Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations
File(s)
Publishing version
Author(s)
Type
Journal Article
Abstract
Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-β reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/β receptor (IFNAR1−/−) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-β therapy may protect.
Date Issued
2018-06-08
Date Acceptance
2018-05-10
Citation
Nature Communications, 2018, 9 (2229), pp.1-16
ISSN
2041-1723
Publisher
Nature Publishing Group
Start Page
1
End Page
16
Journal / Book Title
Nature Communications
Volume
9
Issue
2229
Copyright Statement
© The Author(s) 2018. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/.
Sponsor
Wellcome Trust
British Medical Association
British Lung Foundation
National Institute for Health Research
The Academy of Medical Sciences
Imperial College Healthcare NHS Trust- BRC Funding
Asthma UK
Wellcome Trust
Identifier
https://www.nature.com/articles/s41467-018-04574-1
Grant Number
096382/Z/11/Z
H C ROSCOE (2015) GRANT
PPRG15-9
NF-SI-0514-10092
n/a
P33132
Asthma UK Centre
096964/Z/11/Z
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
OBSTRUCTIVE PULMONARY-DISEASE
NF-KAPPA-B
EXPERIMENTAL RHINOVIRUS INFECTION
BRONCHIAL EPITHELIAL-CELLS
FLUTICASONE PROPIONATE
AIRWAY INFLAMMATION
INDUCED ASTHMA
IFN-BETA
SALMETEROL/FLUTICASONE PROPIONATE
ANTIMICROBIAL PEPTIDES
Administration, Inhalation
Adrenal Cortex Hormones
Animals
Bacterial Infections
Bacterial Load
Cell Line
Fluticasone
Humans
Immunity, Innate
Lung
Mice, Knockout
Mucus
Picornaviridae Infections
Pulmonary Disease, Chronic Obstructive
Receptor, Interferon alpha-beta
Rhinovirus
Lung
Cell Line
Mucus
Animals
Mice, Knockout
Humans
Rhinovirus
Bacterial Infections
Picornaviridae Infections
Pulmonary Disease, Chronic Obstructive
Adrenal Cortex Hormones
Administration, Inhalation
Receptor, Interferon alpha-beta
Immunity, Innate
Bacterial Load
Fluticasone
Publication Status
Published
Article Number
ARTN 2229
Date Publish Online
2018-06-08