyright Statement: This article is protected by copyright. All rights reserved. This is the accepted version of the following article: Ravanetti, L., Dijkhuis, A., Sabogal Pineros, Y. S., Bal, S. M., Dierdorp, B. S., Dekker, T., Logiantara, A., Adcock, I. M., Rao, N. L., Boon, L., Villetti, G., Sterk, P. J., Facchinetti, F., Lutter, R. and The U-BIOPRED Study Group. (2016), An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5 responsive mouse model. Allergy, which has been published in final form at http://dx.doi.org/10.1111/all.13057.
Sponsor/Funder: Medical Research Council (MRC)
Commission of the European Communities
Medical Research Council (MRC)
Funder's Grant Number: G1000758
115010
G1000758
Keywords: Science & Technology
Life Sciences & Biomedicine
Allergy
Immunology
animal models
asthma
basic immunology
innate immunity
virus
RESPIRATORY SYNCYTIAL VIRUS
REFRACTORY EOSINOPHILIC ASTHMA
ALLERGIC AIRWAY INFLAMMATION
LUNG-TISSUE
INFECTION
MEPOLIZUMAB
CELLS
MICE
IMMUNITY
DISEASE
U-BIOPRED Study Group
1107 Immunology
Publication Status: Published
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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