Antiviral immunity is impaired in COPD patients with frequent exacerbations.

Aran Singanayagam,Punnam Veerati,Prabuddha S Pathinayake,Peter A B Wark,Eteri Bakhsoliani,Nathan W Bartlett,Maria-Belen Trujillo Torralbo,Christopher L Grainge,Jason Girkin,Kristy S Nichol,Su-Ling Loo,Joseph Footitt,Patrick Mallia,Maria Calderazzo,Andrew Reid,Sebastian L Johnston,Lydia J Finney

doi:10.1152/ajplung.00253.2019

Abstract

Patients with frequent exacerbations represent a chronic obstructive pulmonary disease (COPD) subgroup requiring better treatment options. The aim of this study was to determine the innate immune mechanisms that underlie susceptibility to frequent exacerbations in COPD. We measured sputum expression of immune mediators and bacterial loads in samples from patients with COPD at stable state and during virus-associated exacerbations. In vitro immune responses to rhinovirus infection in differentiated primary bronchial epithelial cells (BECs) sampled from patients with COPD were additionally evaluated. Patients were stratified as frequent exacerbators (≥2 exacerbations in the preceding year) or infrequent exacerbators (<2 exacerbations in the preceding year) with comparisons made between these groups. Frequent exacerbators had reduced sputum cell mRNA expression of the antiviral immune mediators type I and III interferons and reduced interferon-stimulated gene (ISG) expression when clinically stable and during virus-associated exacerbation. A role for epithelial cell-intrinsic innate immune dysregulation was identified: induction of interferons and ISGs during in vitro rhinovirus (RV) infection was also impaired in differentiated BECs from frequent exacerbators. Frequent exacerbators additionally had increased sputum bacterial loads at 2 wk following virus-associated exacerbation onset. These data implicate deficient airway innate immunity involving epithelial cells in the increased propensity to exacerbations observed in some patients with COPD. Therapeutic approaches to boost innate antimicrobial immunity in the lung could be a viable strategy for prevention and treatment of frequent exacerbations.

Highlights

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disorder in which acute exacerbations represent a major complication
For the first time, that patients with COPD, who have a history of frequent exacerbations, have reduced airway antimicrobial immunity when assessed at clinical stability and during subsequent virus-associated exacerbation with an associated increase in bacterial loads
Previous studies have shown that ex vivo type I IFN responses to RV infection in bronchoalveolar cells and to influenza infection in bronchial epithelial cells (BECs) are impaired in COPD [17, 22]

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disorder in which acute exacerbations represent a major complication. Viruses are a major etiological trigger for exacerbations [28, 30], and data exist to suggest that COPD may be associated with deficient antiviral immunity [17, 22]. Frequent exacerbators could represent one subgroup in whom defective antiviral immunity is more prominent. Both experimental and naturally occurring exacerbation studies confirm that an initial virus infection can precipitate secondary bacterial infection in COPD [13, 21]. Bacterial colonization at a stable state has been shown to be associated with increased exacerbation frequency [26], propensity to develop secondary bacterial infection during virus infections in frequent versus infrequent exacerbators has not previously been studied

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