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Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations

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Title: Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations
Authors: Singanayagam, A
Glanville, N
Girkin, J
Ching, YM
Marcellini, A
Porter, J
Toussaint, M
Walton, R
Finney, L
Julia, A
Zhu, J
Trujillo-Torralbo, M
Calderazzo, M
Grainge, C
Loo, S-L
Veerati, PC
Pathinayake, P
Nichol, K
Reid, A
James, P
Solari, R
Wark, P
Knight, D
Moffatt, M
Cookson, W
Edwards, M
Mallia, P
Bartlett, N
Johnston, SL
Item 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.
Issue Date: 8-Jun-2018
Date of Acceptance: 10-May-2018
URI: http://hdl.handle.net/10044/1/60020
DOI: https://dx.doi.org/10.1038/s41467-018-04574-1
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
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/Funder: 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
Funder's Grant Number: 096382/Z/11/Z
H C ROSCOE (2015) GRANT
PPRG15-9
NF-SI-0514-10092
n/a
P33132
Asthma UK Centre
Keywords: 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
MD Multidisciplinary
Publication Status: Published
Article Number: ARTN 2229
Appears in Collections:National Heart and Lung Institute
Airway Disease
Faculty of Medicine



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