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

Aran Singanayagam, Nicholas Glanville, Jason L. Girkin, Yee Man Ching, Andrea Marcellini, James D. Porter, Marie Toussaint, Ross P. Walton, Lydia J. Finney, Julia Aniscenko, Jie Zhu, Maria-Belen Trujillo-Torralbo, Maria Adelaide Calderazzo, Chris Grainge, Su-Ling Loo, Punnam Chander Veerati, Prabuddha S. Pathinayake, Kristy S. Nichol, Andrew T. Reid, Phillip L. James, Roberto Solari, Peter A. B. Wark, Darryl A. Knight, Miriam F. Moffatt, William O. Cookson, Michael R. Edwards, Patrick Mallia, Nathan W. Bartlett () and Sebastian L. Johnston ()
Additional contact information
Aran Singanayagam: Imperial College London
Nicholas Glanville: Imperial College London
Jason L. Girkin: Hunter Medical Research Institute and University of Newcastle
Yee Man Ching: Imperial College London
Andrea Marcellini: Imperial College London
James D. Porter: Imperial College London
Marie Toussaint: Imperial College London
Ross P. Walton: Imperial College London
Lydia J. Finney: Imperial College London
Julia Aniscenko: Imperial College London
Jie Zhu: Imperial College London
Maria-Belen Trujillo-Torralbo: Imperial College London
Maria Adelaide Calderazzo: Imperial College London
Chris Grainge: Hunter Medical Research Institute and University of Newcastle
Su-Ling Loo: Hunter Medical Research Institute and University of Newcastle
Punnam Chander Veerati: Hunter Medical Research Institute and University of Newcastle
Prabuddha S. Pathinayake: Hunter Medical Research Institute and University of Newcastle
Kristy S. Nichol: Hunter Medical Research Institute and University of Newcastle
Andrew T. Reid: Hunter Medical Research Institute and University of Newcastle
Phillip L. James: Imperial College London
Roberto Solari: Imperial College London
Peter A. B. Wark: Hunter Medical Research Institute and University of Newcastle
Darryl A. Knight: Hunter Medical Research Institute and University of Newcastle
Miriam F. Moffatt: Imperial College London
William O. Cookson: Imperial College London
Michael R. Edwards: Imperial College London
Patrick Mallia: Imperial College London
Nathan W. Bartlett: Imperial College London
Sebastian L. Johnston: Imperial College London

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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: 2018
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DOI: 10.1038/s41467-018-04574-1

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